id
stringlengths 8
11
| title
stringlengths 14
124
| content
stringlengths 0
34k
| contents
stringlengths 20
34k
| nordid
int64 0
1.32k
| rare-disease
stringlengths 4
103
|
|---|---|---|---|---|---|
nord_1314_2 | Causes of X-linked Retinoschisis | XLRS is caused by a change (mutation) in a gene. Genes provide information and instruction to make proteins, much like a blueprint. Proteins are the building blocks of cells and allow cells to have their unique functions.XLRS is caused by mutations in a gene on the X chromosome called RS1.XLRS is inherited as an X-linked trait. Men only have one X chromosome, whereas women have two. Women who have an abnormal RS1 gene “carry” the condition, but do not have any vision problems associated with XLRS since they almost always have a second normal RS1 gene. Men who have an abnormal RS1 gene have symptoms of XLRS. Women who are carriers have a 50% chance of passing on their abnormal RS1 gene to each of their children. When passed to a daughter, the daughter will also be a carrier for XLRS. When passed to a son, the son will have XLRS. When men with XLRS have children, all of their daughters will be carriers and none of their sons will have XLRS. | Causes of X-linked Retinoschisis. XLRS is caused by a change (mutation) in a gene. Genes provide information and instruction to make proteins, much like a blueprint. Proteins are the building blocks of cells and allow cells to have their unique functions.XLRS is caused by mutations in a gene on the X chromosome called RS1.XLRS is inherited as an X-linked trait. Men only have one X chromosome, whereas women have two. Women who have an abnormal RS1 gene “carry” the condition, but do not have any vision problems associated with XLRS since they almost always have a second normal RS1 gene. Men who have an abnormal RS1 gene have symptoms of XLRS. Women who are carriers have a 50% chance of passing on their abnormal RS1 gene to each of their children. When passed to a daughter, the daughter will also be a carrier for XLRS. When passed to a son, the son will have XLRS. When men with XLRS have children, all of their daughters will be carriers and none of their sons will have XLRS. | 1,314 | X-linked Retinoschisis |
nord_1314_3 | Affects of X-linked Retinoschisis | The prevalence of XLRS is approximatley1 in 10,000. | Affects of X-linked Retinoschisis. The prevalence of XLRS is approximatley1 in 10,000. | 1,314 | X-linked Retinoschisis |
nord_1314_4 | Related disorders of X-linked Retinoschisis | Related disorders of X-linked Retinoschisis. | 1,314 | X-linked Retinoschisis |
|
nord_1314_5 | Diagnosis of X-linked Retinoschisis | Diagnosis of XLRS is made by eye examination using various testing modalities. Individuals have reduced vision, schisis that can be seen on examination and imaging, and abnormal electroretinograms (a test that assesses the function of the retina) in most cases. Some individuals also have a family history consistent with X-linked inheritance. Molecular genetic testing for mutations in the RS1 gene is available to confirm the diagnosis. | Diagnosis of X-linked Retinoschisis. Diagnosis of XLRS is made by eye examination using various testing modalities. Individuals have reduced vision, schisis that can be seen on examination and imaging, and abnormal electroretinograms (a test that assesses the function of the retina) in most cases. Some individuals also have a family history consistent with X-linked inheritance. Molecular genetic testing for mutations in the RS1 gene is available to confirm the diagnosis. | 1,314 | X-linked Retinoschisis |
nord_1314_6 | Therapies of X-linked Retinoschisis | Treatment
Treatment is generally symptomatic and supportive. Low-vision aids such as large-print textbooks; preferential seating in the front of the classroom; and use of handouts with high contrast can be useful. Treatment of retinoschisis may require the care of a retinal surgeon to address the infrequent complications of vitreous hemorrhage (bleeding in the eye) and retinal detachment. Affected boys and men are recommended to avoid activities such as contact sports, which may pose an increased risk for retinal detachment.Genetic counseling is recommended for boys and men with XLRS and their families. | Therapies of X-linked Retinoschisis. Treatment
Treatment is generally symptomatic and supportive. Low-vision aids such as large-print textbooks; preferential seating in the front of the classroom; and use of handouts with high contrast can be useful. Treatment of retinoschisis may require the care of a retinal surgeon to address the infrequent complications of vitreous hemorrhage (bleeding in the eye) and retinal detachment. Affected boys and men are recommended to avoid activities such as contact sports, which may pose an increased risk for retinal detachment.Genetic counseling is recommended for boys and men with XLRS and their families. | 1,314 | X-linked Retinoschisis |
nord_1315_0 | Overview of Xeroderma Pigmentosum | SummaryXeroderma pigmentosum (XP) is a rare inherited multisystem disorder characterized by a heightened sensitivity to the DNA damaging effects of ultraviolet radiation (UV). The main source of UV is the sun. The major signs and symptoms of XP can be seen in sun-exposed areas of the body. The effects are greatest on the skin, and the tissues of the eyes including eyelids, the surface of the eyes and the surrounding tissues. The tip of the tongue and lips may also be damaged. In addition, approximately 25% of XP patients develop abnormalities of the nervous system manifesting as progressive neuro-degeneration with hearing loss. People with XP have a 10,000-fold increased risk for developing skin cancer including basal cell carcinoma, squamous cell carcinoma and melanoma. They also have a 2,000-fold increased risk for cancer of the eye and surrounding ocular tissues. These symptoms appear early in life, typically before age 10 years.XP is managed by preventative techniques (i.e., avoiding the sun, using sunscreen, wearing protective clothing) and regular screening for changes in the skin, vision, and neurologic status. Many symptoms can be treated with medication and/or surgery, but some cancers and neurologic problems can be life threatening.XP is an autosomal recessive genetic condition caused by alterations (mutations) in nine different genes. Eight of the genes make up the nucleotide excision repair pathway (NER) that identities and repairs UV induced DNA damage. The ninth gene acts to bypass unrepaired damage.IntroductionXP was first described in Vienna, Austria in 1870. In a dermatology textbook, Moriz Kaposi described a new disorder called xeroderma, which translates to “parchment skin.” | Overview of Xeroderma Pigmentosum. SummaryXeroderma pigmentosum (XP) is a rare inherited multisystem disorder characterized by a heightened sensitivity to the DNA damaging effects of ultraviolet radiation (UV). The main source of UV is the sun. The major signs and symptoms of XP can be seen in sun-exposed areas of the body. The effects are greatest on the skin, and the tissues of the eyes including eyelids, the surface of the eyes and the surrounding tissues. The tip of the tongue and lips may also be damaged. In addition, approximately 25% of XP patients develop abnormalities of the nervous system manifesting as progressive neuro-degeneration with hearing loss. People with XP have a 10,000-fold increased risk for developing skin cancer including basal cell carcinoma, squamous cell carcinoma and melanoma. They also have a 2,000-fold increased risk for cancer of the eye and surrounding ocular tissues. These symptoms appear early in life, typically before age 10 years.XP is managed by preventative techniques (i.e., avoiding the sun, using sunscreen, wearing protective clothing) and regular screening for changes in the skin, vision, and neurologic status. Many symptoms can be treated with medication and/or surgery, but some cancers and neurologic problems can be life threatening.XP is an autosomal recessive genetic condition caused by alterations (mutations) in nine different genes. Eight of the genes make up the nucleotide excision repair pathway (NER) that identities and repairs UV induced DNA damage. The ninth gene acts to bypass unrepaired damage.IntroductionXP was first described in Vienna, Austria in 1870. In a dermatology textbook, Moriz Kaposi described a new disorder called xeroderma, which translates to “parchment skin.” | 1,315 | Xeroderma Pigmentosum |
nord_1315_1 | Symptoms of Xeroderma Pigmentosum | Individuals with XP are particularly sensitive to the DNA damaging effects of UV. Sources of UV include the sun, unshielded florescent light bulbs, mercury vapor lights and halogen light bulbs. Symptoms may differ from person to person, but typically impact the skin, eyes, nervous system. Patients with XP may develop multiple thyroid nodules, premature menopause or leukemia.Cutaneous (Skin) Effects
Approximately half of XP patients develop blistering burns on sun exposed skin after minimal sun exposure (sometimes less than 10 minutes in the sun). These burns evolve over several days and may take greater than a week to heal. Sometimes these burns are so severe, child abuse is suspected. The other 50% of XP patients do not burn, but tan after sun exposure. However, both types of sun reactions result in the early onset of lentigos (freckling) of the skin.Lentigos, are a patchy freckling of the skin that often appear before the age of two years in XP patients. The lentigos can be visible on all sun exposed skin but are often seen first on the face. Lentigos are a sign of unrepaired UV damage in the skin. Repeated sun exposure also results in xerosis (dry, parchment-like skin) and poikiloderma a mixture of both hyper (increased) and hypo (decreased) skin pigmentation, skin atrophy (thinning of skin tissue), and telangiectasia (a widening of the small blood vessels, which produces red lines and patterns on the skin). In people who do not have XP, poikiloderma is typically seen in older adults, who work outdoors, such as farmers or sailors, with many years of sun exposure.For people with XP continuous repeated sun exposure has severe effects, resulting in the early development of precancerous skin lesions (such as, actinic keratosis) and skin cancers (see below).Ocular (Eye) Effects
The eyelids and the surface of the eyes exposed to sunlight will usually be affected within the first decade of life.Photophobia (light sensitivity, or pain upon seeing light) is common and is often noted in infancy or early childhood. The conjunctiva (the white portion of the eye) may show sunlight induced inflammation. People with XP also develop dry eye. Symptoms of dry eye include a feeling of ‘something being in the eye’, constant irritation and redness of the eye. Dry eye can result in chronic inflammation and keratitis. Keratitis, or inflammation of the cornea (the clear outer portion of the eye) may also occur in response to sunlight. In severe cases, keratitis can result in corneal opacification (lack of transparency) and vascularization (an increase in blood vessel density). These combined effects may obscure vision, leading to blindness. With repeated sun exposure, the lids of the eyes may atrophy (degenerate) and eyelashes may fall out, leaving the eyes unprotected and contributing to vision loss.Cancers of the eyelids, tissues surrounding the eyes, cornea and sclera (white part of the eye) can occur very early in life. Surgeries to remove ocular cancers can lead to lid abnormalities resulting in difficulty completely closing the eyes and vision loss. When cancers in or near the eye are large or invasive, the globe of the eye may need to be removed.Neurologic (Nerve) Effects
Approximately 25% of patients with XP develop progressive neurodegeneration. The degeneration can vary in time of onset and rate of progression. Symptoms of neurodegeneration include: acquired microcephaly (a condition marked by smaller head size and structural changes in the brain), diminishing (or absent) deep tendon reflexes, progressive high-frequency sensorineural hearing loss (deafness caused by damage to the nerves of the inner ear), progressive cognitive impairment, spasticity (tightness/rigidity of the skeletal muscles), ataxia (poor muscle control and coordination), seizures, difficulty swallowing and/or vocal cord paralysis.These issues are thought to arise due to the loss of nerve cells in the brain. On imaging such as MRI or CT scans, the brains of XP patients with neurologic degeneration show atrophy (shrinkage) with marked dilation of the ventricles (fluid filled spaces in the middle of the brain). It is thought that accumulating unrepaired DNA damage in the brain cells results in their death, however, the source of this damage has not been identified.Neoplasias (Cancer)
Individuals with XP have a much greater chance of developing certain cancers. The risk of acquiring non-melanoma skin cancers (e.g., basal cell carcinoma and squamous cell carcinoma) is 10,000 times greater than in the general population in patients under 20 years of age. Median age of first non-melanoma cancer for XP patients is 9 years old, which is 50 years earlier than in the general population. For melanoma skin cancer, the risk is 2,000 times greater for those with XP. The median age of onset is 22 years, which is 30 years earlier than in the general population.Oral cavity neoplasms, specifically squamous cell carcinoma of the tip of the tongue (a non-pigmented sun exposed area), is common especially in XP patients who live in very sunny and warm climates. Internal cancers that have been reported in individuals with XP include: glioblastoma of the brain, astrocytoma of the spinal cord, and cancer of the lung in patients who smoke, and rarely, leukemia (cancer of the white blood cells). Cancers of the thyroid, uterus, breast, pancreas, stomach, kidney, and testicles have also been reported. | Symptoms of Xeroderma Pigmentosum. Individuals with XP are particularly sensitive to the DNA damaging effects of UV. Sources of UV include the sun, unshielded florescent light bulbs, mercury vapor lights and halogen light bulbs. Symptoms may differ from person to person, but typically impact the skin, eyes, nervous system. Patients with XP may develop multiple thyroid nodules, premature menopause or leukemia.Cutaneous (Skin) Effects
Approximately half of XP patients develop blistering burns on sun exposed skin after minimal sun exposure (sometimes less than 10 minutes in the sun). These burns evolve over several days and may take greater than a week to heal. Sometimes these burns are so severe, child abuse is suspected. The other 50% of XP patients do not burn, but tan after sun exposure. However, both types of sun reactions result in the early onset of lentigos (freckling) of the skin.Lentigos, are a patchy freckling of the skin that often appear before the age of two years in XP patients. The lentigos can be visible on all sun exposed skin but are often seen first on the face. Lentigos are a sign of unrepaired UV damage in the skin. Repeated sun exposure also results in xerosis (dry, parchment-like skin) and poikiloderma a mixture of both hyper (increased) and hypo (decreased) skin pigmentation, skin atrophy (thinning of skin tissue), and telangiectasia (a widening of the small blood vessels, which produces red lines and patterns on the skin). In people who do not have XP, poikiloderma is typically seen in older adults, who work outdoors, such as farmers or sailors, with many years of sun exposure.For people with XP continuous repeated sun exposure has severe effects, resulting in the early development of precancerous skin lesions (such as, actinic keratosis) and skin cancers (see below).Ocular (Eye) Effects
The eyelids and the surface of the eyes exposed to sunlight will usually be affected within the first decade of life.Photophobia (light sensitivity, or pain upon seeing light) is common and is often noted in infancy or early childhood. The conjunctiva (the white portion of the eye) may show sunlight induced inflammation. People with XP also develop dry eye. Symptoms of dry eye include a feeling of ‘something being in the eye’, constant irritation and redness of the eye. Dry eye can result in chronic inflammation and keratitis. Keratitis, or inflammation of the cornea (the clear outer portion of the eye) may also occur in response to sunlight. In severe cases, keratitis can result in corneal opacification (lack of transparency) and vascularization (an increase in blood vessel density). These combined effects may obscure vision, leading to blindness. With repeated sun exposure, the lids of the eyes may atrophy (degenerate) and eyelashes may fall out, leaving the eyes unprotected and contributing to vision loss.Cancers of the eyelids, tissues surrounding the eyes, cornea and sclera (white part of the eye) can occur very early in life. Surgeries to remove ocular cancers can lead to lid abnormalities resulting in difficulty completely closing the eyes and vision loss. When cancers in or near the eye are large or invasive, the globe of the eye may need to be removed.Neurologic (Nerve) Effects
Approximately 25% of patients with XP develop progressive neurodegeneration. The degeneration can vary in time of onset and rate of progression. Symptoms of neurodegeneration include: acquired microcephaly (a condition marked by smaller head size and structural changes in the brain), diminishing (or absent) deep tendon reflexes, progressive high-frequency sensorineural hearing loss (deafness caused by damage to the nerves of the inner ear), progressive cognitive impairment, spasticity (tightness/rigidity of the skeletal muscles), ataxia (poor muscle control and coordination), seizures, difficulty swallowing and/or vocal cord paralysis.These issues are thought to arise due to the loss of nerve cells in the brain. On imaging such as MRI or CT scans, the brains of XP patients with neurologic degeneration show atrophy (shrinkage) with marked dilation of the ventricles (fluid filled spaces in the middle of the brain). It is thought that accumulating unrepaired DNA damage in the brain cells results in their death, however, the source of this damage has not been identified.Neoplasias (Cancer)
Individuals with XP have a much greater chance of developing certain cancers. The risk of acquiring non-melanoma skin cancers (e.g., basal cell carcinoma and squamous cell carcinoma) is 10,000 times greater than in the general population in patients under 20 years of age. Median age of first non-melanoma cancer for XP patients is 9 years old, which is 50 years earlier than in the general population. For melanoma skin cancer, the risk is 2,000 times greater for those with XP. The median age of onset is 22 years, which is 30 years earlier than in the general population.Oral cavity neoplasms, specifically squamous cell carcinoma of the tip of the tongue (a non-pigmented sun exposed area), is common especially in XP patients who live in very sunny and warm climates. Internal cancers that have been reported in individuals with XP include: glioblastoma of the brain, astrocytoma of the spinal cord, and cancer of the lung in patients who smoke, and rarely, leukemia (cancer of the white blood cells). Cancers of the thyroid, uterus, breast, pancreas, stomach, kidney, and testicles have also been reported. | 1,315 | Xeroderma Pigmentosum |
nord_1315_2 | Causes of Xeroderma Pigmentosum | Inheritance
XP is an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits two non-working copies of a gene for the same trait. One gene comes from the mother and the other from the father. If an individual inherits one working gene and one non-working gene for the condition, the person will be a carrier for the condition but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and have an affected child is 25% with each pregnancy. The risk for them to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk for inheriting the disease is the same for males and females.Parents who are blood relatives (consanguineous) have a higher chance than unrelated parents to both carry the same non-working gene, increasing their risk to have children with a recessive genetic disorder.Relevant Genes
There are 9 different genes that may be non-working in patients with XP and include: DDB2 (XP-E), ERCC1, ERCC2 (XP-D), ERCC3 (XP-G), ERCC4 (XP-F), ERCC5 (XP-B), POLH (XP-V or variant), XPA and XPC. The proteins resulting from normal expression of these genes are involved in DNA repair and serve to recognize damaged DNA, remove the damage and fill in the resulting gap. When a person inherits a pair of non-working XP genes, they are unable to properly repair damage from UV and will exhibit signs of the condition. | Causes of Xeroderma Pigmentosum. Inheritance
XP is an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits two non-working copies of a gene for the same trait. One gene comes from the mother and the other from the father. If an individual inherits one working gene and one non-working gene for the condition, the person will be a carrier for the condition but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and have an affected child is 25% with each pregnancy. The risk for them to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk for inheriting the disease is the same for males and females.Parents who are blood relatives (consanguineous) have a higher chance than unrelated parents to both carry the same non-working gene, increasing their risk to have children with a recessive genetic disorder.Relevant Genes
There are 9 different genes that may be non-working in patients with XP and include: DDB2 (XP-E), ERCC1, ERCC2 (XP-D), ERCC3 (XP-G), ERCC4 (XP-F), ERCC5 (XP-B), POLH (XP-V or variant), XPA and XPC. The proteins resulting from normal expression of these genes are involved in DNA repair and serve to recognize damaged DNA, remove the damage and fill in the resulting gap. When a person inherits a pair of non-working XP genes, they are unable to properly repair damage from UV and will exhibit signs of the condition. | 1,315 | Xeroderma Pigmentosum |
nord_1315_3 | Affects of Xeroderma Pigmentosum | XP affects males and females in equal numbers. Some gene mutations associated with XP are more common in certain parts of the world; in these locations there is a higher prevalence of XP. In the United States and Europe, prevalence of XP is about 1 in 1,000,000. In Japan, XP is much more common, affecting 1 in 22,000. Areas of North Africa (e.g., Tunisia, Algeria, Morocco, Libya, Egypt) and the Middle East (e.g., Turkey, Israel, Syria) also show a greatly increased prevalence of XP. | Affects of Xeroderma Pigmentosum. XP affects males and females in equal numbers. Some gene mutations associated with XP are more common in certain parts of the world; in these locations there is a higher prevalence of XP. In the United States and Europe, prevalence of XP is about 1 in 1,000,000. In Japan, XP is much more common, affecting 1 in 22,000. Areas of North Africa (e.g., Tunisia, Algeria, Morocco, Libya, Egypt) and the Middle East (e.g., Turkey, Israel, Syria) also show a greatly increased prevalence of XP. | 1,315 | Xeroderma Pigmentosum |
nord_1315_4 | Related disorders of Xeroderma Pigmentosum | There are several genetically related disorders caused by mutations in genes in the nucleotide excision (NER) pathway. People with these disorders demonstrate very different symptoms despite having mutations in some of the same genes as XP patients. These conditions include Cockayne syndrome (CS), cerebro-oculo-facio-skeletal (COFS) syndrome, trichothiodystrophy (TTD), and UV-sensitive syndrome.Cockayne syndrome is a rare form of dwarfism characterized by short stature, UV sensitivity, and prematurely aged appearance (progeria). Although prenatal growth is normal, developmental abnormalities usually appear within two years of life; height, weight, and head circumferences tend to fall below the 5th percentile, and death usually occurs within the first two decades. People with CS do not have an increased risk for cancer. For more information on this disorder, choose “Cockayne syndrome” as your search term in the Rare Disease Database.Cerebro-oculo-facio-skeletal syndrome (COFS) is a genetic neuro-degenerative disorder of the brain and spinal cord that begins before birth. The disorder is characterized by growth failure at birth, little or no neurological development, structural abnormalities of the eye, and fixed bending of the spine and joints. Abnormalities of the skull, face, limbs, and other parts of the body may also occur. COFS syndrome is inherited an autosomal recessive pattern and is now considered to be part of the spectrum of disorders within Cockayne syndrome. For more information on this disorder, choose “cerebro oculo facio skeletal syndrome” as your search term in the Rare Disease Database.Trichothiodystrophy (TTD) is a rare inherited, genetic disease characterized a broad spectrum of abnormalities. Patients with different manifestations are linked together by the common feature of short, dry, brittle, sulfur-deficient hair which has a characteristic tiger tail pattern under polarizing microscopy. The signs and symptoms vary widely between patients. Typically, patients are born pre-term and with low birth weight. Maternal pregnancy complications are common. For more information on this disorder, choose “trichothiodystrophy” as your search term in the Rare Disease Database.UV-sensitive syndrome is a form of photosensitivity that does not involve pigmentary abnormalities or nervous system deficits. People with UV sensitive syndrome develop sun burns after very minimal sun exposure but do not have increased cancer risk.In addition, there are patients who demonstrate combinations of XP with other NER disorders, most notably, xeroderma pigmentosum with Cockayne syndrome (XP/CS) and xeroderma pigmentosum with trichothiodystrophy (XP/TTD). There have been a few patients reported with cerebro-oculo-facio-skeletal syndrome and trichothiodystrophy (COFS/TTD) and Cockayne syndrome and trichothiodystrophy (CS/TTD). Individuals with these ‘overlap’ syndromes show a mixture of the symptoms normally present in both of the disorders. For example, those with XP/CS show facial freckling (typical of XP), as well as short stature, sunken eyes and wasting (typical of CS). XP/CS differs from XP alone in that there is dysmyelination (defective structure/function of the myelin sheath) along with the neuronal degeneration typically seen in people with XP and neurologic disease. | Related disorders of Xeroderma Pigmentosum. There are several genetically related disorders caused by mutations in genes in the nucleotide excision (NER) pathway. People with these disorders demonstrate very different symptoms despite having mutations in some of the same genes as XP patients. These conditions include Cockayne syndrome (CS), cerebro-oculo-facio-skeletal (COFS) syndrome, trichothiodystrophy (TTD), and UV-sensitive syndrome.Cockayne syndrome is a rare form of dwarfism characterized by short stature, UV sensitivity, and prematurely aged appearance (progeria). Although prenatal growth is normal, developmental abnormalities usually appear within two years of life; height, weight, and head circumferences tend to fall below the 5th percentile, and death usually occurs within the first two decades. People with CS do not have an increased risk for cancer. For more information on this disorder, choose “Cockayne syndrome” as your search term in the Rare Disease Database.Cerebro-oculo-facio-skeletal syndrome (COFS) is a genetic neuro-degenerative disorder of the brain and spinal cord that begins before birth. The disorder is characterized by growth failure at birth, little or no neurological development, structural abnormalities of the eye, and fixed bending of the spine and joints. Abnormalities of the skull, face, limbs, and other parts of the body may also occur. COFS syndrome is inherited an autosomal recessive pattern and is now considered to be part of the spectrum of disorders within Cockayne syndrome. For more information on this disorder, choose “cerebro oculo facio skeletal syndrome” as your search term in the Rare Disease Database.Trichothiodystrophy (TTD) is a rare inherited, genetic disease characterized a broad spectrum of abnormalities. Patients with different manifestations are linked together by the common feature of short, dry, brittle, sulfur-deficient hair which has a characteristic tiger tail pattern under polarizing microscopy. The signs and symptoms vary widely between patients. Typically, patients are born pre-term and with low birth weight. Maternal pregnancy complications are common. For more information on this disorder, choose “trichothiodystrophy” as your search term in the Rare Disease Database.UV-sensitive syndrome is a form of photosensitivity that does not involve pigmentary abnormalities or nervous system deficits. People with UV sensitive syndrome develop sun burns after very minimal sun exposure but do not have increased cancer risk.In addition, there are patients who demonstrate combinations of XP with other NER disorders, most notably, xeroderma pigmentosum with Cockayne syndrome (XP/CS) and xeroderma pigmentosum with trichothiodystrophy (XP/TTD). There have been a few patients reported with cerebro-oculo-facio-skeletal syndrome and trichothiodystrophy (COFS/TTD) and Cockayne syndrome and trichothiodystrophy (CS/TTD). Individuals with these ‘overlap’ syndromes show a mixture of the symptoms normally present in both of the disorders. For example, those with XP/CS show facial freckling (typical of XP), as well as short stature, sunken eyes and wasting (typical of CS). XP/CS differs from XP alone in that there is dysmyelination (defective structure/function of the myelin sheath) along with the neuronal degeneration typically seen in people with XP and neurologic disease. | 1,315 | Xeroderma Pigmentosum |
nord_1315_5 | Diagnosis of Xeroderma Pigmentosum | XP is typically first diagnosed on the basis of clinical symptoms (see “Signs & Symptoms”) and many patients with XP do not have a past family history of the condition (see “Causes”).Molecular genetic testing for mutations in the XP genes is available to confirm the diagnosis. | Diagnosis of Xeroderma Pigmentosum. XP is typically first diagnosed on the basis of clinical symptoms (see “Signs & Symptoms”) and many patients with XP do not have a past family history of the condition (see “Causes”).Molecular genetic testing for mutations in the XP genes is available to confirm the diagnosis. | 1,315 | Xeroderma Pigmentosum |
nord_1315_6 | Therapies of Xeroderma Pigmentosum | Prevention
Rigorous sun (UV) protection is necessary beginning as soon as the diagnosis is suspected to prevent continued DNA damage and disease progression. Individuals with XP should avoid exposing the skin and eyes to ultraviolet (UV) radiation. This can be done by wearing protective clothing such as hats, hoods with UV blocking face shields, long sleeves, pants, and gloves. High sun-protective factor (SPF) sunscreens, UV-blocking glasses with side-shields, and long hair can also provide protection.The XP patient’s surroundings (e.g., home, school, and work) should be tested for levels of UV using a UV light meter. The meter can help identify areas of increased UV and sources of damaging UV (e.g., from halogen, and unshielded florescent light bulbs and mercury vapor lamps). These sources of UV should be eliminated from the environment. Since UV can pass through glass, widows in homes, schools, workplaces, and cars of XP patient should be treated with UV blocking film.Vitamin D is an essential vitamin, which helps maintain healthy bones. Vitamin D is manufactured by the interaction of UV with the skin. Since people with XP avoid UV, oral dietary supplements may be taken as needed to avoid complications of inadequate vitamin D levels.Certain carcinogens in cigarette smoke damage DNA in ways similar to UV and exposure to secondhand cigarette smoke should be avoided. XP patients who have smoked cigarettes have developed lung cancers.Dermatologic Care
The skin (including the scalp, lips, tongue, and eyelids) should be examined by a dermatologist every 6-12 months (or more often if necessary) to detect precancerous and cancerous lesions. Prompt removal of any skin cancers is necessary to prevent further growth or spread of the lesions. Affected individuals and guardians of children should be instructed in skin examination techniques to aid in the early detection of possible skin cancers.Individuals should also undergo routine eye exams by an ophthalmologist. The eyelids should be examined for ectropion (drooping and sagging), entropion (inward rotation, which may cause eye irritation), and pterygia/pinguecula (benign growths on the surface of the eyes). The cornea, which covers the eye, should be assessed for clouding, and the eyes should be tested for dryness; in the Schirmer test, a filter paper is placed under the eyelids to measure absorption of tears. A dilated eye exam is important to assess for any changes in the retina (back of the eye).Basic neurologic examinations including measuring the occipital frontal circumference (to determine the presence of microcephaly) and assessing for the presence of deep tendon reflexes, should be part of the routine care of an XP patient. Hearing exams should be done on a regular basis to assess for early onset hearing loss, which is an indicator of XP with neurologic disease. If hearing loss is detected, hearing aids can be very beneficial in correcting the deficits. If neurologic problems are identified, more in-depth exams by a neurologist are indicated. In addition, MRIs can assess for changes that are commonly seen in the brains of XP patients who have neurodegeneration. XP patients who develop neurologic disease can have a peripheral neuropathy, which may be assessed by testing nerve conduction velocity (speed of electrical transmission) through the nerves of the arms and legs.Treatment of Skin Cancers
Small, premalignant skin lesions, (e.g., actinic keratosis) can be treated by freezing with liquid nitrogen. For larger areas of damaged skin, topical creams such as 5-fluorouracil or imiquimod may be applied. Surgical procedures such as dermatome shaving and dermabrasion have been used for larger areas of skin. Small skin cancers on the trunk and extremities can be treated with electrodessication and curettage, or surgical excision. Deeply invasive skin cancers or skin cancers on the face and areas that require tissue-sparing techniques can be treated with Mohs micrographic surgery. In severe cases, large portions of skin may be re-grafted (or replaced) with sun-protected skin. X-ray therapy can be used to treat inoperable or larger neoplasms or as adjuvant therapy to surgery. Multiple basal cell carcinomas can be treated with oral vismodegib, a sonic hedgehog pathway inhibitor. Recently, new chemotherapy agents called checkpoint inhibitors have been used to treat large skin tumors and metastatic cancers. They have been successful in treating the tumors; however serious side effects can be seen. The oral retinoids isotretinoin or acitretin can be used to prevent new skin neoplasms, but have many side effects including liver toxicity, elevated levels of cholesterol, calcification of the ligaments and tendons, and premature closure of the growing bone shafts. These retinoid drugs are known to cause birth defects and are contraindicated in pregnant women or women who are trying to become pregnant.Treatment of XP Eye Abnormalities
Lubricating eye drops used frequently keep the cornea moist and protects against the inflammatory effects of dry eye. Soft contact lenses can be worn to protect against mechanical trauma caused by deformed eyelids. It is best to start with simpler treatments first.Neoplasms of eyelids, conjunctiva, and cornea can be treated with surgery. In some cases, corneal transplantation has been attempted to correct UV induced ocular damage and corneal clouding. However, the transplants may not be successful due to immune rejection. Unfortunately, immunosuppressive drugs used to prevent immune rejection may lead to additional skin cancers. Topical chemotherapy agents can be used to treat tumors on the conjunctiva and sclera of the eye.Treatment of XP Neurologic Abnormalities
Neurologic abnormalities are associated with increased high frequency sensory-neural hearing loss. The hearing loss is progressive (gets worse over time) and can be treated with hearing aids. Recently, cochlear implants have been used for some XP patients. Cognitive delays can be seen in childhood and special education classes, physical and occupational therapies along with UV safe accommodations at school are very helpful for XP children. As they get older, people with XP neurologic disease also experience increasing ataxia, dysphagia (difficulty swallowing) and dysarthria (difficulty speaking) as the condition progresses. They may require wheelchairs, feeding tubes and long-term nursing care. | Therapies of Xeroderma Pigmentosum. Prevention
Rigorous sun (UV) protection is necessary beginning as soon as the diagnosis is suspected to prevent continued DNA damage and disease progression. Individuals with XP should avoid exposing the skin and eyes to ultraviolet (UV) radiation. This can be done by wearing protective clothing such as hats, hoods with UV blocking face shields, long sleeves, pants, and gloves. High sun-protective factor (SPF) sunscreens, UV-blocking glasses with side-shields, and long hair can also provide protection.The XP patient’s surroundings (e.g., home, school, and work) should be tested for levels of UV using a UV light meter. The meter can help identify areas of increased UV and sources of damaging UV (e.g., from halogen, and unshielded florescent light bulbs and mercury vapor lamps). These sources of UV should be eliminated from the environment. Since UV can pass through glass, widows in homes, schools, workplaces, and cars of XP patient should be treated with UV blocking film.Vitamin D is an essential vitamin, which helps maintain healthy bones. Vitamin D is manufactured by the interaction of UV with the skin. Since people with XP avoid UV, oral dietary supplements may be taken as needed to avoid complications of inadequate vitamin D levels.Certain carcinogens in cigarette smoke damage DNA in ways similar to UV and exposure to secondhand cigarette smoke should be avoided. XP patients who have smoked cigarettes have developed lung cancers.Dermatologic Care
The skin (including the scalp, lips, tongue, and eyelids) should be examined by a dermatologist every 6-12 months (or more often if necessary) to detect precancerous and cancerous lesions. Prompt removal of any skin cancers is necessary to prevent further growth or spread of the lesions. Affected individuals and guardians of children should be instructed in skin examination techniques to aid in the early detection of possible skin cancers.Individuals should also undergo routine eye exams by an ophthalmologist. The eyelids should be examined for ectropion (drooping and sagging), entropion (inward rotation, which may cause eye irritation), and pterygia/pinguecula (benign growths on the surface of the eyes). The cornea, which covers the eye, should be assessed for clouding, and the eyes should be tested for dryness; in the Schirmer test, a filter paper is placed under the eyelids to measure absorption of tears. A dilated eye exam is important to assess for any changes in the retina (back of the eye).Basic neurologic examinations including measuring the occipital frontal circumference (to determine the presence of microcephaly) and assessing for the presence of deep tendon reflexes, should be part of the routine care of an XP patient. Hearing exams should be done on a regular basis to assess for early onset hearing loss, which is an indicator of XP with neurologic disease. If hearing loss is detected, hearing aids can be very beneficial in correcting the deficits. If neurologic problems are identified, more in-depth exams by a neurologist are indicated. In addition, MRIs can assess for changes that are commonly seen in the brains of XP patients who have neurodegeneration. XP patients who develop neurologic disease can have a peripheral neuropathy, which may be assessed by testing nerve conduction velocity (speed of electrical transmission) through the nerves of the arms and legs.Treatment of Skin Cancers
Small, premalignant skin lesions, (e.g., actinic keratosis) can be treated by freezing with liquid nitrogen. For larger areas of damaged skin, topical creams such as 5-fluorouracil or imiquimod may be applied. Surgical procedures such as dermatome shaving and dermabrasion have been used for larger areas of skin. Small skin cancers on the trunk and extremities can be treated with electrodessication and curettage, or surgical excision. Deeply invasive skin cancers or skin cancers on the face and areas that require tissue-sparing techniques can be treated with Mohs micrographic surgery. In severe cases, large portions of skin may be re-grafted (or replaced) with sun-protected skin. X-ray therapy can be used to treat inoperable or larger neoplasms or as adjuvant therapy to surgery. Multiple basal cell carcinomas can be treated with oral vismodegib, a sonic hedgehog pathway inhibitor. Recently, new chemotherapy agents called checkpoint inhibitors have been used to treat large skin tumors and metastatic cancers. They have been successful in treating the tumors; however serious side effects can be seen. The oral retinoids isotretinoin or acitretin can be used to prevent new skin neoplasms, but have many side effects including liver toxicity, elevated levels of cholesterol, calcification of the ligaments and tendons, and premature closure of the growing bone shafts. These retinoid drugs are known to cause birth defects and are contraindicated in pregnant women or women who are trying to become pregnant.Treatment of XP Eye Abnormalities
Lubricating eye drops used frequently keep the cornea moist and protects against the inflammatory effects of dry eye. Soft contact lenses can be worn to protect against mechanical trauma caused by deformed eyelids. It is best to start with simpler treatments first.Neoplasms of eyelids, conjunctiva, and cornea can be treated with surgery. In some cases, corneal transplantation has been attempted to correct UV induced ocular damage and corneal clouding. However, the transplants may not be successful due to immune rejection. Unfortunately, immunosuppressive drugs used to prevent immune rejection may lead to additional skin cancers. Topical chemotherapy agents can be used to treat tumors on the conjunctiva and sclera of the eye.Treatment of XP Neurologic Abnormalities
Neurologic abnormalities are associated with increased high frequency sensory-neural hearing loss. The hearing loss is progressive (gets worse over time) and can be treated with hearing aids. Recently, cochlear implants have been used for some XP patients. Cognitive delays can be seen in childhood and special education classes, physical and occupational therapies along with UV safe accommodations at school are very helpful for XP children. As they get older, people with XP neurologic disease also experience increasing ataxia, dysphagia (difficulty swallowing) and dysarthria (difficulty speaking) as the condition progresses. They may require wheelchairs, feeding tubes and long-term nursing care. | 1,315 | Xeroderma Pigmentosum |
nord_1316_0 | Overview of XYY Syndrome | XYY syndrome is a rare chromosomal disorder that affects males. It is caused by the presence of an extra Y chromosome. Males normally have one X and one Y chromosome. However, individuals with this syndrome have one X and two Y chromosomes. Affected individuals are usually very tall. Many experience severe acne during adolescence. Additional symptoms may include learning disabilities and behavioral problems such as impulsivity. Intelligence is usually in the normal range, although IQ is on average 10-15 points lower than siblings.In the past, there were many misconceptions about this disease. It was sometimes called the super-male disease because men with this syndrome were thought to be overly-aggressive and lacking in empathy. Recent studies have shown that this is not the case. Although individuals with XYY syndrome have an increased risk for learning disabilities and behavioral problems, they are not overly aggressive, nor are they at an increased risk of any serious mental illness. Because these boys are at a higher risk for having learning disabilities, they may benefit from speech therapy, tutoring, and general awareness of the specific issues they struggle with. Although the first years of school may be more challenging for boys with XYY syndrome, they generally go on to lead full, healthy, and normal lives. | Overview of XYY Syndrome. XYY syndrome is a rare chromosomal disorder that affects males. It is caused by the presence of an extra Y chromosome. Males normally have one X and one Y chromosome. However, individuals with this syndrome have one X and two Y chromosomes. Affected individuals are usually very tall. Many experience severe acne during adolescence. Additional symptoms may include learning disabilities and behavioral problems such as impulsivity. Intelligence is usually in the normal range, although IQ is on average 10-15 points lower than siblings.In the past, there were many misconceptions about this disease. It was sometimes called the super-male disease because men with this syndrome were thought to be overly-aggressive and lacking in empathy. Recent studies have shown that this is not the case. Although individuals with XYY syndrome have an increased risk for learning disabilities and behavioral problems, they are not overly aggressive, nor are they at an increased risk of any serious mental illness. Because these boys are at a higher risk for having learning disabilities, they may benefit from speech therapy, tutoring, and general awareness of the specific issues they struggle with. Although the first years of school may be more challenging for boys with XYY syndrome, they generally go on to lead full, healthy, and normal lives. | 1,316 | XYY Syndrome |
nord_1316_1 | Symptoms of XYY Syndrome | Characteristics of XYY syndrome are often subtle and do not necessarily suggest a serious chromosomal disorder. Thus, males with this condition are often undiagnosed or misdiagnosed. The most common physical difference is increased height, which usually becomes apparent after the age of five or six, and results in an average height of about 6 feet, 3 inches by adulthood. Some individuals with XYY also develop severe cystic acne during adolescence. Fertility and sexual development are normal. Besides the potential for increased height, most affected individuals typically have a normal physical appearance (phenotype).Boys with XYY syndrome typically have normal intelligence, although, on average, IQ is 10 to 15 points lower than siblings. Affected boys may exhibit mild delays in reaching developmental milestones. Learning disabilities have been reported in up to 50 percent of cases, most commonly speech delays and language problems. Reading difficulties are common due to an increased incidence of dyslexia.In some cases, affected individuals develop behavioral problems such as an explosive temper, hyperactivity, impulsivity, defiant actions, or, in some cases, antisocial behavior. There is a higher rate of attention deficit and hyperactivity disorder and a smaller increased risk for having an autism spectrum disorder. | Symptoms of XYY Syndrome. Characteristics of XYY syndrome are often subtle and do not necessarily suggest a serious chromosomal disorder. Thus, males with this condition are often undiagnosed or misdiagnosed. The most common physical difference is increased height, which usually becomes apparent after the age of five or six, and results in an average height of about 6 feet, 3 inches by adulthood. Some individuals with XYY also develop severe cystic acne during adolescence. Fertility and sexual development are normal. Besides the potential for increased height, most affected individuals typically have a normal physical appearance (phenotype).Boys with XYY syndrome typically have normal intelligence, although, on average, IQ is 10 to 15 points lower than siblings. Affected boys may exhibit mild delays in reaching developmental milestones. Learning disabilities have been reported in up to 50 percent of cases, most commonly speech delays and language problems. Reading difficulties are common due to an increased incidence of dyslexia.In some cases, affected individuals develop behavioral problems such as an explosive temper, hyperactivity, impulsivity, defiant actions, or, in some cases, antisocial behavior. There is a higher rate of attention deficit and hyperactivity disorder and a smaller increased risk for having an autism spectrum disorder. | 1,316 | XYY Syndrome |
nord_1316_2 | Causes of XYY Syndrome | XYY syndrome is a rare chromosomal disorder caused by the presence of an extra Y chromosome. Normally, males have 46 chromosomes including one X and one Y chromosome. Males with XYY syndrome have 47 chromosomes, two of which are Y chromosomes. Most cases of XYY syndrome are due to a cell division error in the sperm prior to conception. Rarely, the cell division error occurs after conception resulting in a mosiac of cells with 46 chromosomes and 47 chromosomes. The exact cause for why these errors in cell division occur is not understood. | Causes of XYY Syndrome. XYY syndrome is a rare chromosomal disorder caused by the presence of an extra Y chromosome. Normally, males have 46 chromosomes including one X and one Y chromosome. Males with XYY syndrome have 47 chromosomes, two of which are Y chromosomes. Most cases of XYY syndrome are due to a cell division error in the sperm prior to conception. Rarely, the cell division error occurs after conception resulting in a mosiac of cells with 46 chromosomes and 47 chromosomes. The exact cause for why these errors in cell division occur is not understood. | 1,316 | XYY Syndrome |
nord_1316_3 | Affects of XYY Syndrome | XYY syndrome is a rare chromosomal disorder present at birth that affects only males. It is estimated to occur in approximately one in 1,000 live births. | Affects of XYY Syndrome. XYY syndrome is a rare chromosomal disorder present at birth that affects only males. It is estimated to occur in approximately one in 1,000 live births. | 1,316 | XYY Syndrome |
nord_1316_4 | Related disorders of XYY Syndrome | Symptoms of the following disorders can be similar to those of XYY syndrome. Comparisons may be useful for a differential diagnosis:Klinefelter syndrome is associated with a group of chromosomal disorders in males in which one or more extra X chromosomes are present. Males with the classic form of the disorder have one extra X chromosome. Males with variant forms of Klinefelter syndrome have additional X and/or Y chromosomes. The extra X and/or Y chromosome can affect physical, developmental, behavioral, and cognitive functioning. Common physical features may include tall stature, lack of secondary pubertal development, small testes (hypogonadism), delayed pubertal development, and breast development (gynecomastia) in late puberty. These features may be associated with low testosterone level and elevated gonadotropin levels. (For more information on this disorder, choose “Klinefelter” as your search term in the Rare Disease Database.)Sotos syndrome is a variable genetic disorder characterized by excessive growth before and after birth. One of the major features of Sotos syndrome is a particular facial appearance that includes facial flushing, an abnormally prominent forehead (frontal bossing), down-slanting eyelid folds (palpebral fissures), prominent, narrow jaw, a long narrow face and a head shape that is similar to an inverted pear. Height and head circumference are measured to be greater than average for most affected children. Developmental delays are present in most children with Sotos syndrome and can include motor and language delays as well as mental retardation ranging from mild to severe. Other problems associated with Sotos syndrome include jaundice in newborns, curved spine (scoliosis), seizures, crossed eyes (strabismus), conductive hearing loss, congenital heart defects, kidney abnormalities and behavioral problems. Affected individuals also have a slightly increased risk to develop specific types of tumors. Sotos syndrome is caused by an abnormality (mutation) in the NSD1 gene. (For more information on this disorder, choose “Sotos” as your search term in the Rare Disease Database.)Marfan syndrome is a genetic disorder that affects connective tissue, which is the material between cells of the body that gives the tissues form and strength. Connective tissue is found all over the body and multiple organ systems may be affected in individuals with Marfan syndrome. The heart and blood vessels (cardiovascular), skeletal, and eye (ocular) systems are most often affected. Major symptoms include overgrowth of the long bones of the arms and legs, abnormal side-to-side curvature of the spine (scoliosis), indentation or protrusion of the chest wall (pectus), dislocation of the lenses of the eyes (ectopia lentis), nearsightedness (myopia), widening (aneurysm) and tear (dissection) of the main artery that carries blood away from the heart (aorta), floppiness of the mitral valve (mitral valve prolapse) and backward flow of blood through the aortic and mitral valves (aortic and mitral regurgitation). The specific symptoms and the severity of Marfan syndrome vary greatly from case to case. Marfan syndrome is inherited as an autosomal dominant trait. Defects or disruptions (mutations) of the fibrillin-1 (FBN1) gene have been linked to Marfan syndrome and related disorders.. (For more information on this disorder, choose “Marfan” as your search term in the Rare Disease Database.) | Related disorders of XYY Syndrome. Symptoms of the following disorders can be similar to those of XYY syndrome. Comparisons may be useful for a differential diagnosis:Klinefelter syndrome is associated with a group of chromosomal disorders in males in which one or more extra X chromosomes are present. Males with the classic form of the disorder have one extra X chromosome. Males with variant forms of Klinefelter syndrome have additional X and/or Y chromosomes. The extra X and/or Y chromosome can affect physical, developmental, behavioral, and cognitive functioning. Common physical features may include tall stature, lack of secondary pubertal development, small testes (hypogonadism), delayed pubertal development, and breast development (gynecomastia) in late puberty. These features may be associated with low testosterone level and elevated gonadotropin levels. (For more information on this disorder, choose “Klinefelter” as your search term in the Rare Disease Database.)Sotos syndrome is a variable genetic disorder characterized by excessive growth before and after birth. One of the major features of Sotos syndrome is a particular facial appearance that includes facial flushing, an abnormally prominent forehead (frontal bossing), down-slanting eyelid folds (palpebral fissures), prominent, narrow jaw, a long narrow face and a head shape that is similar to an inverted pear. Height and head circumference are measured to be greater than average for most affected children. Developmental delays are present in most children with Sotos syndrome and can include motor and language delays as well as mental retardation ranging from mild to severe. Other problems associated with Sotos syndrome include jaundice in newborns, curved spine (scoliosis), seizures, crossed eyes (strabismus), conductive hearing loss, congenital heart defects, kidney abnormalities and behavioral problems. Affected individuals also have a slightly increased risk to develop specific types of tumors. Sotos syndrome is caused by an abnormality (mutation) in the NSD1 gene. (For more information on this disorder, choose “Sotos” as your search term in the Rare Disease Database.)Marfan syndrome is a genetic disorder that affects connective tissue, which is the material between cells of the body that gives the tissues form and strength. Connective tissue is found all over the body and multiple organ systems may be affected in individuals with Marfan syndrome. The heart and blood vessels (cardiovascular), skeletal, and eye (ocular) systems are most often affected. Major symptoms include overgrowth of the long bones of the arms and legs, abnormal side-to-side curvature of the spine (scoliosis), indentation or protrusion of the chest wall (pectus), dislocation of the lenses of the eyes (ectopia lentis), nearsightedness (myopia), widening (aneurysm) and tear (dissection) of the main artery that carries blood away from the heart (aorta), floppiness of the mitral valve (mitral valve prolapse) and backward flow of blood through the aortic and mitral valves (aortic and mitral regurgitation). The specific symptoms and the severity of Marfan syndrome vary greatly from case to case. Marfan syndrome is inherited as an autosomal dominant trait. Defects or disruptions (mutations) of the fibrillin-1 (FBN1) gene have been linked to Marfan syndrome and related disorders.. (For more information on this disorder, choose “Marfan” as your search term in the Rare Disease Database.) | 1,316 | XYY Syndrome |
nord_1316_5 | Diagnosis of XYY Syndrome | A diagnosis of XYY syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and specialized tests (i.e., chromosomal analysis) that detect the presence of an extra Y chromosome (47,XYY karyotype).A diagnosis of XYY syndrome may be made before birth (prenatally) through amniocentesis or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. Chromosomal studies performed on such fluid or tissue samples may reveal the presence of an extra Y chromosome.Clinical Testing and Work-UpSpeech and language assessment should occur during the first 24 months. Reading assessment should occur by school age to rule out dyslexia. Behavioral assessment should be considered for children who are having difficulty with symptoms such as impulsivity, poor attention, or social skills. | Diagnosis of XYY Syndrome. A diagnosis of XYY syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and specialized tests (i.e., chromosomal analysis) that detect the presence of an extra Y chromosome (47,XYY karyotype).A diagnosis of XYY syndrome may be made before birth (prenatally) through amniocentesis or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. Chromosomal studies performed on such fluid or tissue samples may reveal the presence of an extra Y chromosome.Clinical Testing and Work-UpSpeech and language assessment should occur during the first 24 months. Reading assessment should occur by school age to rule out dyslexia. Behavioral assessment should be considered for children who are having difficulty with symptoms such as impulsivity, poor attention, or social skills. | 1,316 | XYY Syndrome |
nord_1316_6 | Therapies of XYY Syndrome | TreatmentTreatment of XYY syndrome is symptomatic and supportive. Speech therapy, occupational therapy, or assistance for learning disabilities in the school setting may be of benefit. In most cases, affected individuals are very responsive to early intervention and treatment, and problems may resolve altogether within a few years. Treatment of acne may help an affected individual's self-image. Attention deficit and hyperactivity disorder, difficulties with social interactions, or other behavioral problems can be treated with therapy or medication the same as in individuals who do not have XYY. | Therapies of XYY Syndrome. TreatmentTreatment of XYY syndrome is symptomatic and supportive. Speech therapy, occupational therapy, or assistance for learning disabilities in the school setting may be of benefit. In most cases, affected individuals are very responsive to early intervention and treatment, and problems may resolve altogether within a few years. Treatment of acne may help an affected individual's self-image. Attention deficit and hyperactivity disorder, difficulties with social interactions, or other behavioral problems can be treated with therapy or medication the same as in individuals who do not have XYY. | 1,316 | XYY Syndrome |
nord_1317_0 | Overview of Yaws | Yaws is an infectious tropical disease caused by the spirochete (spiral shaped) bacterium known as Treponema pertenue. The disease presents in three stages of which the first and second are easily treated. The third, however, may involve complex changes to the bones in many parts of the body. The first stage is characterized by the appearance of small, painless bumps on the skin that group together and grow until they resemble a strawberry. The skin may break open, forming an ulcer. The second stage (usually starting several weeks or months after the first) presents with a crispy, crunchy rash that may cover arms, legs, buttocks and/or face. If the bottoms of the feet are involved, walking is painful and the stage is known as “crab yaws.” Stage 3 yaws involves the long bones, joints, and/or skin. Yaws is very common in tropical areas of the world but it is not known in the United States. It is not a sexually transmitted disease. It occurs in children younger than 15 years of age. | Overview of Yaws. Yaws is an infectious tropical disease caused by the spirochete (spiral shaped) bacterium known as Treponema pertenue. The disease presents in three stages of which the first and second are easily treated. The third, however, may involve complex changes to the bones in many parts of the body. The first stage is characterized by the appearance of small, painless bumps on the skin that group together and grow until they resemble a strawberry. The skin may break open, forming an ulcer. The second stage (usually starting several weeks or months after the first) presents with a crispy, crunchy rash that may cover arms, legs, buttocks and/or face. If the bottoms of the feet are involved, walking is painful and the stage is known as “crab yaws.” Stage 3 yaws involves the long bones, joints, and/or skin. Yaws is very common in tropical areas of the world but it is not known in the United States. It is not a sexually transmitted disease. It occurs in children younger than 15 years of age. | 1,317 | Yaws |
nord_1317_1 | Symptoms of Yaws | Stage 1 yaws typically occurs in early childhood, with peak incidence at about six years of age. A single itchy, strawberry-like growth appears on the skin over which a thin yellow crust forms (papillomatous lesion). This growth, the “mother yaw”, appears at the spot where the organism entered the body (inoculation site), typically on the leg or foot. Stage 2 yaws typically follows several weeks or months after the initial symptoms. Similar skin sores appear on the face, legs, arms, and/or around the rectum and genitals. These sores usually heal slowly and may recur. Lesions on the bottom of the feet may produce painful cracks and ulcerations (keratosis), resulting in an awkward “crab-like” walk or “crab yaws.”At this stage, swollen glands (swollen lymph nodes) are not uncommon and the rash may develop a brown crust.The symptoms of stage 3 yaws occur in only about 10% of the people who are infected and may follow a dormant period of several years. Painful ulcers or nodules may develop on the skin (cutaneous) and cause facial disfigurement. Painful, granular sores (gummatous lesions) may also develop on the bones, especially the long bones of the legs (tibia). Painful skin and bone nodules may impair joint function and mobility.Stage 3 yaws may also produce different and distinct syndromes. One, known as goundou syndrome, is characterized by inflammation and swelling of the tissues surrounding the nose (paranasal swelling), as well as overgrowth of the bones in the same region of the face (hypertrophic osteitis). Another, known as gangosa syndrome (also known as rhinopharyngitis mutilans), is characterized by degenerative changes of the nose, throat (pharynx), and the roof of the mouth (hard palate). | Symptoms of Yaws. Stage 1 yaws typically occurs in early childhood, with peak incidence at about six years of age. A single itchy, strawberry-like growth appears on the skin over which a thin yellow crust forms (papillomatous lesion). This growth, the “mother yaw”, appears at the spot where the organism entered the body (inoculation site), typically on the leg or foot. Stage 2 yaws typically follows several weeks or months after the initial symptoms. Similar skin sores appear on the face, legs, arms, and/or around the rectum and genitals. These sores usually heal slowly and may recur. Lesions on the bottom of the feet may produce painful cracks and ulcerations (keratosis), resulting in an awkward “crab-like” walk or “crab yaws.”At this stage, swollen glands (swollen lymph nodes) are not uncommon and the rash may develop a brown crust.The symptoms of stage 3 yaws occur in only about 10% of the people who are infected and may follow a dormant period of several years. Painful ulcers or nodules may develop on the skin (cutaneous) and cause facial disfigurement. Painful, granular sores (gummatous lesions) may also develop on the bones, especially the long bones of the legs (tibia). Painful skin and bone nodules may impair joint function and mobility.Stage 3 yaws may also produce different and distinct syndromes. One, known as goundou syndrome, is characterized by inflammation and swelling of the tissues surrounding the nose (paranasal swelling), as well as overgrowth of the bones in the same region of the face (hypertrophic osteitis). Another, known as gangosa syndrome (also known as rhinopharyngitis mutilans), is characterized by degenerative changes of the nose, throat (pharynx), and the roof of the mouth (hard palate). | 1,317 | Yaws |
nord_1317_2 | Causes of Yaws | Yaws is an infectious disease caused by a spiral-shaped bacterium (spirochete) known as Treponema pertenue. Yaws is usually transmitted by direct contact with the infected skin sores of affected individuals. In some cases, yaws may be transmitted through the bite of an infected insect. | Causes of Yaws. Yaws is an infectious disease caused by a spiral-shaped bacterium (spirochete) known as Treponema pertenue. Yaws is usually transmitted by direct contact with the infected skin sores of affected individuals. In some cases, yaws may be transmitted through the bite of an infected insect. | 1,317 | Yaws |
nord_1317_3 | Affects of Yaws | Yaws is a common infectious disease among children living in the tropical areas of Africa, South and Central America, the West Indies, and the Far East. It is not known in the United States. Yaws affects males and females in equal numbers and is most common in children between the ages of six and 10. The prevalence of yaws declined greatly following a mass treatment campaign with penicillin by the World Health Organization (WHO) in the 1950s and '60s. However, there has been a resurgence of yaws in certain countries in Africa and Southeast Asia. | Affects of Yaws. Yaws is a common infectious disease among children living in the tropical areas of Africa, South and Central America, the West Indies, and the Far East. It is not known in the United States. Yaws affects males and females in equal numbers and is most common in children between the ages of six and 10. The prevalence of yaws declined greatly following a mass treatment campaign with penicillin by the World Health Organization (WHO) in the 1950s and '60s. However, there has been a resurgence of yaws in certain countries in Africa and Southeast Asia. | 1,317 | Yaws |
nord_1317_4 | Related disorders of Yaws | Symptoms of the following disorders can be similar to those of Yaws. Comparisons may be useful for a differential diagnosis:Bejel is an infectious disease which is rare in the United States but common in certain parts of the world. It is characterized by lesions of the skin and bones and is caused by a bacteria known as Treponema pallidum II. The infection is very similar to syphilis but is not sexually transmitted. Children with Bejel have patchy ulcerations on mucous membranes particularly in or near the mouth. (For more information on this disorder, choose “Bejel” as your search term in the Rare Disease Database.)Acquired Syphilis is a chronic infectious disease caused by the bacteria Treponema pallidum. It is transmitted by direct contact with an infected individual, usually through sexual intercourse. When left untreated, the symptoms of Syphilis progress (i.e., primary, secondary, and latent stages). Eventually any tissue or organ in the body may be affected. Early symptoms include lesions (chancres) of the skin, anus, vagina, or the moist surfaces of the mouth. The symptoms may remain dormant for years. (For more information on this disorder, choose “Syphilis” as your search term in the Rare Disease Database.)Pinta is a rare infectious disease characterized by skin rash and discoloration. It is caused by the spiral-shaped bacteria Treponema carateum. Pimple-like bumps appear on the skin; they are small, reddish, and patchy. These lesions change in color and eventually lose all color (depigmentation). Pinta may be acquired by direct nonsexual contact. (For more information on this disorder, choose “Pinta” as your search term in the Rare Disease Database.)Leprosy is a progressive, chronic infectious disease caused by the bacteria, Mycobacterium leprae. This disease affects the nerves that are located outside the central nervous system (peripheral nerves), and the skin, mucous membranes, and eyes. In severe cases of Leprosy, loss of sensation, disfigurement, and/or blindness may occur. Symptoms may include burning or tingling sensations (paresthesias), a lack of sensation or feeling in the affected areas (anesthesia), weakness, paralysis, and/or the loss of muscle tissue (atrophy). Skin lesions include flat, spotty discolorations (macules), raised areas of red skin (papules), small solid masses (nodules), and raised discolorations. (For more information on this disorder, choose “Leprosy” as your search term in the Rare Disease Database.) | Related disorders of Yaws. Symptoms of the following disorders can be similar to those of Yaws. Comparisons may be useful for a differential diagnosis:Bejel is an infectious disease which is rare in the United States but common in certain parts of the world. It is characterized by lesions of the skin and bones and is caused by a bacteria known as Treponema pallidum II. The infection is very similar to syphilis but is not sexually transmitted. Children with Bejel have patchy ulcerations on mucous membranes particularly in or near the mouth. (For more information on this disorder, choose “Bejel” as your search term in the Rare Disease Database.)Acquired Syphilis is a chronic infectious disease caused by the bacteria Treponema pallidum. It is transmitted by direct contact with an infected individual, usually through sexual intercourse. When left untreated, the symptoms of Syphilis progress (i.e., primary, secondary, and latent stages). Eventually any tissue or organ in the body may be affected. Early symptoms include lesions (chancres) of the skin, anus, vagina, or the moist surfaces of the mouth. The symptoms may remain dormant for years. (For more information on this disorder, choose “Syphilis” as your search term in the Rare Disease Database.)Pinta is a rare infectious disease characterized by skin rash and discoloration. It is caused by the spiral-shaped bacteria Treponema carateum. Pimple-like bumps appear on the skin; they are small, reddish, and patchy. These lesions change in color and eventually lose all color (depigmentation). Pinta may be acquired by direct nonsexual contact. (For more information on this disorder, choose “Pinta” as your search term in the Rare Disease Database.)Leprosy is a progressive, chronic infectious disease caused by the bacteria, Mycobacterium leprae. This disease affects the nerves that are located outside the central nervous system (peripheral nerves), and the skin, mucous membranes, and eyes. In severe cases of Leprosy, loss of sensation, disfigurement, and/or blindness may occur. Symptoms may include burning or tingling sensations (paresthesias), a lack of sensation or feeling in the affected areas (anesthesia), weakness, paralysis, and/or the loss of muscle tissue (atrophy). Skin lesions include flat, spotty discolorations (macules), raised areas of red skin (papules), small solid masses (nodules), and raised discolorations. (For more information on this disorder, choose “Leprosy” as your search term in the Rare Disease Database.) | 1,317 | Yaws |
nord_1317_5 | Diagnosis of Yaws | The diagnosis of stage 1 and stage 2 yaws is made by microscopic examination of tissue samples (darkfield examination) from the skin lesions of affected individuals. Stage 3 yaws may be diagnosed by specialized blood tests (i.e., VDRL and treponemal antibodies). | Diagnosis of Yaws. The diagnosis of stage 1 and stage 2 yaws is made by microscopic examination of tissue samples (darkfield examination) from the skin lesions of affected individuals. Stage 3 yaws may be diagnosed by specialized blood tests (i.e., VDRL and treponemal antibodies). | 1,317 | Yaws |
nord_1317_6 | Therapies of Yaws | TreatmentStage 1 and 2 yaws is treated with antibiotics, especially with benzathine penicillin G. A single large dose of these medications usually heals the skin lesions and eliminates the organism. These antibiotic drugs may also be used to prevent this disease in family members and others who are in frequent contact with affected individuals. At the present time, there is no treatment for the destructive bone lesions or scars associated with stage 3 yaws. | Therapies of Yaws. TreatmentStage 1 and 2 yaws is treated with antibiotics, especially with benzathine penicillin G. A single large dose of these medications usually heals the skin lesions and eliminates the organism. These antibiotic drugs may also be used to prevent this disease in family members and others who are in frequent contact with affected individuals. At the present time, there is no treatment for the destructive bone lesions or scars associated with stage 3 yaws. | 1,317 | Yaws |
nord_1318_0 | Overview of Yellow Fever | Yellow Fever is a viral infection that causes damage to the liver, kidney, heart and gastrointestinal tract. Major symptoms may include sudden onset of fever, yellowing of the skin (jaundice) and hemorrhage. It occurs predominately in South America, the Caribbean Islands and Africa. The disease is spread through bites of infected mosquitos. Incidence of the disease tends to increase in the summer as the mosquito population increases, and it occurs year round in tropical climates.Yellow Fever has two cycles: the sylvan cycle in which mosquitos primarily spread the disease among forest-dwelling primates, and the urban cycle in which the infection is spread from human to human. | Overview of Yellow Fever. Yellow Fever is a viral infection that causes damage to the liver, kidney, heart and gastrointestinal tract. Major symptoms may include sudden onset of fever, yellowing of the skin (jaundice) and hemorrhage. It occurs predominately in South America, the Caribbean Islands and Africa. The disease is spread through bites of infected mosquitos. Incidence of the disease tends to increase in the summer as the mosquito population increases, and it occurs year round in tropical climates.Yellow Fever has two cycles: the sylvan cycle in which mosquitos primarily spread the disease among forest-dwelling primates, and the urban cycle in which the infection is spread from human to human. | 1,318 | Yellow Fever |
nord_1318_1 | Symptoms of Yellow Fever | The symptoms of Yellow Fever are the sudden onset of fever and chills along with headache, backache, generalized pain, nausea, vomiting, flushed face and infection of the inner eyelid. The fever usually disappears after three days, reappearing several days later with new symptoms of jaundice, bleeding gums, soft palate hemorrhages, and the vomiting of blood (black vomit). The patient may go into shock during this phase.Yellow Fever may also appear in a mild form with symptoms resembling influenza, malaria, dengue fever or typhoid. In this case, the fever usually lasts less than one week. | Symptoms of Yellow Fever. The symptoms of Yellow Fever are the sudden onset of fever and chills along with headache, backache, generalized pain, nausea, vomiting, flushed face and infection of the inner eyelid. The fever usually disappears after three days, reappearing several days later with new symptoms of jaundice, bleeding gums, soft palate hemorrhages, and the vomiting of blood (black vomit). The patient may go into shock during this phase.Yellow Fever may also appear in a mild form with symptoms resembling influenza, malaria, dengue fever or typhoid. In this case, the fever usually lasts less than one week. | 1,318 | Yellow Fever |
nord_1318_2 | Causes of Yellow Fever | Yellow Fever is caused by a virus spread by the bite by an infected mosquito. Initially, a mosquito acquires the disease by ingesting the blood of an infected host. The mosquito then transmits the infection to its next bite victim. | Causes of Yellow Fever. Yellow Fever is caused by a virus spread by the bite by an infected mosquito. Initially, a mosquito acquires the disease by ingesting the blood of an infected host. The mosquito then transmits the infection to its next bite victim. | 1,318 | Yellow Fever |
nord_1318_3 | Affects of Yellow Fever | Yellow Fever affects males and females equally. People living in semitropical or tropical climates are at risk unless they are vaccinated against this infection. People in southern areas of the United States, living near marshes and swamps may be at risk during the summer months. However, most cases of Yellow Fever occur in Africa and South America. | Affects of Yellow Fever. Yellow Fever affects males and females equally. People living in semitropical or tropical climates are at risk unless they are vaccinated against this infection. People in southern areas of the United States, living near marshes and swamps may be at risk during the summer months. However, most cases of Yellow Fever occur in Africa and South America. | 1,318 | Yellow Fever |
nord_1318_4 | Related disorders of Yellow Fever | Symptoms of the following disorders can be similar to those of Yellow Fever. Comparisons may be useful for a differential diagnosis:Dengue Fever is a disease also transmitted by a mosquito bite and characterized by a skin rash and a high fever with severe pain in the head and muscles. There is a sudden onset of symptoms with pain also occuring in the lower back, legs and joints. (For more information on this disorder, choose “Dengue Fever” as your search term in the Rare Disease Database.)Viral Encephalitis is a disease characterized by fever, headache, vomiting, rigidity of the neck, lethargy and convulsions. Generalized muscular weakness and paralysis may also occur.Malaria is a communicable disorder also spread through the bite of a mosquito. Symptoms include chills and fever, although not every case follows the same pattern. Symptoms may begin a week after exposure to the mosquito or months later. (For more information of this disorder, choose “Malaria” as your search term in the Rare Disease Database.) | Related disorders of Yellow Fever. Symptoms of the following disorders can be similar to those of Yellow Fever. Comparisons may be useful for a differential diagnosis:Dengue Fever is a disease also transmitted by a mosquito bite and characterized by a skin rash and a high fever with severe pain in the head and muscles. There is a sudden onset of symptoms with pain also occuring in the lower back, legs and joints. (For more information on this disorder, choose “Dengue Fever” as your search term in the Rare Disease Database.)Viral Encephalitis is a disease characterized by fever, headache, vomiting, rigidity of the neck, lethargy and convulsions. Generalized muscular weakness and paralysis may also occur.Malaria is a communicable disorder also spread through the bite of a mosquito. Symptoms include chills and fever, although not every case follows the same pattern. Symptoms may begin a week after exposure to the mosquito or months later. (For more information of this disorder, choose “Malaria” as your search term in the Rare Disease Database.) | 1,318 | Yellow Fever |
nord_1318_5 | Diagnosis of Yellow Fever | Diagnosis of Yellow Fever. | 1,318 | Yellow Fever |
|
nord_1318_6 | Therapies of Yellow Fever | The treatment of Yellow Fever is symptomatic and supportive. Preventative measures consist of mosquito control and a vaccine that prevents development of the infection. Immunity from a vaccination usually develops after 10 days and lasts for more than 10 years. In some cases, side effects associated with vaccination may occur five to 10 days later. These side effects affect approximately 5 percent of individuals receiving immunization and may include headache, fever, and/or aching muscles. | Therapies of Yellow Fever. The treatment of Yellow Fever is symptomatic and supportive. Preventative measures consist of mosquito control and a vaccine that prevents development of the infection. Immunity from a vaccination usually develops after 10 days and lasts for more than 10 years. In some cases, side effects associated with vaccination may occur five to 10 days later. These side effects affect approximately 5 percent of individuals receiving immunization and may include headache, fever, and/or aching muscles. | 1,318 | Yellow Fever |
nord_1319_0 | Overview of Yellow Nail syndrome | Yellow nail syndrome is an extremely rare disorder characterized by malformations affecting the fingernails and toenails, abnormalities affecting the lungs and the airways (respiratory tract) and swelling or puffiness in different parts of the body because of the accumulation of protein-rich fluid (lymph) in the soft layers of tissue under the skin (lymphedema). Yellow nail syndrome usually affects older adults. The exact cause of yellow nail syndrome is not known. Occasionally, yellow nail syndrome has been reported to run in families suggesting that genetic factors may play a role in the development of the disorder in some patients. | Overview of Yellow Nail syndrome. Yellow nail syndrome is an extremely rare disorder characterized by malformations affecting the fingernails and toenails, abnormalities affecting the lungs and the airways (respiratory tract) and swelling or puffiness in different parts of the body because of the accumulation of protein-rich fluid (lymph) in the soft layers of tissue under the skin (lymphedema). Yellow nail syndrome usually affects older adults. The exact cause of yellow nail syndrome is not known. Occasionally, yellow nail syndrome has been reported to run in families suggesting that genetic factors may play a role in the development of the disorder in some patients. | 1,319 | Yellow Nail syndrome |
nord_1319_1 | Symptoms of Yellow Nail syndrome | The characteristic finding associated with yellow nail syndrome is the development of yellow, thickened, and excessively curved nails with almost complete stoppage of nail growth. Loss of the strip of hardened skin at the base and sides of a fingernail (cuticles) may also occur. Separation of the nails from the nail bed (onycholysis) may cause the nails to fall out. Some individuals may develop infection of the soft tissue around edge of the nails (paronychia). Any nail (both toenails and fingernails) may be affected. Yellow nail syndrome is occasionally associated with the accumulation of fluid in the membranes surrounding the lungs and lining the chest cavity (pleural effusion). Pleural effusions can cause shortness of breath, chest pain and a cough. Additional respiratory problems may occur in yellow nail syndrome such as chronic infection and inflammation of the main air passages (bronchial tubes) out of the lungs (bronchitis), destruction and widening of the small air passages out of the lung (bronchiectasis), ongoing inflammation of the membranes that line the sinus cavities (sinusitis) and/or chronic inflammation or infection of the lungs (recurrent pneumonias). Individuals with yellow nail syndrome may have a history of respiratory problems before developing characteristic nail findings.Individuals with yellow nail syndrome often have swelling of the arms and legs due to the accumulation of a fluid known as lymph (peripheral lymphedema). The legs are especially affected in yellow nail syndrome. The onset of lymphedema may occur around puberty. Areas affected by lymphedema may feel heavy or tight. Decreased flexibility may develop in the hands, feet, wrists or ankles if lymphedema is present in the corresponding arm or leg. The skin on areas affected by lymphedema may become hardened or thickened. | Symptoms of Yellow Nail syndrome. The characteristic finding associated with yellow nail syndrome is the development of yellow, thickened, and excessively curved nails with almost complete stoppage of nail growth. Loss of the strip of hardened skin at the base and sides of a fingernail (cuticles) may also occur. Separation of the nails from the nail bed (onycholysis) may cause the nails to fall out. Some individuals may develop infection of the soft tissue around edge of the nails (paronychia). Any nail (both toenails and fingernails) may be affected. Yellow nail syndrome is occasionally associated with the accumulation of fluid in the membranes surrounding the lungs and lining the chest cavity (pleural effusion). Pleural effusions can cause shortness of breath, chest pain and a cough. Additional respiratory problems may occur in yellow nail syndrome such as chronic infection and inflammation of the main air passages (bronchial tubes) out of the lungs (bronchitis), destruction and widening of the small air passages out of the lung (bronchiectasis), ongoing inflammation of the membranes that line the sinus cavities (sinusitis) and/or chronic inflammation or infection of the lungs (recurrent pneumonias). Individuals with yellow nail syndrome may have a history of respiratory problems before developing characteristic nail findings.Individuals with yellow nail syndrome often have swelling of the arms and legs due to the accumulation of a fluid known as lymph (peripheral lymphedema). The legs are especially affected in yellow nail syndrome. The onset of lymphedema may occur around puberty. Areas affected by lymphedema may feel heavy or tight. Decreased flexibility may develop in the hands, feet, wrists or ankles if lymphedema is present in the corresponding arm or leg. The skin on areas affected by lymphedema may become hardened or thickened. | 1,319 | Yellow Nail syndrome |
nord_1319_2 | Causes of Yellow Nail syndrome | The exact cause of yellow nail syndrome is not known. Most cases seem to occur randomly, for no apparent reason (sporadically). Some researchers believe that yellow nail syndrome is a sporadic, acquired condition. However, some sources in the medical literature currently classify yellow nail syndrome as a primary genetic disorder.Some cases of yellow nail syndrome have run in families suggesting that, in these cases, genetic factors may play a role in the development of the disorder. Some researchers have speculated that yellow nail syndrome is inherited in an autosomal dominant pattern, although the evidence for this remains scarce. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.Some reports in the medical literature have linked some cases of yellow nail syndrome to changes (called mutations or variants) of the FOXC2 gene. This gene is known to cause a similar disorder called lymphedema-distichiasis syndrome. Some researchers believe that the only primary lymphedema disorder caused by mutation of this gene is lymphedema-distichiasis syndrome and that individuals with yellow nail syndrome linked to this gene may have been misdiagnosed.Yellow nail syndrome has occurred with greater frequency than would be expected in individuals with certain forms of cancer, immunodeficiency syndromes, nephrotic syndrome, thyroid disease, and rheumatoid arthritis. In individuals with rheumatoid arthritis and yellow nail syndrome, researchers believe certain drugs used to treat the arthritis (thiol drugs) play a role in the development of yellow nail syndrome. Recent reports have suggested the possibility of titanium toxicity as a potential cause of the syndrome, prompting some physicians to recommend removal of titanium prostheses or dental implants on occasions. It should be emphasized that due to the rarity of the syndrome, this association remains entirely speculative. In addition, symptoms do not seem to improve significantly after removal. Accordingly, removal of titanium-based medical devices cannot be recommended.Many of the symptoms of yellow nail syndrome are commonly associated with malfunction of the lymphatic system including yellow nails, lymphedema, and breathing (respiratory abnormalities). The lymphatic system is a circulatory network of vessels, ducts, and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body. Researchers believe that in yellow nail syndrome, lymphatic fluid collects in the soft tissues in and under the skin (subcutaneous) due to obstruction, malformation, or underdevelopment (hypoplasia) of various lymphatic vessels. Researchers have also speculated that abnormal of leakage of fluid through very tiny vessels (microvascular permeability) may also contribute to the development of lymphedema in yellow nail syndrome. | Causes of Yellow Nail syndrome. The exact cause of yellow nail syndrome is not known. Most cases seem to occur randomly, for no apparent reason (sporadically). Some researchers believe that yellow nail syndrome is a sporadic, acquired condition. However, some sources in the medical literature currently classify yellow nail syndrome as a primary genetic disorder.Some cases of yellow nail syndrome have run in families suggesting that, in these cases, genetic factors may play a role in the development of the disorder. Some researchers have speculated that yellow nail syndrome is inherited in an autosomal dominant pattern, although the evidence for this remains scarce. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.Some reports in the medical literature have linked some cases of yellow nail syndrome to changes (called mutations or variants) of the FOXC2 gene. This gene is known to cause a similar disorder called lymphedema-distichiasis syndrome. Some researchers believe that the only primary lymphedema disorder caused by mutation of this gene is lymphedema-distichiasis syndrome and that individuals with yellow nail syndrome linked to this gene may have been misdiagnosed.Yellow nail syndrome has occurred with greater frequency than would be expected in individuals with certain forms of cancer, immunodeficiency syndromes, nephrotic syndrome, thyroid disease, and rheumatoid arthritis. In individuals with rheumatoid arthritis and yellow nail syndrome, researchers believe certain drugs used to treat the arthritis (thiol drugs) play a role in the development of yellow nail syndrome. Recent reports have suggested the possibility of titanium toxicity as a potential cause of the syndrome, prompting some physicians to recommend removal of titanium prostheses or dental implants on occasions. It should be emphasized that due to the rarity of the syndrome, this association remains entirely speculative. In addition, symptoms do not seem to improve significantly after removal. Accordingly, removal of titanium-based medical devices cannot be recommended.Many of the symptoms of yellow nail syndrome are commonly associated with malfunction of the lymphatic system including yellow nails, lymphedema, and breathing (respiratory abnormalities). The lymphatic system is a circulatory network of vessels, ducts, and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body. Researchers believe that in yellow nail syndrome, lymphatic fluid collects in the soft tissues in and under the skin (subcutaneous) due to obstruction, malformation, or underdevelopment (hypoplasia) of various lymphatic vessels. Researchers have also speculated that abnormal of leakage of fluid through very tiny vessels (microvascular permeability) may also contribute to the development of lymphedema in yellow nail syndrome. | 1,319 | Yellow Nail syndrome |
nord_1319_3 | Affects of Yellow Nail syndrome | Yellow nail syndrome affects males and females in equal numbers. More than 100 cases have been reported in the medical literature. Yellow nail syndrome usually occurs in older adults with most cases occurring in individuals over 50 years of age. Although uncommon, yellow nail syndrome can occur in children.Yellow nail syndrome was first described in the medical literature in 1964. | Affects of Yellow Nail syndrome. Yellow nail syndrome affects males and females in equal numbers. More than 100 cases have been reported in the medical literature. Yellow nail syndrome usually occurs in older adults with most cases occurring in individuals over 50 years of age. Although uncommon, yellow nail syndrome can occur in children.Yellow nail syndrome was first described in the medical literature in 1964. | 1,319 | Yellow Nail syndrome |
nord_1319_4 | Related disorders of Yellow Nail syndrome | Symptoms of the following disorders can be similar to those of yellow nail syndrome. Comparisons may be useful for a differential diagnosis.Lymphedema-distichiasis syndrome is a rare genetic multisystem disorder characterized by swelling of the legs because of fluid accumulation and the development of extra eyelashes (distichiasis). Distichiasis may range from a few extra lashes to a full set of extra eyelashes. Swelling most often affects both legs (bilateral) and usually occurs around puberty. Additional anomalies sometimes associated with this disorder include cleft palate, droopy eyelids (ptosis), abnormalities of the curved transparent outer layer of fibrous tissue covering the eyeball (cornea), cysts on the spinal cord, an abnormal sensitivity to light (photophobia), and cardiac (heart) defects. Lymphedema-distichiasis syndrome is caused by mutations of the FOXC2 gene and is inherited as an autosomal dominant trait. (For more information on this disorder, choose “lymphedema distichiasis” as your search term in the Rare Disease Database.)Hereditary lymphedema is a genetic developmental disorder affecting the lymphatic system. It is characterized by abnormal swelling of certain parts of the body. The lymphatic system is a circulatory network of vessels, ducts, and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body. In hereditary lymphedema, lymphatic fluid collects in the soft tissues in and under the skin (subcutaneous) due to obstruction, malformation, or underdevelopment (hypoplasia) of various lymphatic vessels. There are three forms of hereditary lymphedema: congenital hereditary lymphedema or Milroy disease; lymphedema praecox or Meige disease; and lymphedema tarda. Symptoms include swelling (lymphedema) and thickening and hardening of the skin in affected areas. In most cases, hereditary lymphedema is inherited as an autosomal dominant trait. (For more information on this disorder, choose “hereditary lymphedema” as your search term in the Rare Disease Database.) | Related disorders of Yellow Nail syndrome. Symptoms of the following disorders can be similar to those of yellow nail syndrome. Comparisons may be useful for a differential diagnosis.Lymphedema-distichiasis syndrome is a rare genetic multisystem disorder characterized by swelling of the legs because of fluid accumulation and the development of extra eyelashes (distichiasis). Distichiasis may range from a few extra lashes to a full set of extra eyelashes. Swelling most often affects both legs (bilateral) and usually occurs around puberty. Additional anomalies sometimes associated with this disorder include cleft palate, droopy eyelids (ptosis), abnormalities of the curved transparent outer layer of fibrous tissue covering the eyeball (cornea), cysts on the spinal cord, an abnormal sensitivity to light (photophobia), and cardiac (heart) defects. Lymphedema-distichiasis syndrome is caused by mutations of the FOXC2 gene and is inherited as an autosomal dominant trait. (For more information on this disorder, choose “lymphedema distichiasis” as your search term in the Rare Disease Database.)Hereditary lymphedema is a genetic developmental disorder affecting the lymphatic system. It is characterized by abnormal swelling of certain parts of the body. The lymphatic system is a circulatory network of vessels, ducts, and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body. In hereditary lymphedema, lymphatic fluid collects in the soft tissues in and under the skin (subcutaneous) due to obstruction, malformation, or underdevelopment (hypoplasia) of various lymphatic vessels. There are three forms of hereditary lymphedema: congenital hereditary lymphedema or Milroy disease; lymphedema praecox or Meige disease; and lymphedema tarda. Symptoms include swelling (lymphedema) and thickening and hardening of the skin in affected areas. In most cases, hereditary lymphedema is inherited as an autosomal dominant trait. (For more information on this disorder, choose “hereditary lymphedema” as your search term in the Rare Disease Database.) | 1,319 | Yellow Nail syndrome |
nord_1319_5 | Diagnosis of Yellow Nail syndrome | A diagnosis of yellow nail syndrome is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. The nail changes in yellow nail syndrome are distinct from the nail changes that occur in most other lymphedema syndromes. | Diagnosis of Yellow Nail syndrome. A diagnosis of yellow nail syndrome is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. The nail changes in yellow nail syndrome are distinct from the nail changes that occur in most other lymphedema syndromes. | 1,319 | Yellow Nail syndrome |
nord_1319_6 | Therapies of Yellow Nail syndrome | Treatment
The treatment of yellow nail syndrome is geared toward the symptoms present in each individual. Treatment may include antibiotic therapy for repeated respiratory infections. The yellowed, malformed nails may improve without therapy. In some cases, the changes may be permanent. Vitamin E has been used to treat nail changes. Corticosteroids have also been used to treat individuals with yellow nail syndrome. Surgical management of respiratory problems such as pleural effusions has been used in some cases. Removal of titanium prostheses or dental implants is not recommended, as the evidence for a causal relationship between titanium and yellow nail syndrome is at best speculative, and symptoms do not appear dramatically improved after these interventions.Genetic counseling may be helpful for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Yellow Nail syndrome. Treatment
The treatment of yellow nail syndrome is geared toward the symptoms present in each individual. Treatment may include antibiotic therapy for repeated respiratory infections. The yellowed, malformed nails may improve without therapy. In some cases, the changes may be permanent. Vitamin E has been used to treat nail changes. Corticosteroids have also been used to treat individuals with yellow nail syndrome. Surgical management of respiratory problems such as pleural effusions has been used in some cases. Removal of titanium prostheses or dental implants is not recommended, as the evidence for a causal relationship between titanium and yellow nail syndrome is at best speculative, and symptoms do not appear dramatically improved after these interventions.Genetic counseling may be helpful for affected individuals and their families. Other treatment is symptomatic and supportive. | 1,319 | Yellow Nail syndrome |
nord_1320_0 | Overview of Yunis Varon Syndrome | Yunis-Varon syndrome is a rare genetic multisystem disorder with defects affecting mostly the skeletal system, the nervous system, and ectodermal tissue (hair and teeth). It is characterized by large fontanelles, clavicular hypoplasia, characteristic facial features and/or abnormalities of fingers and toes. Characteristic features may include microcephaly, ear abnormalities, anteverted nares, midfacial hypoplasia, tented upper lip and small jaw (micrognathia), sparse or absent eyebrows and/or eyelashes. Abnormalities of the fingers and toes may include absence (aplasia) or underdevelopment (hypoplasia) of the fingers and toes. Most infants with this disorder experience severe feeding problems and respiratory difficulties. Some of these difficulties are related to the severe involvement of the central nervous system, with malformations of the brain affecting half of the children and hypotonia (low tone) affecting all of them. In addition, affected infants may have heart defects (e.g., abnormal enlargement of the heart muscle [hypertrophic cardiomyopathy]). Frequently, feeding problems, respiratory difficulties, and/or heart defects may result in life-threatening complications during infancy. Yunis-Varon syndrome is inherited as an autosomal recessive condition. | Overview of Yunis Varon Syndrome. Yunis-Varon syndrome is a rare genetic multisystem disorder with defects affecting mostly the skeletal system, the nervous system, and ectodermal tissue (hair and teeth). It is characterized by large fontanelles, clavicular hypoplasia, characteristic facial features and/or abnormalities of fingers and toes. Characteristic features may include microcephaly, ear abnormalities, anteverted nares, midfacial hypoplasia, tented upper lip and small jaw (micrognathia), sparse or absent eyebrows and/or eyelashes. Abnormalities of the fingers and toes may include absence (aplasia) or underdevelopment (hypoplasia) of the fingers and toes. Most infants with this disorder experience severe feeding problems and respiratory difficulties. Some of these difficulties are related to the severe involvement of the central nervous system, with malformations of the brain affecting half of the children and hypotonia (low tone) affecting all of them. In addition, affected infants may have heart defects (e.g., abnormal enlargement of the heart muscle [hypertrophic cardiomyopathy]). Frequently, feeding problems, respiratory difficulties, and/or heart defects may result in life-threatening complications during infancy. Yunis-Varon syndrome is inherited as an autosomal recessive condition. | 1,320 | Yunis Varon Syndrome |
nord_1320_1 | Symptoms of Yunis Varon Syndrome | Yunis-Varon syndrome is a rare genetic multisystem disorder characterized by large fontanelles, clavicular hypoplasia, characteristic facial features and/or abnormalities of fingers and toes. Characteristic features may include microcephaly, ear abnormalities, anteverted nares, midfacial hypoplasia, tented upper lip and small jaw (micrognathia), sparse or absent eyebrows and/or eyelashes.As infants with Yunis-Varon syndrome mature, they may also exhibit failure to gain weight or grow at the expected rate (failure to thrive), severe developmental delays, and/or intellectual disability.Infants with Yunis-Varon syndrome exhibit absence or severe underdevelopment (hypoplasia) of one or both of the collarbones (clavicles) and delayed closure of the two soft membraned-covered openings (fontanels) on an infant’s head, with abnormal separation of the fibrous joints (sutures) that connect certain bones of the skull. Children without collarbones or with underdeveloped collarbones may have “droopy” shoulders or, in extreme cases, may be able to bring their shoulders together in front of their bodies.Infants with Yunis-Varon syndrome also have abnormalities of the fingers and toes (digits). The thumbs and the bones at the ends of the fingers and the great toes (distal phalanges) may be absent (aplastic) or underdeveloped (hypoplastic). In some cases, other bones may be underdeveloped including the bones between the wrists and the fingers (metacarpals), the bones between the knuckles of the fingers (middle phalanges), the bones of the great toes nearest to the feet (proximal phalanges) or other toes, and/or the bones between the ankles and the toes (metatarsals). As a result of these abnormalities, the fingers and toes may be unusually short. In addition, some affected infants may exhibit absence or underdevelopment of the fingernails and/or toenails and/or webbing between the fingers and/or toes (syndactyly).Some affected infants may exhibit additional skeletal abnormalities including deformity of the pelvis (pelvic dysplasia), dislocation of both (bilateral) hips, lack of sternal ossification, slender ribs or bone fractures.Additional findings that may be associated with Yunis-Varon syndrome include abnormalities of the heart such as cardiomyopathy or congenital heart defects.In some children, urinary tract abnormalities may occur, including abnormal placement of the urinary opening (meatus) on the underside of the penis (hypospadias), failure of the testes to descend into the scrotum (cryptorchidism) and micropenis.Additional findings have been reported in individuals with Yunis-Varon syndrome including central nervous system abnormalities and hypodontia. | Symptoms of Yunis Varon Syndrome. Yunis-Varon syndrome is a rare genetic multisystem disorder characterized by large fontanelles, clavicular hypoplasia, characteristic facial features and/or abnormalities of fingers and toes. Characteristic features may include microcephaly, ear abnormalities, anteverted nares, midfacial hypoplasia, tented upper lip and small jaw (micrognathia), sparse or absent eyebrows and/or eyelashes.As infants with Yunis-Varon syndrome mature, they may also exhibit failure to gain weight or grow at the expected rate (failure to thrive), severe developmental delays, and/or intellectual disability.Infants with Yunis-Varon syndrome exhibit absence or severe underdevelopment (hypoplasia) of one or both of the collarbones (clavicles) and delayed closure of the two soft membraned-covered openings (fontanels) on an infant’s head, with abnormal separation of the fibrous joints (sutures) that connect certain bones of the skull. Children without collarbones or with underdeveloped collarbones may have “droopy” shoulders or, in extreme cases, may be able to bring their shoulders together in front of their bodies.Infants with Yunis-Varon syndrome also have abnormalities of the fingers and toes (digits). The thumbs and the bones at the ends of the fingers and the great toes (distal phalanges) may be absent (aplastic) or underdeveloped (hypoplastic). In some cases, other bones may be underdeveloped including the bones between the wrists and the fingers (metacarpals), the bones between the knuckles of the fingers (middle phalanges), the bones of the great toes nearest to the feet (proximal phalanges) or other toes, and/or the bones between the ankles and the toes (metatarsals). As a result of these abnormalities, the fingers and toes may be unusually short. In addition, some affected infants may exhibit absence or underdevelopment of the fingernails and/or toenails and/or webbing between the fingers and/or toes (syndactyly).Some affected infants may exhibit additional skeletal abnormalities including deformity of the pelvis (pelvic dysplasia), dislocation of both (bilateral) hips, lack of sternal ossification, slender ribs or bone fractures.Additional findings that may be associated with Yunis-Varon syndrome include abnormalities of the heart such as cardiomyopathy or congenital heart defects.In some children, urinary tract abnormalities may occur, including abnormal placement of the urinary opening (meatus) on the underside of the penis (hypospadias), failure of the testes to descend into the scrotum (cryptorchidism) and micropenis.Additional findings have been reported in individuals with Yunis-Varon syndrome including central nervous system abnormalities and hypodontia. | 1,320 | Yunis Varon Syndrome |
nord_1320_2 | Causes of Yunis Varon Syndrome | Yunis-Varon syndrome is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits a changed gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. Some cases of Yunis-Varon syndrome have occurred among children who had parents who were related by blood (consanguineous). All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same non-working gene, which increases the risk to have children with a recessive genetic disorder.The gene causing Yunis-Varon syndrome in some families was identified as FIG4. FIG4 codes for a protein regulating the transport of vesicles inside cells by modifying molecules called phosphoinositides. Different mutations in FIG4 can also cause Charcot-Marie-Tooth disease, a condition where the peripheral nerves lose their proper function, and polymicrogyria, a condition with brain malformations. Some researchers thought that mutations in FIG4 could also predispose mutation carriers to ALS (amyotrophic lateral sclerosis) but subsequent larger studies did not support this finding. Some researchers have speculated that Yunis-Varon syndrome may occur as a result of defects in lysosomal storage. Lysosomal storage diseases comprise a group of metabolic disorders characterized by an abnormal build-up of various toxic materials in the body’s cells as a result of enzyme deficiencies. These disorders affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. FIG4 is involved in regulating the transport of various vesicles, including lysosomes, which could help explain the findings suggestive of abnormal lysosomal function.Mutations in the VAC14 gene have also been found to be associated with Yunis-Varon syndrome. | Causes of Yunis Varon Syndrome. Yunis-Varon syndrome is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits a changed gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. Some cases of Yunis-Varon syndrome have occurred among children who had parents who were related by blood (consanguineous). All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same non-working gene, which increases the risk to have children with a recessive genetic disorder.The gene causing Yunis-Varon syndrome in some families was identified as FIG4. FIG4 codes for a protein regulating the transport of vesicles inside cells by modifying molecules called phosphoinositides. Different mutations in FIG4 can also cause Charcot-Marie-Tooth disease, a condition where the peripheral nerves lose their proper function, and polymicrogyria, a condition with brain malformations. Some researchers thought that mutations in FIG4 could also predispose mutation carriers to ALS (amyotrophic lateral sclerosis) but subsequent larger studies did not support this finding. Some researchers have speculated that Yunis-Varon syndrome may occur as a result of defects in lysosomal storage. Lysosomal storage diseases comprise a group of metabolic disorders characterized by an abnormal build-up of various toxic materials in the body’s cells as a result of enzyme deficiencies. These disorders affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. FIG4 is involved in regulating the transport of various vesicles, including lysosomes, which could help explain the findings suggestive of abnormal lysosomal function.Mutations in the VAC14 gene have also been found to be associated with Yunis-Varon syndrome. | 1,320 | Yunis Varon Syndrome |
nord_1320_3 | Affects of Yunis Varon Syndrome | Yunis-Varon syndrome is an extremely rare inherited disorder that affects males and females in equal numbers. 25 cases from 19 families have been reported since the disorder’s initial description in the medical literature in 1980. | Affects of Yunis Varon Syndrome. Yunis-Varon syndrome is an extremely rare inherited disorder that affects males and females in equal numbers. 25 cases from 19 families have been reported since the disorder’s initial description in the medical literature in 1980. | 1,320 | Yunis Varon Syndrome |
nord_1320_4 | Related disorders of Yunis Varon Syndrome | Symptoms of the following disorders can be similar to those of Yunis-Varon syndrome. Comparisons may be useful for a differential diagnosis: Cleidocranial dysplasia is a rare genetic disorder characterized by the association of the three following features: absence or severe underdevelopment (hypoplasia) of one or both of the collar bones (clavicles); delayed closure of the two soft openings (fontanels) on an infant’s head with abnormal separation of the fibrous joints (sutures) that connect certain bones of the skull; and an abnormally large skull (macrocrania). Characteristic findings may include an unusually short, wide head (brachycephaly); dental abnormalities such as delayed growth (eruption) of both the “baby” and “adult” teeth; a short middle bone (phalanx) in the fifth fingers; abnormally short fingers (brachydactyly); and/or growth retardation, resulting in moderate short stature. Other physical findings may include a wide pelvic joint (pubic symphysis), and deformities of the spine such as abnormal side-to-side curvature of the spine (scoliosis), which may worsen (progress) with age. Some affected infants may exhibit respiratory problems. Cleidocranial dysplasia is inherited as an autosomal dominant genetic condition. (For more information on this disorder, choose “cleidocranial dysplasia” as your search term in the Rare Disease Database). Mandibuloacral dysplasia is an extremely rare inherited disorder characterized by underdeveloped (hypoplastic) collarbones (clavicles); abnormally wide fibrous joints between certain bones of the skull (cranial sutures); joint stiffness; and an underdeveloped (hypoplastic) lower jaw (mandible) causing crowding of the teeth. Individuals with this disorder may also exhibit increased sensitivity to cold in the fingers as well as loss of bone tissue in the hands (acroosteolysis). Some affected children may exhibit short stature, patchy loss of hair (alopecia), and/or degeneration (atrophy) of the skin on the hands and feet. Mandibuloacral dysplasia is thought to be inherited as an autosomal recessive genetic condition. (For more information on this disorder, choose “mandibuloacral dysplasia” as your search term in the Rare Disease Database). | Related disorders of Yunis Varon Syndrome. Symptoms of the following disorders can be similar to those of Yunis-Varon syndrome. Comparisons may be useful for a differential diagnosis: Cleidocranial dysplasia is a rare genetic disorder characterized by the association of the three following features: absence or severe underdevelopment (hypoplasia) of one or both of the collar bones (clavicles); delayed closure of the two soft openings (fontanels) on an infant’s head with abnormal separation of the fibrous joints (sutures) that connect certain bones of the skull; and an abnormally large skull (macrocrania). Characteristic findings may include an unusually short, wide head (brachycephaly); dental abnormalities such as delayed growth (eruption) of both the “baby” and “adult” teeth; a short middle bone (phalanx) in the fifth fingers; abnormally short fingers (brachydactyly); and/or growth retardation, resulting in moderate short stature. Other physical findings may include a wide pelvic joint (pubic symphysis), and deformities of the spine such as abnormal side-to-side curvature of the spine (scoliosis), which may worsen (progress) with age. Some affected infants may exhibit respiratory problems. Cleidocranial dysplasia is inherited as an autosomal dominant genetic condition. (For more information on this disorder, choose “cleidocranial dysplasia” as your search term in the Rare Disease Database). Mandibuloacral dysplasia is an extremely rare inherited disorder characterized by underdeveloped (hypoplastic) collarbones (clavicles); abnormally wide fibrous joints between certain bones of the skull (cranial sutures); joint stiffness; and an underdeveloped (hypoplastic) lower jaw (mandible) causing crowding of the teeth. Individuals with this disorder may also exhibit increased sensitivity to cold in the fingers as well as loss of bone tissue in the hands (acroosteolysis). Some affected children may exhibit short stature, patchy loss of hair (alopecia), and/or degeneration (atrophy) of the skin on the hands and feet. Mandibuloacral dysplasia is thought to be inherited as an autosomal recessive genetic condition. (For more information on this disorder, choose “mandibuloacral dysplasia” as your search term in the Rare Disease Database). | 1,320 | Yunis Varon Syndrome |
nord_1320_5 | Diagnosis of Yunis Varon Syndrome | Yunis-Varon syndrome may be diagnosed or confirmed after birth based upon a thorough clinical evaluation, the identification of characteristic findings (e.g., hypoplastic claviculae, limb abnormalities, sparse hair, characteristic facial features). Genetic testing for mutations in FIG4 can also confirm a diagnosis. Certain findings that may suggest a diagnosis of Yunis-Varon syndrome (e.g. limb and bone abnormalities or congenital heart defect) may be identified before birth (prenatally) using ultrasonography. In fetal ultrasonography, reflected sound waves are used to create an image of the developing fetus. | Diagnosis of Yunis Varon Syndrome. Yunis-Varon syndrome may be diagnosed or confirmed after birth based upon a thorough clinical evaluation, the identification of characteristic findings (e.g., hypoplastic claviculae, limb abnormalities, sparse hair, characteristic facial features). Genetic testing for mutations in FIG4 can also confirm a diagnosis. Certain findings that may suggest a diagnosis of Yunis-Varon syndrome (e.g. limb and bone abnormalities or congenital heart defect) may be identified before birth (prenatally) using ultrasonography. In fetal ultrasonography, reflected sound waves are used to create an image of the developing fetus. | 1,320 | Yunis Varon Syndrome |
nord_1320_6 | Therapies of Yunis Varon Syndrome | Treatment
Specific therapies for individuals with Yunis-Varon syndrome are symptomatic and supportive. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat skeletal abnormalities (orthopedists), physical therapists, physicians who specialize in diagnosing and treating disorders of the heart (cardiologists), and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.Physicians should closely monitor infants with Yunis-Varon syndrome to promptly detect any feeding or breathing difficulties associated with the disorder. Physicians may recommend preventive measures and/or institute immediate appropriate therapy. Treatment for feeding difficulties may include artificial feeding methods such as tube feeding, which administers food through a tube directly into the infant’s stomach, or intravenous feeding, in which essential nutrients are administered into a vein using a tube. Breathing difficulties, when severe and life-threatening, may require special measures such as the use of a special machine (ventilator) that supports breathing (artificial respiration).Early intervention is important in Yunis-Varon syndrome. Special services that may be beneficial to affected children may include special remedial education, special social support, physical therapy, and other medical, social, and/or vocational services.Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive. | Therapies of Yunis Varon Syndrome. Treatment
Specific therapies for individuals with Yunis-Varon syndrome are symptomatic and supportive. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat skeletal abnormalities (orthopedists), physical therapists, physicians who specialize in diagnosing and treating disorders of the heart (cardiologists), and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.Physicians should closely monitor infants with Yunis-Varon syndrome to promptly detect any feeding or breathing difficulties associated with the disorder. Physicians may recommend preventive measures and/or institute immediate appropriate therapy. Treatment for feeding difficulties may include artificial feeding methods such as tube feeding, which administers food through a tube directly into the infant’s stomach, or intravenous feeding, in which essential nutrients are administered into a vein using a tube. Breathing difficulties, when severe and life-threatening, may require special measures such as the use of a special machine (ventilator) that supports breathing (artificial respiration).Early intervention is important in Yunis-Varon syndrome. Special services that may be beneficial to affected children may include special remedial education, special social support, physical therapy, and other medical, social, and/or vocational services.Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive. | 1,320 | Yunis Varon Syndrome |
nord_1321_0 | Overview of ZC4H2-Associated Rare Disorders (ZARD) | SummaryZC4H2 Associated Rare Disorders (ZARD) 1 is an ultra-rare genetic condition with central and peripheral nervous system involvement caused by harmful changes (pathogenic variants) of the ZC4H2 gene. ZC4H2 is located on the X chromosome and encodes the ZC4H2 (zinc finger C4H2-type containing) protein essential for normal development. ZARD can manifest in a broad range of clinical severity. Clinical presentations of affected individuals who carry the same pathogenic ZC4H2 gene variant can vary within families and between families.1-3 Males and females can be affected.IntroductionMany conditions have been described as associated with pathogenic variants in the ZC4H2 gene. 2,4,5 These conditions are now thought to be included in the spectrum of ZARD 1. This previously used nomenclature describes limited populations of individual or family-specific cases, provides partial descriptions of the condition, and should no longer be used. These conditions include the following: • Wieacker-Wolff syndrome, WRWF 2
• Miles-Carpenter syndrome 3
• ZC4H2 deficiency 4
• Wieacker syndrome
• contractures of the feet, muscle atrophy and oculomotor apraxia
• apraxia, oculomotor with congenital contractures and muscle atrophy
• Miles-Carpenter X-linked mental retardation syndrome; MCS
• mental retardation, X-linked, syndromic 4; MRXS4
• mental retardation, X-linked with congenital contractures and low fingertip arches
• Wieacker-Wolff syndrome, female restricted; WRWFFR | Overview of ZC4H2-Associated Rare Disorders (ZARD). SummaryZC4H2 Associated Rare Disorders (ZARD) 1 is an ultra-rare genetic condition with central and peripheral nervous system involvement caused by harmful changes (pathogenic variants) of the ZC4H2 gene. ZC4H2 is located on the X chromosome and encodes the ZC4H2 (zinc finger C4H2-type containing) protein essential for normal development. ZARD can manifest in a broad range of clinical severity. Clinical presentations of affected individuals who carry the same pathogenic ZC4H2 gene variant can vary within families and between families.1-3 Males and females can be affected.IntroductionMany conditions have been described as associated with pathogenic variants in the ZC4H2 gene. 2,4,5 These conditions are now thought to be included in the spectrum of ZARD 1. This previously used nomenclature describes limited populations of individual or family-specific cases, provides partial descriptions of the condition, and should no longer be used. These conditions include the following: • Wieacker-Wolff syndrome, WRWF 2
• Miles-Carpenter syndrome 3
• ZC4H2 deficiency 4
• Wieacker syndrome
• contractures of the feet, muscle atrophy and oculomotor apraxia
• apraxia, oculomotor with congenital contractures and muscle atrophy
• Miles-Carpenter X-linked mental retardation syndrome; MCS
• mental retardation, X-linked, syndromic 4; MRXS4
• mental retardation, X-linked with congenital contractures and low fingertip arches
• Wieacker-Wolff syndrome, female restricted; WRWFFR | 1,321 | ZC4H2-Associated Rare Disorders (ZARD) |
nord_1321_1 | Symptoms of ZC4H2-Associated Rare Disorders (ZARD) | Patients with ZARD can have multiple disabilities and health concerns. These can include orthopedic and musculoskeletal conditions and neurological/neuromuscular conditions. The most common clinical features include:• arthrogryposis multiplex congenita (multiple joint contractures before birth that involve at least two different body areas; sometimes caused by decreased fetal movement)
• joint and soft-tissue abnormalities often expressed as contractures
• hand and feet deformities
• hip deformities
• muscular atrophy
• osteopenia (weak bones)
• scoliosis (sideways curvature of the spine)
• motor planning impairments, generalized or localized
• mobility impairments
• variable muscle tone
• difficulty eating and breathing
• speech disorders often including apraxia of speech that can make it difficult for a child to connect syllables, words and phrases
• oculomotor apraxia (abnormal eye movements)
• seizures
• tethered cord (spinal cord attached to surrounding tissues in the spine)
• autism
• global developmental delay (longer time for a child to reach developmental milestones)
• intellectual disabilities
• learning difficultiesAn affected individual can have the full range of symptoms or only some of them. 1-4,6,7 MRI brain and spine images can show variable and global brain atrophy, delayed central nervous system myelination, abnormality of periventricular white matter, corpus callosum abnormality, abnormal cortical gyration, ventriculomegaly, tethered cord and hydromyelia. 1There are some gender specific clinical features such as cardiovascular (heart and blood vessel) associated clinical features, hypogonadism (low testosterone) and hypoglycemia (low blood sugar) that have so far only been reported in affected males.1Arthrogryposis multiplex congenita (AMC) and muscular atrophy, which are observed in most affected males and females, could be a possible secondary consequence of reduced fetal movement. Like affected individuals with other types of arthrogryposis multiplex congenita who develop joint contractures during pregnancy, abnormal fetal movement during pregnancy can be identified using real time ultrasound prenatally. However, AMC and abnormal fetal movements can occur late in pregnancy and therefore suspicion of the diagnosis can be easily missed. 1There is currently no evidence of any progressive or regressive nature in the condition. Life expectancy is yet undetermined. | Symptoms of ZC4H2-Associated Rare Disorders (ZARD). Patients with ZARD can have multiple disabilities and health concerns. These can include orthopedic and musculoskeletal conditions and neurological/neuromuscular conditions. The most common clinical features include:• arthrogryposis multiplex congenita (multiple joint contractures before birth that involve at least two different body areas; sometimes caused by decreased fetal movement)
• joint and soft-tissue abnormalities often expressed as contractures
• hand and feet deformities
• hip deformities
• muscular atrophy
• osteopenia (weak bones)
• scoliosis (sideways curvature of the spine)
• motor planning impairments, generalized or localized
• mobility impairments
• variable muscle tone
• difficulty eating and breathing
• speech disorders often including apraxia of speech that can make it difficult for a child to connect syllables, words and phrases
• oculomotor apraxia (abnormal eye movements)
• seizures
• tethered cord (spinal cord attached to surrounding tissues in the spine)
• autism
• global developmental delay (longer time for a child to reach developmental milestones)
• intellectual disabilities
• learning difficultiesAn affected individual can have the full range of symptoms or only some of them. 1-4,6,7 MRI brain and spine images can show variable and global brain atrophy, delayed central nervous system myelination, abnormality of periventricular white matter, corpus callosum abnormality, abnormal cortical gyration, ventriculomegaly, tethered cord and hydromyelia. 1There are some gender specific clinical features such as cardiovascular (heart and blood vessel) associated clinical features, hypogonadism (low testosterone) and hypoglycemia (low blood sugar) that have so far only been reported in affected males.1Arthrogryposis multiplex congenita (AMC) and muscular atrophy, which are observed in most affected males and females, could be a possible secondary consequence of reduced fetal movement. Like affected individuals with other types of arthrogryposis multiplex congenita who develop joint contractures during pregnancy, abnormal fetal movement during pregnancy can be identified using real time ultrasound prenatally. However, AMC and abnormal fetal movements can occur late in pregnancy and therefore suspicion of the diagnosis can be easily missed. 1There is currently no evidence of any progressive or regressive nature in the condition. Life expectancy is yet undetermined. | 1,321 | ZC4H2-Associated Rare Disorders (ZARD) |
nord_1321_2 | Causes of ZC4H2-Associated Rare Disorders (ZARD) | ZARD is caused by harmful changes of the X chromosome linked ZC4H2 gene. Males and females can be affected. ZC4H2 gene variants can be inherited or occur spontaneously, meaning there is no family history of the disorder (de novo). 1Males have one X chromosome and one Y chromosome. If a male has a pathogenic ZC4H2 gene variant (inherited from his mother or de novo), he will develop the disease. In very rare cases, healthy males may have somatic/germline mosaicism for a pathogenic ZC4H2 gene variant. They will pass this variant to all their daughters, who will be carriers. Males cannot pass the ZC4H2 gene variant to their sons because they always pass their Y chromosome instead of their X chromosome to male offspring. Females have two X chromosomes but many genes of one of the X chromosomes are silenced to correct a dosage imbalance through a process which is called X-inactivation. ZC4H2 is one of these many genes which is silenced through this process (subject to X-inactivation). 3 Results obtained so far by performing X-inactivation studies in blood and skin fibroblasts of carrier females indicated that X-inactivation status does not predict the clinical outcome. 1Variants of the ZC4H2 gene can be inherited from the healthy or mildly affected mother who carries the variant on one of her X chromosomes. 1 Female carriers have a 25% chance with each pregnancy to pass on the ZC4H2 variant to a daughter, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with ZARD, and a 25% chance to have an unaffected son. Females with a maternally inherited ZC4H2 gene variant may be unaffected or mildly affected. In contrast, females who carry a de novo pathogenic ZC4H2 variant can present with a highly variable clinical expression which ranges from mild to severe 1In very rare cases, healthy females who carry a ZC4H2 variant in a small number of somatic cells and germ cells (gonosomal mosaicism) can pass the variant to their children. 1The ZC4H2 gene is expressed in all human tissues. Understanding of ZC4H2’s gene functions and the functions of its corresponding ZC4H2 protein is currently limited. There is currently no evidence for a clear relationship between the genetic abnormality and the clinical features. The spectrum of ZC4H2 gene abnormalities comprises novel (not reported before) and recurrent (present in at least two unrelated families) mostly inherited missense variants which cause a single amino acid exchange in the ZC4H2 protein in affected male individuals, and de novo missense, splicing, frameshift, nonsense and partial ZC4H2 deletions on one of the X chromosomes in carrier females and are predicted to be loss-of function alleles in affected female individuals suggesting ZC4H2 insufficiency as the most likely pathological mechanism leading to the clinical phenotype in females.Thus far, missense variants cluster in the last exon of the ZC4H2 gene, which encodes the zinc-finger domain and the most C-terminal part of the protein.Analysis of the in vivo expression pattern of the mouse Zc4h2 gene during neurodevelopment in various brain regions and spinal cord of different developmental stages revealed that in all brain areas investigated, Zc4h2 gene expression was highest during embryonic development and declined after birth, suggesting an important function during mouse brain development. 3In zebrafish zc4h2 is primarily expressed in brain cells called “myelinating oligodendrocytes”, with decrease in expression as these mature into another type of brain cells. 6 This may suggest a function of ZC4H2 in myelination – which has not been studied to date.It is believed that the ZC4H2 protein plays an important role in the development of the neurologic system during the early stages of human development, particularly through the development of neuromuscular junctions, spinal cord motor-neuron differentiation and neural tube formation. 3,6,8 | Causes of ZC4H2-Associated Rare Disorders (ZARD). ZARD is caused by harmful changes of the X chromosome linked ZC4H2 gene. Males and females can be affected. ZC4H2 gene variants can be inherited or occur spontaneously, meaning there is no family history of the disorder (de novo). 1Males have one X chromosome and one Y chromosome. If a male has a pathogenic ZC4H2 gene variant (inherited from his mother or de novo), he will develop the disease. In very rare cases, healthy males may have somatic/germline mosaicism for a pathogenic ZC4H2 gene variant. They will pass this variant to all their daughters, who will be carriers. Males cannot pass the ZC4H2 gene variant to their sons because they always pass their Y chromosome instead of their X chromosome to male offspring. Females have two X chromosomes but many genes of one of the X chromosomes are silenced to correct a dosage imbalance through a process which is called X-inactivation. ZC4H2 is one of these many genes which is silenced through this process (subject to X-inactivation). 3 Results obtained so far by performing X-inactivation studies in blood and skin fibroblasts of carrier females indicated that X-inactivation status does not predict the clinical outcome. 1Variants of the ZC4H2 gene can be inherited from the healthy or mildly affected mother who carries the variant on one of her X chromosomes. 1 Female carriers have a 25% chance with each pregnancy to pass on the ZC4H2 variant to a daughter, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with ZARD, and a 25% chance to have an unaffected son. Females with a maternally inherited ZC4H2 gene variant may be unaffected or mildly affected. In contrast, females who carry a de novo pathogenic ZC4H2 variant can present with a highly variable clinical expression which ranges from mild to severe 1In very rare cases, healthy females who carry a ZC4H2 variant in a small number of somatic cells and germ cells (gonosomal mosaicism) can pass the variant to their children. 1The ZC4H2 gene is expressed in all human tissues. Understanding of ZC4H2’s gene functions and the functions of its corresponding ZC4H2 protein is currently limited. There is currently no evidence for a clear relationship between the genetic abnormality and the clinical features. The spectrum of ZC4H2 gene abnormalities comprises novel (not reported before) and recurrent (present in at least two unrelated families) mostly inherited missense variants which cause a single amino acid exchange in the ZC4H2 protein in affected male individuals, and de novo missense, splicing, frameshift, nonsense and partial ZC4H2 deletions on one of the X chromosomes in carrier females and are predicted to be loss-of function alleles in affected female individuals suggesting ZC4H2 insufficiency as the most likely pathological mechanism leading to the clinical phenotype in females.Thus far, missense variants cluster in the last exon of the ZC4H2 gene, which encodes the zinc-finger domain and the most C-terminal part of the protein.Analysis of the in vivo expression pattern of the mouse Zc4h2 gene during neurodevelopment in various brain regions and spinal cord of different developmental stages revealed that in all brain areas investigated, Zc4h2 gene expression was highest during embryonic development and declined after birth, suggesting an important function during mouse brain development. 3In zebrafish zc4h2 is primarily expressed in brain cells called “myelinating oligodendrocytes”, with decrease in expression as these mature into another type of brain cells. 6 This may suggest a function of ZC4H2 in myelination – which has not been studied to date.It is believed that the ZC4H2 protein plays an important role in the development of the neurologic system during the early stages of human development, particularly through the development of neuromuscular junctions, spinal cord motor-neuron differentiation and neural tube formation. 3,6,8 | 1,321 | ZC4H2-Associated Rare Disorders (ZARD) |
nord_1321_3 | Affects of ZC4H2-Associated Rare Disorders (ZARD) | Harmful ZC4H2 gene variants have been identified in many ethnic groups, with both males and females being affected who present with a broad spectrum of severity. To date, there are less than 250 diagnosed patients with ZARD worldwide. 1,3,6,7,9-21
About 30% are males and 70% are females. 7 | Affects of ZC4H2-Associated Rare Disorders (ZARD). Harmful ZC4H2 gene variants have been identified in many ethnic groups, with both males and females being affected who present with a broad spectrum of severity. To date, there are less than 250 diagnosed patients with ZARD worldwide. 1,3,6,7,9-21
About 30% are males and 70% are females. 7 | 1,321 | ZC4H2-Associated Rare Disorders (ZARD) |
nord_1321_4 | Related disorders of ZC4H2-Associated Rare Disorders (ZARD) | There are several genetic diseases that may be characterized by similar or overlapping symptoms to those that may occur with ZARD with varying clinical severity, including arthrogryposis multiplex congenita, hand and feet deformities such as talipes equinovarus and/or camptodactyly.Clinical genetic differential diagnosis in males: 1Pettigrew syndrome
developmental and epileptic encephalopathy 1
alpha-thalassemia X-linked intellectual disability syndrome
FG syndrome 4
MEHMO syndrome
Uruguay faciocardiomusculoskeletal syndrome
intellectual developmental disorder, X-linked, Turner type
myotubular myopathy, X-linked
Renpenning syndrome
TARP syndrome
intellectual developmental disorder, X-linked syndromic, Christianson type
Allan-Herndon-Dudley syndrome
Abruzzo-Erickson syndrome
spinal muscular atrophy, X-linked 2, infantile | Related disorders of ZC4H2-Associated Rare Disorders (ZARD). There are several genetic diseases that may be characterized by similar or overlapping symptoms to those that may occur with ZARD with varying clinical severity, including arthrogryposis multiplex congenita, hand and feet deformities such as talipes equinovarus and/or camptodactyly.Clinical genetic differential diagnosis in males: 1Pettigrew syndrome
developmental and epileptic encephalopathy 1
alpha-thalassemia X-linked intellectual disability syndrome
FG syndrome 4
MEHMO syndrome
Uruguay faciocardiomusculoskeletal syndrome
intellectual developmental disorder, X-linked, Turner type
myotubular myopathy, X-linked
Renpenning syndrome
TARP syndrome
intellectual developmental disorder, X-linked syndromic, Christianson type
Allan-Herndon-Dudley syndrome
Abruzzo-Erickson syndrome
spinal muscular atrophy, X-linked 2, infantile | 1,321 | ZC4H2-Associated Rare Disorders (ZARD) |
nord_1321_5 | Diagnosis of ZC4H2-Associated Rare Disorders (ZARD) | A diagnosis of ZARD may be considered based upon a thorough clinical evaluation, a detailed patient and family history and the identification of characteristic findings. Molecular genetic testing for ZC4H2 gene variants (gene sequencing, panel next generation sequencing and microarray analysis) is available to confirm the diagnosis.The diagnosis of ZARD is established in a male with suggestive findings and a de novo or inherited pathogenic variant in the ZC4H2 gene identified by molecular genetic testing. The diagnosis of ZARD is usually established in a female with suggestive findings and a de novo or inherited pathogenic variant in ZC4H2 identified by molecular genetic testing.Identification of a ZC4H2 variant in a male or female interpreted as variant of uncertain clinical significance (VUS) does not establish the diagnosis or rule out the diagnosis of ZARD.If a ZC4H2 gene variant is not identified, molecular genetic testing for genes associated with similar conditions may be suggested. | Diagnosis of ZC4H2-Associated Rare Disorders (ZARD). A diagnosis of ZARD may be considered based upon a thorough clinical evaluation, a detailed patient and family history and the identification of characteristic findings. Molecular genetic testing for ZC4H2 gene variants (gene sequencing, panel next generation sequencing and microarray analysis) is available to confirm the diagnosis.The diagnosis of ZARD is established in a male with suggestive findings and a de novo or inherited pathogenic variant in the ZC4H2 gene identified by molecular genetic testing. The diagnosis of ZARD is usually established in a female with suggestive findings and a de novo or inherited pathogenic variant in ZC4H2 identified by molecular genetic testing.Identification of a ZC4H2 variant in a male or female interpreted as variant of uncertain clinical significance (VUS) does not establish the diagnosis or rule out the diagnosis of ZARD.If a ZC4H2 gene variant is not identified, molecular genetic testing for genes associated with similar conditions may be suggested. | 1,321 | ZC4H2-Associated Rare Disorders (ZARD) |
nord_1321_6 | Therapies of ZC4H2-Associated Rare Disorders (ZARD) | TreatmentThere is currently no cure or effective treatment for this ultra-rare condition. Current treatments consist mainly of different supportive therapies and medical interventions when necessary. However, there is an observed correlation between early therapeutic and supportive interventions (pre-verbal and speech as well as physical therapies) and favorable short- and long-term outcomes. 7Surgery may be necessary to treat specific congenital or structural malformations associated with ZARD.Genetic counseling is recommended for affected individuals and their families to clarify the genetic and clinical characteristics, inheritance and recurrence risks of the condition in their families. | Therapies of ZC4H2-Associated Rare Disorders (ZARD). TreatmentThere is currently no cure or effective treatment for this ultra-rare condition. Current treatments consist mainly of different supportive therapies and medical interventions when necessary. However, there is an observed correlation between early therapeutic and supportive interventions (pre-verbal and speech as well as physical therapies) and favorable short- and long-term outcomes. 7Surgery may be necessary to treat specific congenital or structural malformations associated with ZARD.Genetic counseling is recommended for affected individuals and their families to clarify the genetic and clinical characteristics, inheritance and recurrence risks of the condition in their families. | 1,321 | ZC4H2-Associated Rare Disorders (ZARD) |
nord_1322_0 | Overview of Zellweger Spectrum Disorders | Summary Zellweger spectrum disorders (ZSD) are a group of rare, genetic, multisystem disorders that were once thought to be separate entities. These disorders are now classified as different expressions (variants) of one disease process due to their shared biochemical basis. Collectively, they form a spectrum or continuum of disease. The most severe form of these disorders was previously referred to as Zellweger syndrome, the intermediate form was referred to as neonatal adrenoleukodystrophy, and the milder forms were referred to as infantile Refsum disease or Heimler syndrome, depending on the clinical presentation. ZSD can affect most organs of the body. Neurological deficits, loss of muscle tone (hypotonia), hearing loss, vision problems, liver dysfunction, and kidney abnormalities are common findings. ZSD often result in severe, life-threatening complications early during infancy. Some individuals with milder forms have lived into adulthood. ZSD are inherited in an autosomal recessive pattern.IntroductionZSD are also known as peroxisome biogenesis disorders (PBDs) – a group of disorders characterized by the failure of the body to produce peroxisomes that function properly. Peroxisomes are very small, membrane-bound structures within the gel-like fluid (cytoplasm) of cells that play a vital role in numerous biochemical processes in the body. PBDs are subdivided into ZSD and rhizomelic chondrodysplasia punctata. Zellweger syndrome was described in the medical literature in 1964 by Dr. Hans Zellweger. Neonatal adrenoleukodystrophy, infantile Refsum disease and Heimler syndrome were described later. As the molecular and biochemical understanding of these disorders improved, it became apparent that they represented variants of one disorder and some researchers started using the term “Zellweger spectrum disorder” to describe these disorders. | Overview of Zellweger Spectrum Disorders. Summary Zellweger spectrum disorders (ZSD) are a group of rare, genetic, multisystem disorders that were once thought to be separate entities. These disorders are now classified as different expressions (variants) of one disease process due to their shared biochemical basis. Collectively, they form a spectrum or continuum of disease. The most severe form of these disorders was previously referred to as Zellweger syndrome, the intermediate form was referred to as neonatal adrenoleukodystrophy, and the milder forms were referred to as infantile Refsum disease or Heimler syndrome, depending on the clinical presentation. ZSD can affect most organs of the body. Neurological deficits, loss of muscle tone (hypotonia), hearing loss, vision problems, liver dysfunction, and kidney abnormalities are common findings. ZSD often result in severe, life-threatening complications early during infancy. Some individuals with milder forms have lived into adulthood. ZSD are inherited in an autosomal recessive pattern.IntroductionZSD are also known as peroxisome biogenesis disorders (PBDs) – a group of disorders characterized by the failure of the body to produce peroxisomes that function properly. Peroxisomes are very small, membrane-bound structures within the gel-like fluid (cytoplasm) of cells that play a vital role in numerous biochemical processes in the body. PBDs are subdivided into ZSD and rhizomelic chondrodysplasia punctata. Zellweger syndrome was described in the medical literature in 1964 by Dr. Hans Zellweger. Neonatal adrenoleukodystrophy, infantile Refsum disease and Heimler syndrome were described later. As the molecular and biochemical understanding of these disorders improved, it became apparent that they represented variants of one disorder and some researchers started using the term “Zellweger spectrum disorder” to describe these disorders. | 1,322 | Zellweger Spectrum Disorders |
nord_1322_1 | Symptoms of Zellweger Spectrum Disorders | The symptoms of ZSD vary greatly from one individual to another. The specific number and severity of symptoms present in an individual are highly variable and affected individuals will not have all of the symptoms discussed below. The most severe forms are usually noticeable shortly after birth. Severely affected infants often have distinct craniofacial features, neurological deficits, progressive dysfunction of the liver and kidneys and usually develop life-threatening complications during the first year of life. Children with milder forms of ZSD may not develop symptoms until later during infancy. Some of these children reach adolescence or adulthood although most have some degree of intellectual disability, hearing loss and vision problems. Some have profound loss of muscle tone (hypotonia or floppiness), but some learn to walk and speak. Some children with these milder forms of ZSD do not have any craniofacial abnormalities or only very mild ones. In extremely rare cases, affected individuals have gone undetected until older childhood or adulthood. These individuals have had only mild symptoms such as adult-onset hearing loss or vision problems and/or mild developmental delays. Many symptoms of ZSD are present at birth (congenital). Affected infants often exhibit prenatal growth failure in spite of a normal period of gestation and may also have a profound lack of muscle tone (hypotonia or floppiness). Affected infants may be limp, show little movement (lethargic) and poorly respond to environmental stimuli. Infants may be unable to suck and/or swallow leading to feeding difficulties and failure to gain weight and grow as expected (failure to thrive). Infants may also develop a variety of neurological complications including frequent seizures, poor or absent reflexes, intellectual disability, and delays in reaching developmental milestones such as sitting, crawling or walking (developmental delays). Affected infants have various brain abnormalities including defects caused by the abnormal migration of brain cells (neurons). Neurons are created in the center of the developing brain and must travel to other areas of the brain to function properly. In individuals with ZSD, the neurons fail to migrate properly resulting in a variety of brain abnormalities (neuronal migration defects). Some affected infants also develop progressive degeneration of the nerve fibers (white matter) of the brain (leukodystrophy). Infants may have distinctive facial features including a flattened appearance to the face, a high forehead, abnormally large “soft spots” (fontanelles) on the skull, broad bridge of the nose, a small nose with upturned nostrils (anteverted nares), an abnormally small jaw (micrognathia), a highly arched roof of the mouth (palate), a small chin, extra (redundant) folds of skin on the neck, and minor malformation of the outer part of the ears. The bony ridges of the eye socket may be abnormally shallow and the back of the head may be abnormally flat (flat occiput). A variety of eye abnormalities may occur including eyes that are spaced widely apart (hypertelorism), clouding of the lenses of the eyes (cataracts) or the clear (transparent) outer layer of the eye (corneal opacities), degeneration of the nerve that carries visual images from the eye to the brain (optic atrophy), and rapid, involuntary eye movements (nystagmus). Many infants with ZSD develop degeneration of the retina, which is the thin layer of nerve cells that sense light and convert it into nerve signals, which are then relayed to the brain through the optic nerve. Glaucoma, a condition characterized by increased pressure within the eye causing a distinctive pattern of visual impairment, may also occur. The various eye abnormalities associated with ZSD can cause loss of vision to varying degrees. In addition to vision loss, infants with ZSD also experience hearing loss with onset during the first few months of life. Some infants may have an abnormally large spleen (splenomegaly) and/or liver (hepatomegaly). The liver may also be scarred (fibrotic) and inflamed (cirrhosis), with progressive loss of function resulting in a variety of symptoms such as yellowing of the skin and whites of the eyes (jaundice). Additional findings include small cysts on the kidneys and gastrointestinal bleeding due to deficiency of a coagulation factor in the blood. Some children may develop episodes of exaggerated or uncontrolled bleeding (hemorrhaging) including bleeding within the skull (intracranial bleeding). Eventually, liver failure may occur. Minor skeletal abnormalities may also be present in ZSD including clubfoot, fingers that are fixed or stuck in a bent position and cannot extend or straighten fully (camptodactyly), and chondrodysplasia punctata, a condition characterized by the formation of small, hardened spots of calcium (stippling) on the knee cap (patella) and long bones of the arms and legs. Certain heart defects may also occur in infants with ZSD including septal defects and patent ductus arteriosus. Septal defects are “holes” in the heart, specifically holes in the thin partition (septum) that separates the chambers of the heart. Small septal defects may close on their own; larger defects may cause various symptoms including breathing irregularities and high blood pressure. Patent ductus arteriosus is a condition in which the two large arteries of the body (aorta and pulmonary artery) remain connected by a small blood vessel (ductus arteriosus) that is supposed to close after birth. Due to the lack of muscle tone, laryngomalacia (floppy airway) and other respiratory problems may occur in infants with ZSD. Respiratory support may entail the use of a nasal cannula for oxygen to more aggressive forms of support as the disease progresses. In some male infants with ZSD, additional symptoms may occur including the abnormal placement of the urinary opening on the underside of the penis (hypospadias) and failure of the testes to descend into the scrotum (cryptorchidism). Intermediate/milder forms of ZSD may present in the newborn period or be detected by newborn screening, but generally come to attention later because of developmental delays and sensory impairment. The clinical course for ZSD is variable. Despite low tone, some may learn to walk, speak and achieve some developmental milestones. Some develop adrenal insufficiency, osteopenia, or seizures over time. Teeth eruption is often delayed, and individuals often have tooth enamel abnormalities in their secondary teeth. Disease progression is often attributed to a leukodystrophy, or progressive degeneration of myelin in the central nervous system, which often results in loss of skills and untimely death. Even milder forms of ZSD present with primarily sensory impairment and little to no developmental delay. | Symptoms of Zellweger Spectrum Disorders. The symptoms of ZSD vary greatly from one individual to another. The specific number and severity of symptoms present in an individual are highly variable and affected individuals will not have all of the symptoms discussed below. The most severe forms are usually noticeable shortly after birth. Severely affected infants often have distinct craniofacial features, neurological deficits, progressive dysfunction of the liver and kidneys and usually develop life-threatening complications during the first year of life. Children with milder forms of ZSD may not develop symptoms until later during infancy. Some of these children reach adolescence or adulthood although most have some degree of intellectual disability, hearing loss and vision problems. Some have profound loss of muscle tone (hypotonia or floppiness), but some learn to walk and speak. Some children with these milder forms of ZSD do not have any craniofacial abnormalities or only very mild ones. In extremely rare cases, affected individuals have gone undetected until older childhood or adulthood. These individuals have had only mild symptoms such as adult-onset hearing loss or vision problems and/or mild developmental delays. Many symptoms of ZSD are present at birth (congenital). Affected infants often exhibit prenatal growth failure in spite of a normal period of gestation and may also have a profound lack of muscle tone (hypotonia or floppiness). Affected infants may be limp, show little movement (lethargic) and poorly respond to environmental stimuli. Infants may be unable to suck and/or swallow leading to feeding difficulties and failure to gain weight and grow as expected (failure to thrive). Infants may also develop a variety of neurological complications including frequent seizures, poor or absent reflexes, intellectual disability, and delays in reaching developmental milestones such as sitting, crawling or walking (developmental delays). Affected infants have various brain abnormalities including defects caused by the abnormal migration of brain cells (neurons). Neurons are created in the center of the developing brain and must travel to other areas of the brain to function properly. In individuals with ZSD, the neurons fail to migrate properly resulting in a variety of brain abnormalities (neuronal migration defects). Some affected infants also develop progressive degeneration of the nerve fibers (white matter) of the brain (leukodystrophy). Infants may have distinctive facial features including a flattened appearance to the face, a high forehead, abnormally large “soft spots” (fontanelles) on the skull, broad bridge of the nose, a small nose with upturned nostrils (anteverted nares), an abnormally small jaw (micrognathia), a highly arched roof of the mouth (palate), a small chin, extra (redundant) folds of skin on the neck, and minor malformation of the outer part of the ears. The bony ridges of the eye socket may be abnormally shallow and the back of the head may be abnormally flat (flat occiput). A variety of eye abnormalities may occur including eyes that are spaced widely apart (hypertelorism), clouding of the lenses of the eyes (cataracts) or the clear (transparent) outer layer of the eye (corneal opacities), degeneration of the nerve that carries visual images from the eye to the brain (optic atrophy), and rapid, involuntary eye movements (nystagmus). Many infants with ZSD develop degeneration of the retina, which is the thin layer of nerve cells that sense light and convert it into nerve signals, which are then relayed to the brain through the optic nerve. Glaucoma, a condition characterized by increased pressure within the eye causing a distinctive pattern of visual impairment, may also occur. The various eye abnormalities associated with ZSD can cause loss of vision to varying degrees. In addition to vision loss, infants with ZSD also experience hearing loss with onset during the first few months of life. Some infants may have an abnormally large spleen (splenomegaly) and/or liver (hepatomegaly). The liver may also be scarred (fibrotic) and inflamed (cirrhosis), with progressive loss of function resulting in a variety of symptoms such as yellowing of the skin and whites of the eyes (jaundice). Additional findings include small cysts on the kidneys and gastrointestinal bleeding due to deficiency of a coagulation factor in the blood. Some children may develop episodes of exaggerated or uncontrolled bleeding (hemorrhaging) including bleeding within the skull (intracranial bleeding). Eventually, liver failure may occur. Minor skeletal abnormalities may also be present in ZSD including clubfoot, fingers that are fixed or stuck in a bent position and cannot extend or straighten fully (camptodactyly), and chondrodysplasia punctata, a condition characterized by the formation of small, hardened spots of calcium (stippling) on the knee cap (patella) and long bones of the arms and legs. Certain heart defects may also occur in infants with ZSD including septal defects and patent ductus arteriosus. Septal defects are “holes” in the heart, specifically holes in the thin partition (septum) that separates the chambers of the heart. Small septal defects may close on their own; larger defects may cause various symptoms including breathing irregularities and high blood pressure. Patent ductus arteriosus is a condition in which the two large arteries of the body (aorta and pulmonary artery) remain connected by a small blood vessel (ductus arteriosus) that is supposed to close after birth. Due to the lack of muscle tone, laryngomalacia (floppy airway) and other respiratory problems may occur in infants with ZSD. Respiratory support may entail the use of a nasal cannula for oxygen to more aggressive forms of support as the disease progresses. In some male infants with ZSD, additional symptoms may occur including the abnormal placement of the urinary opening on the underside of the penis (hypospadias) and failure of the testes to descend into the scrotum (cryptorchidism). Intermediate/milder forms of ZSD may present in the newborn period or be detected by newborn screening, but generally come to attention later because of developmental delays and sensory impairment. The clinical course for ZSD is variable. Despite low tone, some may learn to walk, speak and achieve some developmental milestones. Some develop adrenal insufficiency, osteopenia, or seizures over time. Teeth eruption is often delayed, and individuals often have tooth enamel abnormalities in their secondary teeth. Disease progression is often attributed to a leukodystrophy, or progressive degeneration of myelin in the central nervous system, which often results in loss of skills and untimely death. Even milder forms of ZSD present with primarily sensory impairment and little to no developmental delay. | 1,322 | Zellweger Spectrum Disorders |
nord_1322_2 | Causes of Zellweger Spectrum Disorders | ZSD develop due to changes (mutations) of one of 13 different genes involved in the creation and proper function of peroxisomes (peroxisome biogenesis). These 13 genes contain instructions for creating (encoding) proteins known as peroxins that are essential for the proper development of peroxisomes. Approximately 61% of individuals with a ZSD have a mutation in the peroxisome biogenesis factor 1 (PEX1) gene. The other genes that cause ZSD are PEX2, PEX3, PEX5, PEX6, PEX10, PEX11, PEX12, PEX13, PEX14, PEX16, PEX19, and PEX26. Peroxisomes are very small, membrane-bound structures within the cytoplasm of cells that are involved in numerous chemical processes required for the proper function of the body. Peroxisomes are found in nearly every cell type of the body, but are larger and more numerous in the kidney and liver. Some cells contain less than one hundred peroxisomes; others may contain more than a thousand. Some processes for which peroxisomes are vital include the proper breakdown (metabolism) of fatty acids and the production of certain lipids important to the nervous system (plasmalogens) or digestion (bile acids). Peroxisomes are essential parts of the body’s waste disposal system and help ensure the proper development and function of the brain and central nervous system. Defective peroxisomes can cause numerous problems in the body. For example, since affected individuals lack sufficient levels of the enzymes normally produced by peroxisomes, very long chain fatty acids (VLCFA) accumulate in the cells of the affected organ. ZSD is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | Causes of Zellweger Spectrum Disorders. ZSD develop due to changes (mutations) of one of 13 different genes involved in the creation and proper function of peroxisomes (peroxisome biogenesis). These 13 genes contain instructions for creating (encoding) proteins known as peroxins that are essential for the proper development of peroxisomes. Approximately 61% of individuals with a ZSD have a mutation in the peroxisome biogenesis factor 1 (PEX1) gene. The other genes that cause ZSD are PEX2, PEX3, PEX5, PEX6, PEX10, PEX11, PEX12, PEX13, PEX14, PEX16, PEX19, and PEX26. Peroxisomes are very small, membrane-bound structures within the cytoplasm of cells that are involved in numerous chemical processes required for the proper function of the body. Peroxisomes are found in nearly every cell type of the body, but are larger and more numerous in the kidney and liver. Some cells contain less than one hundred peroxisomes; others may contain more than a thousand. Some processes for which peroxisomes are vital include the proper breakdown (metabolism) of fatty acids and the production of certain lipids important to the nervous system (plasmalogens) or digestion (bile acids). Peroxisomes are essential parts of the body’s waste disposal system and help ensure the proper development and function of the brain and central nervous system. Defective peroxisomes can cause numerous problems in the body. For example, since affected individuals lack sufficient levels of the enzymes normally produced by peroxisomes, very long chain fatty acids (VLCFA) accumulate in the cells of the affected organ. ZSD is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | 1,322 | Zellweger Spectrum Disorders |
nord_1322_3 | Affects of Zellweger Spectrum Disorders | Determining the true incidence of ZSD in the general population can be difficult. ZSD are usually diagnosed at birth, although some cases can be diagnosed later in life. ZSD affect individuals of all ethnic groups. In the United States, the estimated incidence of these disorders is somewhere in between 1 in 50,000 and 1 in 75,000 live births. | Affects of Zellweger Spectrum Disorders. Determining the true incidence of ZSD in the general population can be difficult. ZSD are usually diagnosed at birth, although some cases can be diagnosed later in life. ZSD affect individuals of all ethnic groups. In the United States, the estimated incidence of these disorders is somewhere in between 1 in 50,000 and 1 in 75,000 live births. | 1,322 | Zellweger Spectrum Disorders |
nord_1322_4 | Related disorders of Zellweger Spectrum Disorders | Symptoms of the following disorders can be similar to those of Zellweger spectrum disorders. Comparisons may be useful for a differential diagnosis. Rhizomelic chondrodysplasia punctata (RCDP) spectrum are a group of rare disorders that are also classified as peroxisomal biogenesis disorders. RCDP is characterized by shortening of the long bone of the arms (humerus) and legs (femur), a condition known as rhizomelia. Additional findings include distinctive facial features, the formation of small, hardened spots of calcium (stippling) on the knee cap (patella) and long bones of the arms and legs (chondrodysplasia punctata), cataracts that are present at birth or shortly thereafter, profound growth deficiency after birth, intellectual disability, and seizures. RCDP causes life-threatening complications during the first decade of life and in some cases during the newborn (neonatal) period. Milder forms of RCDP have been identified in which affected individuals have less severe intellectual deficits and growth deficiency and often no rhizomelia. Many of these disorders are caused by mutations in the PEX7 gene and are inherited in an autosomal recessive pattern. The leukodystrophies are a group of rare, progressive, metabolic, genetic disorders that can affect the brain, spinal cord and often the nerves outside the central nervous system (peripheral nerves). Each type of leukodystrophy is caused by an abnormality affecting a specific gene that results in abnormal development of one of at least 10 different chemicals that make up the white matter of the brain. The white matter is tissue composed of nerve fibers. Many of these nerve fibers are covered by a collection of fats (lipids) and proteins known as myelin. Myelin, which collectively may be referred to as the myelin sheath, protects the nerve fibers, acts as an insulator and increases the speed of transmission of nerve signals. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of different neurological problems. (For more information on this disorder, choose “leukodystrophy” as your search term in the Rare Disease Database.) Refsum disease is a metabolic disorder characterized by the build-up of a fat (lipid) called phytanic acid in blood plasma and tissues. Individuals with Refsum disease are usually normal at birth, but between the ages of 10 and 20 years old, symptoms begin to develop starting with loss of night vision (retinitis pigmentosa), and eventually including weakness in arms and legs, or unsteadiness (cerebellar ataxia). Other common symptoms include a loss of sense of smell (anosmia), and rough, scaly skin (ichthyosis) and after many years deafness. Treatment for Refsum disease is based on limiting the intake of foods high in phytanic acid. Our bodies cannot make phytanic acid; rather, it is found in foods such as dairy, beef, lamb, and some seafood. Refsum disease is caused by a change (mutation) in the gene that makes an enzyme responsible for breaking down phytanic acid, a particular type of fatty acid which is derived by bacterial fermentation of green plants or algae. The lack of function of the enzyme (phytanoyl-CoA hydroxylase) leads to a build-up of phytanic acid in blood plasma and tissues. The disorder is inherited in an autosomal recessive manner. (For more information on this disorder, choose “Refsum” as your search term in the Rare Disease Database.) X-linked adrenoleukodystrophy (ALD) is a rare genetic disorder that affects the white matter of the nervous system and the adrenal cortex. White matter is made up of nerve fibers called axons that relay nerve impulses from one cell to another. These nerve fibers are covered by myelin, an insulating layer or sheath that protects the nerve fibers. Myelin is made up of proteins and fats and gives white matter its white color. Without myelin, the signals between nerve cells cannot be transmitted properly, resulting in neurological symptoms. The adrenal cortex is the outer layer of cells of the adrenal glands. The adrenal glands sit atop the kidneys and produce hormones that are vital to proper health and development including cortisol and the sex hormones. Many of those affected experience serious neurological problems either during childhood or during adulthood with rather different types of disabilities. Some affected individuals also have adrenal insufficiency, which means that reduced amounts of certain hormones such as adrenaline and cortisol are produced, leading to abnormalities in blood pressure, heart rate, sexual development and reproduction. ALD is an X-linked recessive disorder that is caused by variations (mutations) in the ABCD1 gene. Because it is an X-linked disorder males develop more serious complications than females, while some females will have no symptoms. (For more information on this disorder, choose “adrenoleukodystrophy” as your search term in the Rare Disease Database.) A group of disorders may result from a deficiency of a single peroxisomal enzyme. These disorders include D-bifunctional protein deficiency and pseudo-neonatal adrenoleukodystrophy (acyl-CoA oxidase deficiency). The symptoms of single enzyme peroxisomal disorders vary greatly from one individual to another. Some affect infants have severe complications similar to Zellweger syndrome; others have milder symptoms that resemble neonatal adrenoleukodystrophy or infantile Refsum disease. | Related disorders of Zellweger Spectrum Disorders. Symptoms of the following disorders can be similar to those of Zellweger spectrum disorders. Comparisons may be useful for a differential diagnosis. Rhizomelic chondrodysplasia punctata (RCDP) spectrum are a group of rare disorders that are also classified as peroxisomal biogenesis disorders. RCDP is characterized by shortening of the long bone of the arms (humerus) and legs (femur), a condition known as rhizomelia. Additional findings include distinctive facial features, the formation of small, hardened spots of calcium (stippling) on the knee cap (patella) and long bones of the arms and legs (chondrodysplasia punctata), cataracts that are present at birth or shortly thereafter, profound growth deficiency after birth, intellectual disability, and seizures. RCDP causes life-threatening complications during the first decade of life and in some cases during the newborn (neonatal) period. Milder forms of RCDP have been identified in which affected individuals have less severe intellectual deficits and growth deficiency and often no rhizomelia. Many of these disorders are caused by mutations in the PEX7 gene and are inherited in an autosomal recessive pattern. The leukodystrophies are a group of rare, progressive, metabolic, genetic disorders that can affect the brain, spinal cord and often the nerves outside the central nervous system (peripheral nerves). Each type of leukodystrophy is caused by an abnormality affecting a specific gene that results in abnormal development of one of at least 10 different chemicals that make up the white matter of the brain. The white matter is tissue composed of nerve fibers. Many of these nerve fibers are covered by a collection of fats (lipids) and proteins known as myelin. Myelin, which collectively may be referred to as the myelin sheath, protects the nerve fibers, acts as an insulator and increases the speed of transmission of nerve signals. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of different neurological problems. (For more information on this disorder, choose “leukodystrophy” as your search term in the Rare Disease Database.) Refsum disease is a metabolic disorder characterized by the build-up of a fat (lipid) called phytanic acid in blood plasma and tissues. Individuals with Refsum disease are usually normal at birth, but between the ages of 10 and 20 years old, symptoms begin to develop starting with loss of night vision (retinitis pigmentosa), and eventually including weakness in arms and legs, or unsteadiness (cerebellar ataxia). Other common symptoms include a loss of sense of smell (anosmia), and rough, scaly skin (ichthyosis) and after many years deafness. Treatment for Refsum disease is based on limiting the intake of foods high in phytanic acid. Our bodies cannot make phytanic acid; rather, it is found in foods such as dairy, beef, lamb, and some seafood. Refsum disease is caused by a change (mutation) in the gene that makes an enzyme responsible for breaking down phytanic acid, a particular type of fatty acid which is derived by bacterial fermentation of green plants or algae. The lack of function of the enzyme (phytanoyl-CoA hydroxylase) leads to a build-up of phytanic acid in blood plasma and tissues. The disorder is inherited in an autosomal recessive manner. (For more information on this disorder, choose “Refsum” as your search term in the Rare Disease Database.) X-linked adrenoleukodystrophy (ALD) is a rare genetic disorder that affects the white matter of the nervous system and the adrenal cortex. White matter is made up of nerve fibers called axons that relay nerve impulses from one cell to another. These nerve fibers are covered by myelin, an insulating layer or sheath that protects the nerve fibers. Myelin is made up of proteins and fats and gives white matter its white color. Without myelin, the signals between nerve cells cannot be transmitted properly, resulting in neurological symptoms. The adrenal cortex is the outer layer of cells of the adrenal glands. The adrenal glands sit atop the kidneys and produce hormones that are vital to proper health and development including cortisol and the sex hormones. Many of those affected experience serious neurological problems either during childhood or during adulthood with rather different types of disabilities. Some affected individuals also have adrenal insufficiency, which means that reduced amounts of certain hormones such as adrenaline and cortisol are produced, leading to abnormalities in blood pressure, heart rate, sexual development and reproduction. ALD is an X-linked recessive disorder that is caused by variations (mutations) in the ABCD1 gene. Because it is an X-linked disorder males develop more serious complications than females, while some females will have no symptoms. (For more information on this disorder, choose “adrenoleukodystrophy” as your search term in the Rare Disease Database.) A group of disorders may result from a deficiency of a single peroxisomal enzyme. These disorders include D-bifunctional protein deficiency and pseudo-neonatal adrenoleukodystrophy (acyl-CoA oxidase deficiency). The symptoms of single enzyme peroxisomal disorders vary greatly from one individual to another. Some affect infants have severe complications similar to Zellweger syndrome; others have milder symptoms that resemble neonatal adrenoleukodystrophy or infantile Refsum disease. | 1,322 | Zellweger Spectrum Disorders |
nord_1322_5 | Diagnosis of Zellweger Spectrum Disorders | A ZSD diagnosis is suspected based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. ZSD can be diagnosed by showing peroxisome abnormalities that can be monitored in body fluids. The primary step in ZSD diagnosis involves the detection of elevated very long chain fatty acids. Additional tests on blood and urine samples to detect other substances associated with peroxisome metabolism may be performed. Biochemical testing of skin fibroblasts is useful to confirm the abnormalities seen in the blood and urine and clarify questionable results in body fluids. Genetic testing is available for ZSD. Next generation sequencing methods (sequencing millions of small fragments of DNA at the same time) are being used more frequently as a confirmatory test and may be required for peroxisome disorders that are difficult to determine by traditional biochemical methods. Additionally, genetic determination of mutations in ZSD, in contrast to biochemical tests, will also identify carriers for ZSD, which will allow reliable genetic counseling of families and may also assist with eligibility for future clinical trials. Methods have been developed to detect elevated levels of very long chain fatty acids in newborn screening for X-linked adrenoleukodystrophy, a related peroxisomal disorder. Newborn screening for X-linked adrenoleukodystrophy should increase early diagnosis of ZSD and determination of accurate incidence estimates of the disease. In 2016, the Department of Health and Human Services Advisory Committee for Heritable Disorders for Newborns and Children voted to propose the addition of X-linked adrenoleukodystrophy screening in the Recommend Uniform Screening Panel. Legislation for X-linked adrenoleukodystrophy newborn screening has been passed and initiated in 21 states; continued legislative efforts are expected to expand through movements initiated by patient families and advocacy organizations to lobby their state legislatures. Certain tests (biochemical or genetic) can be performed prenatally in the first or second trimester using chorionic villus sampling or amniocentesis. Ultrasonography, a test that uses reflected sound waves to create a picture of internal organs, may be used to detect cysts on the kidneys or an enlarged liver. Preimplantation genetic diagnosis with in vitro fertilization can also be performed when the gene mutations are known. | Diagnosis of Zellweger Spectrum Disorders. A ZSD diagnosis is suspected based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. ZSD can be diagnosed by showing peroxisome abnormalities that can be monitored in body fluids. The primary step in ZSD diagnosis involves the detection of elevated very long chain fatty acids. Additional tests on blood and urine samples to detect other substances associated with peroxisome metabolism may be performed. Biochemical testing of skin fibroblasts is useful to confirm the abnormalities seen in the blood and urine and clarify questionable results in body fluids. Genetic testing is available for ZSD. Next generation sequencing methods (sequencing millions of small fragments of DNA at the same time) are being used more frequently as a confirmatory test and may be required for peroxisome disorders that are difficult to determine by traditional biochemical methods. Additionally, genetic determination of mutations in ZSD, in contrast to biochemical tests, will also identify carriers for ZSD, which will allow reliable genetic counseling of families and may also assist with eligibility for future clinical trials. Methods have been developed to detect elevated levels of very long chain fatty acids in newborn screening for X-linked adrenoleukodystrophy, a related peroxisomal disorder. Newborn screening for X-linked adrenoleukodystrophy should increase early diagnosis of ZSD and determination of accurate incidence estimates of the disease. In 2016, the Department of Health and Human Services Advisory Committee for Heritable Disorders for Newborns and Children voted to propose the addition of X-linked adrenoleukodystrophy screening in the Recommend Uniform Screening Panel. Legislation for X-linked adrenoleukodystrophy newborn screening has been passed and initiated in 21 states; continued legislative efforts are expected to expand through movements initiated by patient families and advocacy organizations to lobby their state legislatures. Certain tests (biochemical or genetic) can be performed prenatally in the first or second trimester using chorionic villus sampling or amniocentesis. Ultrasonography, a test that uses reflected sound waves to create a picture of internal organs, may be used to detect cysts on the kidneys or an enlarged liver. Preimplantation genetic diagnosis with in vitro fertilization can also be performed when the gene mutations are known. | 1,322 | Zellweger Spectrum Disorders |
nord_1322_6 | Therapies of Zellweger Spectrum Disorders | Treatment
In 2015, Cholbam (cholic acid) was approved as the first treatment for pediatric and adult patients with bile acid synthesis disorders due to single enzyme defects and for patients with peroxisomal disorders (including ZSD). https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-cholbam-peroxisomal-disorders Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, endocrinologists, surgeons, specialists who assess and treat hearing problems (audiologists), specialists who assess and treat vision problems (ophthalmologists), specialists who assess and treat skeletal disorders (orthopedists) and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Children with ZSD may require a feeding (gastrostomy) tube to ensure proper intake of calories. A gastrostomy tube is inserted directly into the stomach. Additional therapies that may be used to treat ZSD include hearing aids, cochlear implants, fat-soluble vitamin supplementation (particularly vitamin K to treat bleeding complications due to clotting defects), surgery to treat cataracts, and glasses to improve vision. Anti-epileptic drugs may be used to treat seizures, but seizures may persist and be difficult to control despite such therapy. Adrenal insufficiency occurs frequently in more intermediate forms of ZSD. It is recommended that yearly adrenal monitoring with adrenocorticotropic hormone (ACTH) and morning cortisol be performed. Treatment with adrenal replacement (Cortef) using standard dosing should be implemented if abnormal. Even if adrenal measurements appear normal, families and clinicians should be aware of the possibility of adrenal insufficiency and consider stress dosing in periods of sudden severe illness, fever, and major surgical procedures. Progressive decreased bone mineral density has been associated with ZSD and pathologic fractures have occurred in patients. Therefore, evaluation for bone disease should be considered. Additionally, many children with ZSD have enamel abnormalities of permanent teeth and should receive appropriate dental care. Early intervention is important in treating children with ZSD. Services that may be beneficial may include special education, physical and orthopedic therapy, special services for children with deaf-blindness, and other medical, social, and/or vocational services. Other treatment is symptomatic and supportive. Genetic counseling is recommended for families of affected individuals. | Therapies of Zellweger Spectrum Disorders. Treatment
In 2015, Cholbam (cholic acid) was approved as the first treatment for pediatric and adult patients with bile acid synthesis disorders due to single enzyme defects and for patients with peroxisomal disorders (including ZSD). https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-cholbam-peroxisomal-disorders Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, endocrinologists, surgeons, specialists who assess and treat hearing problems (audiologists), specialists who assess and treat vision problems (ophthalmologists), specialists who assess and treat skeletal disorders (orthopedists) and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Children with ZSD may require a feeding (gastrostomy) tube to ensure proper intake of calories. A gastrostomy tube is inserted directly into the stomach. Additional therapies that may be used to treat ZSD include hearing aids, cochlear implants, fat-soluble vitamin supplementation (particularly vitamin K to treat bleeding complications due to clotting defects), surgery to treat cataracts, and glasses to improve vision. Anti-epileptic drugs may be used to treat seizures, but seizures may persist and be difficult to control despite such therapy. Adrenal insufficiency occurs frequently in more intermediate forms of ZSD. It is recommended that yearly adrenal monitoring with adrenocorticotropic hormone (ACTH) and morning cortisol be performed. Treatment with adrenal replacement (Cortef) using standard dosing should be implemented if abnormal. Even if adrenal measurements appear normal, families and clinicians should be aware of the possibility of adrenal insufficiency and consider stress dosing in periods of sudden severe illness, fever, and major surgical procedures. Progressive decreased bone mineral density has been associated with ZSD and pathologic fractures have occurred in patients. Therefore, evaluation for bone disease should be considered. Additionally, many children with ZSD have enamel abnormalities of permanent teeth and should receive appropriate dental care. Early intervention is important in treating children with ZSD. Services that may be beneficial may include special education, physical and orthopedic therapy, special services for children with deaf-blindness, and other medical, social, and/or vocational services. Other treatment is symptomatic and supportive. Genetic counseling is recommended for families of affected individuals. | 1,322 | Zellweger Spectrum Disorders |
nord_1323_0 | Overview of Zollinger-Ellison Syndrome | Zollinger-Ellison syndrome (ZES) is characterized by the development of a tumor (gastrinoma) or tumors that secrete excessive levels of gastrin, a hormone that stimulates production of acid by the stomach. Many affected individuals develop multiple gastrinomas, which are thought to have the potential to be cancerous (malignant). In most patients, the tumors arise within the pancreas and/or the upper region of the small intestine (duodenum). Due to excessive acid production (gastric acid hypersecretion), individuals with ZES may develop peptic ulcers of the stomach, the duodenum, and/or other regions of the digestive tract. Peptic ulcers are sores or raw areas within the digestive tract where the lining has been eroded by stomach acid and digestive juices. Symptoms and findings associated with ZES may include mild to severe abdominal pain; diarrhea; increased amounts of fat in the stools (steatorrhea); and/or other abnormalities. In most affected individuals, ZES appears to develop randomly (sporadically) for unknown reasons. In approximately 25 percent of patients, ZES occurs in association with a genetic syndrome known as multiple endocrine neoplasia type 1 (MEN-1). All of the tumors are considered to have malignant potential. Prognosis is related to tumor size and the presence of distant metastases. | Overview of Zollinger-Ellison Syndrome. Zollinger-Ellison syndrome (ZES) is characterized by the development of a tumor (gastrinoma) or tumors that secrete excessive levels of gastrin, a hormone that stimulates production of acid by the stomach. Many affected individuals develop multiple gastrinomas, which are thought to have the potential to be cancerous (malignant). In most patients, the tumors arise within the pancreas and/or the upper region of the small intestine (duodenum). Due to excessive acid production (gastric acid hypersecretion), individuals with ZES may develop peptic ulcers of the stomach, the duodenum, and/or other regions of the digestive tract. Peptic ulcers are sores or raw areas within the digestive tract where the lining has been eroded by stomach acid and digestive juices. Symptoms and findings associated with ZES may include mild to severe abdominal pain; diarrhea; increased amounts of fat in the stools (steatorrhea); and/or other abnormalities. In most affected individuals, ZES appears to develop randomly (sporadically) for unknown reasons. In approximately 25 percent of patients, ZES occurs in association with a genetic syndrome known as multiple endocrine neoplasia type 1 (MEN-1). All of the tumors are considered to have malignant potential. Prognosis is related to tumor size and the presence of distant metastases. | 1,323 | Zollinger-Ellison Syndrome |
nord_1323_1 | Symptoms of Zollinger-Ellison Syndrome | ZES is characterized by abnormally increased acid production (gastric hypersecretion), excessively high levels of gastrin in the blood (hypergastrinemia), and ulceration of the stomach or the upper region of the small intestine (duodenum) due to gastrin-producing tumors (gastrinomas). In most patients, gastrinomas arise within the wall of the duodenum or within the pancreas. The pancreas is a gland that functions as part of the digestive and endocrine systems. Certain pancreatic cells (exocrine cells) secrete digestive juice into ducts, while clusters of other pancreatic cells (pancreatic endocrine cells known as “islet cells”) secrete certain hormones directly into the bloodstream.The gastrinomas associated with ZES are considered to have malignant potential. Evidence suggests that these malignancies are usually slow growing, although a small percentage may be rapidly invasive. The malignancies most commonly spread to regional lymph nodes and the liver. Malignant tumor growth and metastatic disease may result in potentially life-threatening complications.In individuals with ZES, excessive acid secretion may erode the lining of the stomach, duodenum, or other regions of the digestive tract (peptic ulcers). Most affected individuals have single or, less commonly, multiple ulcers of the stomach or the upper region of the duodenum. In those with multiple ulcers, ulceration may extend to the lower duodenum or the middle region of the small intestine (jejunum). Particularly during early disease, ulcer symptoms associated with ZES are often similar to those seen in others with peptic ulcers from other causes. Such symptoms may include a “gnawing” or burning pain in the abdominal area, inflammation of the esophagus (esophagitis), appetite changes, nausea, vomiting, weight loss, and/or other abnormalities.However, in some patients, symptoms associated with peptic ulcers may be more severe, persistent, and progressive and may be associated with potentially life-threatening complications, such as bleeding, perforation, or intestinal obstruction. Bleeding from peptic ulcers may result in vomiting of blood and/or the passage of blood in the stools. In some patients, ulcers may penetrate the wall of the digestive tract, creating an abnormal opening (perforation) into the abdominal cavity. Associated symptoms may include severe, persistent, piercing pain in the abdominal area; inflammation of the abdominal lining (peritonitis); and/or other symptoms and findings. In addition, inflammation and scarring from chronic ulceration may narrow the outlet from the stomach to the duodenum (pyloric stenosis), causing obstruction, a feeling of early fullness, lack of appetite, pain, vomiting, and/or other associated abnormalities. Such complications are considered medical emergencies that require immediate treatment.In some individuals with ZES, diarrhea may be the initial symptom. Excessive acid levels within the digestive tract may also cause increased amounts of fat in the stools (steatorrhea). | Symptoms of Zollinger-Ellison Syndrome. ZES is characterized by abnormally increased acid production (gastric hypersecretion), excessively high levels of gastrin in the blood (hypergastrinemia), and ulceration of the stomach or the upper region of the small intestine (duodenum) due to gastrin-producing tumors (gastrinomas). In most patients, gastrinomas arise within the wall of the duodenum or within the pancreas. The pancreas is a gland that functions as part of the digestive and endocrine systems. Certain pancreatic cells (exocrine cells) secrete digestive juice into ducts, while clusters of other pancreatic cells (pancreatic endocrine cells known as “islet cells”) secrete certain hormones directly into the bloodstream.The gastrinomas associated with ZES are considered to have malignant potential. Evidence suggests that these malignancies are usually slow growing, although a small percentage may be rapidly invasive. The malignancies most commonly spread to regional lymph nodes and the liver. Malignant tumor growth and metastatic disease may result in potentially life-threatening complications.In individuals with ZES, excessive acid secretion may erode the lining of the stomach, duodenum, or other regions of the digestive tract (peptic ulcers). Most affected individuals have single or, less commonly, multiple ulcers of the stomach or the upper region of the duodenum. In those with multiple ulcers, ulceration may extend to the lower duodenum or the middle region of the small intestine (jejunum). Particularly during early disease, ulcer symptoms associated with ZES are often similar to those seen in others with peptic ulcers from other causes. Such symptoms may include a “gnawing” or burning pain in the abdominal area, inflammation of the esophagus (esophagitis), appetite changes, nausea, vomiting, weight loss, and/or other abnormalities.However, in some patients, symptoms associated with peptic ulcers may be more severe, persistent, and progressive and may be associated with potentially life-threatening complications, such as bleeding, perforation, or intestinal obstruction. Bleeding from peptic ulcers may result in vomiting of blood and/or the passage of blood in the stools. In some patients, ulcers may penetrate the wall of the digestive tract, creating an abnormal opening (perforation) into the abdominal cavity. Associated symptoms may include severe, persistent, piercing pain in the abdominal area; inflammation of the abdominal lining (peritonitis); and/or other symptoms and findings. In addition, inflammation and scarring from chronic ulceration may narrow the outlet from the stomach to the duodenum (pyloric stenosis), causing obstruction, a feeling of early fullness, lack of appetite, pain, vomiting, and/or other associated abnormalities. Such complications are considered medical emergencies that require immediate treatment.In some individuals with ZES, diarrhea may be the initial symptom. Excessive acid levels within the digestive tract may also cause increased amounts of fat in the stools (steatorrhea). | 1,323 | Zollinger-Ellison Syndrome |
nord_1323_2 | Causes of Zollinger-Ellison Syndrome | In most individuals with ZES, the condition appears to occur spontaneously for unknown reasons (sporadically). However, in approximately 25 percent of affected individuals, ZES occurs in association with the genetic syndrome known as multiple endocrine neoplasia type 1 (MEN-1). In most patients, MEN-1 is inherited as an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. Most individuals with a disease gene for MEN-1 will develop symptoms and findings associated with the disorder (high penetrance). However, the characteristics that are manifested may vary greatly in range and severity from case to case (variable expressivity).MEN-1 is caused by changes (mutations) in the MEN1 gene. The MEN1 gene regulates production of a protein (termed “menin”) that appears to play some role in preventing tumor development (tumor suppressor). (For more information on MEN-1, please see the “Related Disorders” section of this report below.) | Causes of Zollinger-Ellison Syndrome. In most individuals with ZES, the condition appears to occur spontaneously for unknown reasons (sporadically). However, in approximately 25 percent of affected individuals, ZES occurs in association with the genetic syndrome known as multiple endocrine neoplasia type 1 (MEN-1). In most patients, MEN-1 is inherited as an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. Most individuals with a disease gene for MEN-1 will develop symptoms and findings associated with the disorder (high penetrance). However, the characteristics that are manifested may vary greatly in range and severity from case to case (variable expressivity).MEN-1 is caused by changes (mutations) in the MEN1 gene. The MEN1 gene regulates production of a protein (termed “menin”) that appears to play some role in preventing tumor development (tumor suppressor). (For more information on MEN-1, please see the “Related Disorders” section of this report below.) | 1,323 | Zollinger-Ellison Syndrome |
nord_1323_3 | Affects of Zollinger-Ellison Syndrome | ZES may become apparent at any age. However, symptom onset usually occurs between ages 30 and 60 years. The exact frequency of ZES in the general population is unknown. However, some researchers estimate that ZES represents less than one percent of peptic ulcers. | Affects of Zollinger-Ellison Syndrome. ZES may become apparent at any age. However, symptom onset usually occurs between ages 30 and 60 years. The exact frequency of ZES in the general population is unknown. However, some researchers estimate that ZES represents less than one percent of peptic ulcers. | 1,323 | Zollinger-Ellison Syndrome |
nord_1323_4 | Related disorders of Zollinger-Ellison Syndrome | As discussed above, Zollinger-Ellison syndrome may occur as a component of the following disorder:Multiple endocrine neoplasia type 1 (MEN-1) is a genetic disorder in which tumors may arise from cells of various endocrine glands, such as the parathyroid glands, the pancreas, and the pituitary gland. Individuals with ZES in association with MEN-1 may tend to develop symptoms at an earlier age than those with sporadic ZES. Most individuals with MEN-1 develop hyperparathyroidism or excessive secretion of parathyroid hormone, resulting in increased calcium blood levels. Associated symptoms may include kidneys tones, bone abnormalities and/or other findings. Some individuals with MEN-1 develop tumors that arise within the duodenum or the pancreas causing excessive gastrin secretion and associated ZES. Some patients develop other tumors within the pancreas, in islet cells that secrete the hormone insulin (insulinomas), a hormone that helps to regulate levels of the sugar glucose in the blood. In individuals with insulinomas, excessive insulin secretion leads to abnormally diminished blood glucose levels (hypoglycemia). Some individuals with MEN-1 may also develop tumors of the pituitary, potentially leading to excessive production of certain pituitary hormones. Associated symptoms and findings may vary, depending upon whether the tumors secrete such hormones and which hormone is involved. Some individuals with MEN-1 may also develop tumors affecting other tissues or organs. (For more information on MEN-1, search for this term in the Rare Disease Database.) | Related disorders of Zollinger-Ellison Syndrome. As discussed above, Zollinger-Ellison syndrome may occur as a component of the following disorder:Multiple endocrine neoplasia type 1 (MEN-1) is a genetic disorder in which tumors may arise from cells of various endocrine glands, such as the parathyroid glands, the pancreas, and the pituitary gland. Individuals with ZES in association with MEN-1 may tend to develop symptoms at an earlier age than those with sporadic ZES. Most individuals with MEN-1 develop hyperparathyroidism or excessive secretion of parathyroid hormone, resulting in increased calcium blood levels. Associated symptoms may include kidneys tones, bone abnormalities and/or other findings. Some individuals with MEN-1 develop tumors that arise within the duodenum or the pancreas causing excessive gastrin secretion and associated ZES. Some patients develop other tumors within the pancreas, in islet cells that secrete the hormone insulin (insulinomas), a hormone that helps to regulate levels of the sugar glucose in the blood. In individuals with insulinomas, excessive insulin secretion leads to abnormally diminished blood glucose levels (hypoglycemia). Some individuals with MEN-1 may also develop tumors of the pituitary, potentially leading to excessive production of certain pituitary hormones. Associated symptoms and findings may vary, depending upon whether the tumors secrete such hormones and which hormone is involved. Some individuals with MEN-1 may also develop tumors affecting other tissues or organs. (For more information on MEN-1, search for this term in the Rare Disease Database.) | 1,323 | Zollinger-Ellison Syndrome |
nord_1323_5 | Diagnosis of Zollinger-Ellison Syndrome | The diagnosis of ZES is based upon a thorough clinical evaluation, a detailed patient history, and specialized tests, including certain laboratory studies and advanced imaging techniques. ZES may be suggested by various factors, including the development of frequent or multiple peptic ulcers that are resistant to certain standard ulcer treatments and/or that occur in unusual sites (e.g., the jejunum).In individuals with suspected ZES, diagnostic studies may include blood testing to detect increased gastrin levels and evaluation of samples of gastric juice to detect increased acid levels. In some patients, additional laboratory tests may also be conducted to help confirm ZES. Such tests may include measuring levels of gastrin within the fluid portion of the blood (serum) before and after intravenous infusion of calcium; injection of the digestive hormone secretin, or feeding of a standard meal. Additional laboratory studies may also be conducted to help confirm or rule out MEN-1.The U.S. Food and Drug Administration (FDA) has approved the use of synthetic porcine secretin for use in the diagnosis of gastrinoma associated with ZES. This biological is manufactured by ChiRhoClin, Inc. | Diagnosis of Zollinger-Ellison Syndrome. The diagnosis of ZES is based upon a thorough clinical evaluation, a detailed patient history, and specialized tests, including certain laboratory studies and advanced imaging techniques. ZES may be suggested by various factors, including the development of frequent or multiple peptic ulcers that are resistant to certain standard ulcer treatments and/or that occur in unusual sites (e.g., the jejunum).In individuals with suspected ZES, diagnostic studies may include blood testing to detect increased gastrin levels and evaluation of samples of gastric juice to detect increased acid levels. In some patients, additional laboratory tests may also be conducted to help confirm ZES. Such tests may include measuring levels of gastrin within the fluid portion of the blood (serum) before and after intravenous infusion of calcium; injection of the digestive hormone secretin, or feeding of a standard meal. Additional laboratory studies may also be conducted to help confirm or rule out MEN-1.The U.S. Food and Drug Administration (FDA) has approved the use of synthetic porcine secretin for use in the diagnosis of gastrinoma associated with ZES. This biological is manufactured by ChiRhoClin, Inc. | 1,323 | Zollinger-Ellison Syndrome |
nord_1323_6 | Therapies of Zollinger-Ellison Syndrome | Surgical Therapy
When possible (e.g., if there is no evidence of metastasis of a single tumor), complete surgical removal of the gastrinoma may be considered the optimal treatment for ZES. Evidence suggests that complete and curative removal of gastrinoma is possible in approximately 20 to 30 percent of individuals with ZES. Various advanced imaging techniques may be used before surgery to help localize and characterize the gastrinoma and exclude metastatic disease (e.g., endoscopic ultrasound, nuclear medicine studies, abdominal ultrasounds, computerized tomography [CT] scanning, abdominal angiography). Recent advances in imaging have led to 68G Ga-Dotatate PET CT replacing somatostatin scintigraphy for localization of neuroendocrine tumors including those causing ZES. This test has a high sensitivity and specificity. Gastrinomas are slow growing and hence 18F-FDG PET/CT is not commonly used for initial evaluation. Due to slow metabolic activity of gastrinoma in initial stages, they are not typically avid on 18F-FDG PET/CT. In contrast to FDG PET/CT, 68Ga-Dotatate PET demonstrates a high uptake because neuroendocrine tumors express significant numbers of somatostatin 2 receptors. In addition, in some patients, certain imaging techniques (e.g., intraoperative endoscopic transillumination or ultrasound) may be used during surgical exploration to aid in the localization and possible removal of tumors. Recent studies have shown that intraoperative localization may be facilitated by the intravenous administration of indocyanine- green (ICG) 0.1 mg/kg and within one minute of injection examination of the pancreas and duodenum with near infrared fluorescence visualization.Surgery is the only treatment shown to potentially cure gastrinoma. Biochemical cure of sporadic gastrinoma is reported in 30% to 50% of patients. However, recurrence has been documented in nearly one-third of patients. The average time to recurrence is 5 to 10 years. Regardless of achieving biochemical cure, complete resection of all tumors is associated with improved survival. The 10-year disease-specific survival in patients having complete resection of sporadic gastrinoma is 85% compared to 40% for patients having incomplete resection and 25% for those having no resection.In some studies, MEN-1 patients operated upon with a curative intent, cure was achieved in only 6% of patients. However, the 10-year survival with gastrinoma in MEN-1 with complete resection was 90%, compared with only 45% for patients having an R2 resection or no resection. As incomplete resections do not increase survival, MEN -1 patient with extensive metastatic disease or loco-regional spread that precludes complete resection receive little benefit from surgical resection and these patients are typically not offered surgery.Pancreatic gastrinoma survival fairs well when compared to other pancreatic neuroendocrine tumors (PNETs). It has been reported that between histologic subtypes, there were significant differences in sex and age, and in tumor size, grade, location, and stage. Median survival time for insulinomas was 12.7 years; gastrinomas, 10.2 years; glucagonomas, 7.7 years; VIPomas, 7.9 years; and mixed tumors, 3.4 years. Multivariate analysis has shown that histology (insulinoma, gastrinoma, and VIPoma; p = .009), absence of distant metastases (p = .002), age < 50 years (p = .001), surgical intervention (p = .001), and stage I/II disease (p = .011) were associated with prolonged survival.
Rarely, in severe cases in which other therapy is ineffective, surgical removal of the stomach (gastrectomy) may be considered.
MedicationsInitial treatment commonly includes the use of certain medications called proton pump inhibitors, such as omeprazole. Such medications may reduce stomach acid production, relieve symptoms, and promote ulcer healing. In some patients, another type of acid-suppressing medication called H2 blockers may also be used, such as cimetidine or ranitidine.In 2006, the FDA approved AstraZeneca’s proton pump inhibitor Nexium for management of acid hypersecretion in patients with ZES. The FDA approved a proton pump inhibitor called Protonix (pantoprazole sodium), in the form of delayed-release tablets, for the long-term treatment of individuals with ZES. Protonix is marketed in the United States by Wyeth Pharmaceuticals.Due to the effectiveness of the medications discussed above, serious complications associated with ulcers may often be prevented. However, some affected individuals may remain undiagnosed until developing such complications (e.g., perforation or obstruction). These complications are considered medical emergencies that require immediate treatment, potentially including surgery.In some affected individuals with aggressively invasive gastrinoma, recommended treatment may include the use of certain anticancer drugs (chemotherapy) to help reduce tumor mass and blood gastrin levels.Management of Metastatic Disease
Patients with malignant gastrinoma of the pancreas and duodenum not infrequently present with liver metastases. In these situations, it is essential for the surgeon to work collaboratively with a multidisciplinary team. Liver directed therapy for patients with unresectable liver only or liver-dominant metastases, who present with symptomatic disease is beneficial for those with >25% liver burden. Transarterial chemoembolization (TACE), radionuclide-laden spheres (Yittrium-90) or local ablative therapy (radiofrequency or microwave ablation) are effective liver directed therapies. These modalities will not cure the patient, but they may provide effective cytoreduction of liver metastases, alleviate symptoms attributable to metastatic disease, and possibly extend survival. However, these treatments have not been compared to one another or to best supportive care. Hence, these patients are best served in the context of a multidisciplinary team and perhaps in the framework of a clinical trial.Systemic Treatments/Cytotoxic Chemotherapy
Trials using chemotherapeutic drugs including doxorubicin, streptozocin, 5-fluorouracil (5-FU), temozolomide, and dacarbazine have established cytotoxic effects in PNETs. There have been limited numbers of patients with gastrinoma treated in these trials. Capecitabine and temozolomide have been shown to have a high and durable response in PNETs in a small study with 70% of patients demonstrating a radiographic response with median progression free survival of 18 months. Given this radiographic response this regimen has also been reported in the neoadjuvant setting. Response rates specific to gastrinoma have not been reported. Targeted Therapy
Everolimus and sunitinib are both FDA approved treatments for advanced pancreatic neuroendocrine tumors. A randomized controlled trial of everolimus, an oral inhibitor of mammalian target of rapamycin (mTor) showed an increase in progression free survival from 4.6 months to 11.0 months. Sunitinib, a multi-targeted tyrosine kinase inhibitor has also been shown to increase progression free survival to 11.4 months from 5.5 months and increase in overall survival in patients with metastatic unresectable disease.Somatostatin Analogues
Both octreotide and l long acting octreotide (LAR) have been shown to prolong progression free survival however overall survival has not been significantly increased. These drugs are thought to stabilize tumor growth in addition to relieving symptoms associated with functional tumors. Peptide receptor radionuclide therapy (PRRT) was approved by the FDA for treatment of neuroendocrine tumors in 2017. PRRT is a molecular therapy that uses octreotide combined with a small amount of radioactive material creating a radiopeptide. This is then injected into the bloodstream. The NETTER-1 study, a large phase III randomized clinical trial showed lutetium 177 (177Lu) dotatate improved progression free survival a median of 33 months when compared with LAR. Genetic counseling is recommended for individuals with ZES and their families. | Therapies of Zollinger-Ellison Syndrome. Surgical Therapy
When possible (e.g., if there is no evidence of metastasis of a single tumor), complete surgical removal of the gastrinoma may be considered the optimal treatment for ZES. Evidence suggests that complete and curative removal of gastrinoma is possible in approximately 20 to 30 percent of individuals with ZES. Various advanced imaging techniques may be used before surgery to help localize and characterize the gastrinoma and exclude metastatic disease (e.g., endoscopic ultrasound, nuclear medicine studies, abdominal ultrasounds, computerized tomography [CT] scanning, abdominal angiography). Recent advances in imaging have led to 68G Ga-Dotatate PET CT replacing somatostatin scintigraphy for localization of neuroendocrine tumors including those causing ZES. This test has a high sensitivity and specificity. Gastrinomas are slow growing and hence 18F-FDG PET/CT is not commonly used for initial evaluation. Due to slow metabolic activity of gastrinoma in initial stages, they are not typically avid on 18F-FDG PET/CT. In contrast to FDG PET/CT, 68Ga-Dotatate PET demonstrates a high uptake because neuroendocrine tumors express significant numbers of somatostatin 2 receptors. In addition, in some patients, certain imaging techniques (e.g., intraoperative endoscopic transillumination or ultrasound) may be used during surgical exploration to aid in the localization and possible removal of tumors. Recent studies have shown that intraoperative localization may be facilitated by the intravenous administration of indocyanine- green (ICG) 0.1 mg/kg and within one minute of injection examination of the pancreas and duodenum with near infrared fluorescence visualization.Surgery is the only treatment shown to potentially cure gastrinoma. Biochemical cure of sporadic gastrinoma is reported in 30% to 50% of patients. However, recurrence has been documented in nearly one-third of patients. The average time to recurrence is 5 to 10 years. Regardless of achieving biochemical cure, complete resection of all tumors is associated with improved survival. The 10-year disease-specific survival in patients having complete resection of sporadic gastrinoma is 85% compared to 40% for patients having incomplete resection and 25% for those having no resection.In some studies, MEN-1 patients operated upon with a curative intent, cure was achieved in only 6% of patients. However, the 10-year survival with gastrinoma in MEN-1 with complete resection was 90%, compared with only 45% for patients having an R2 resection or no resection. As incomplete resections do not increase survival, MEN -1 patient with extensive metastatic disease or loco-regional spread that precludes complete resection receive little benefit from surgical resection and these patients are typically not offered surgery.Pancreatic gastrinoma survival fairs well when compared to other pancreatic neuroendocrine tumors (PNETs). It has been reported that between histologic subtypes, there were significant differences in sex and age, and in tumor size, grade, location, and stage. Median survival time for insulinomas was 12.7 years; gastrinomas, 10.2 years; glucagonomas, 7.7 years; VIPomas, 7.9 years; and mixed tumors, 3.4 years. Multivariate analysis has shown that histology (insulinoma, gastrinoma, and VIPoma; p = .009), absence of distant metastases (p = .002), age < 50 years (p = .001), surgical intervention (p = .001), and stage I/II disease (p = .011) were associated with prolonged survival.
Rarely, in severe cases in which other therapy is ineffective, surgical removal of the stomach (gastrectomy) may be considered.
MedicationsInitial treatment commonly includes the use of certain medications called proton pump inhibitors, such as omeprazole. Such medications may reduce stomach acid production, relieve symptoms, and promote ulcer healing. In some patients, another type of acid-suppressing medication called H2 blockers may also be used, such as cimetidine or ranitidine.In 2006, the FDA approved AstraZeneca’s proton pump inhibitor Nexium for management of acid hypersecretion in patients with ZES. The FDA approved a proton pump inhibitor called Protonix (pantoprazole sodium), in the form of delayed-release tablets, for the long-term treatment of individuals with ZES. Protonix is marketed in the United States by Wyeth Pharmaceuticals.Due to the effectiveness of the medications discussed above, serious complications associated with ulcers may often be prevented. However, some affected individuals may remain undiagnosed until developing such complications (e.g., perforation or obstruction). These complications are considered medical emergencies that require immediate treatment, potentially including surgery.In some affected individuals with aggressively invasive gastrinoma, recommended treatment may include the use of certain anticancer drugs (chemotherapy) to help reduce tumor mass and blood gastrin levels.Management of Metastatic Disease
Patients with malignant gastrinoma of the pancreas and duodenum not infrequently present with liver metastases. In these situations, it is essential for the surgeon to work collaboratively with a multidisciplinary team. Liver directed therapy for patients with unresectable liver only or liver-dominant metastases, who present with symptomatic disease is beneficial for those with >25% liver burden. Transarterial chemoembolization (TACE), radionuclide-laden spheres (Yittrium-90) or local ablative therapy (radiofrequency or microwave ablation) are effective liver directed therapies. These modalities will not cure the patient, but they may provide effective cytoreduction of liver metastases, alleviate symptoms attributable to metastatic disease, and possibly extend survival. However, these treatments have not been compared to one another or to best supportive care. Hence, these patients are best served in the context of a multidisciplinary team and perhaps in the framework of a clinical trial.Systemic Treatments/Cytotoxic Chemotherapy
Trials using chemotherapeutic drugs including doxorubicin, streptozocin, 5-fluorouracil (5-FU), temozolomide, and dacarbazine have established cytotoxic effects in PNETs. There have been limited numbers of patients with gastrinoma treated in these trials. Capecitabine and temozolomide have been shown to have a high and durable response in PNETs in a small study with 70% of patients demonstrating a radiographic response with median progression free survival of 18 months. Given this radiographic response this regimen has also been reported in the neoadjuvant setting. Response rates specific to gastrinoma have not been reported. Targeted Therapy
Everolimus and sunitinib are both FDA approved treatments for advanced pancreatic neuroendocrine tumors. A randomized controlled trial of everolimus, an oral inhibitor of mammalian target of rapamycin (mTor) showed an increase in progression free survival from 4.6 months to 11.0 months. Sunitinib, a multi-targeted tyrosine kinase inhibitor has also been shown to increase progression free survival to 11.4 months from 5.5 months and increase in overall survival in patients with metastatic unresectable disease.Somatostatin Analogues
Both octreotide and l long acting octreotide (LAR) have been shown to prolong progression free survival however overall survival has not been significantly increased. These drugs are thought to stabilize tumor growth in addition to relieving symptoms associated with functional tumors. Peptide receptor radionuclide therapy (PRRT) was approved by the FDA for treatment of neuroendocrine tumors in 2017. PRRT is a molecular therapy that uses octreotide combined with a small amount of radioactive material creating a radiopeptide. This is then injected into the bloodstream. The NETTER-1 study, a large phase III randomized clinical trial showed lutetium 177 (177Lu) dotatate improved progression free survival a median of 33 months when compared with LAR. Genetic counseling is recommended for individuals with ZES and their families. | 1,323 | Zollinger-Ellison Syndrome |
Subsets and Splits
No saved queries yet
Save your SQL queries to embed, download, and access them later. Queries will appear here once saved.