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Related disorders of Trichorhinophalangeal Syndrome Type III
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Symptoms of the following disorders can be similar to those of Trichorhinophalangeal Syndrome Type III (TRPS3). Comparisons may be useful for a differential diagnosis:Trichorhinophalangeal Syndrome Type I (TRPS1) is an extremely rare inherited multisystem disorder characterized with symptoms and physical features similar to those associated with TRPS3. These may include fine, thin hair; a rounded (bulbous) “pear-shaped” nose; dental anomalies; multiple abnormalities of the “growing ends” (epiphyses) of bones, particularly in the hands and feet; abnormally short (brachydactyly) and curved fingers and toes; and/or short stature (dwarfism). In most cases, the shortening of the fingers and toes in individuals with TRPS1 is typically much less severe than in individuals with TRPS3. Trichorhinophalangeal Syndrome Type I has autosomal dominant inheritance. (For more information on this disorder, choose “Trichorhinophalangeal Syndrome Type I” as your search term in the Rare Disease Database.)Trichorhinophalangeal Syndrome Type II (TRPS2), also known as Langer-Giedion Syndrome, is an extremely rare inherited disorder with symptoms and physical features similar to those associated with TRPS1 and TRPS3. These may include thin, sparse scalp hair; a rounded (bulbous) nose; a long, prominent groove (philtrum) of the upper lip; abnormally short fingers and toes (brachydactyly); and/or short stature. The shortening of the fingers and toes in individuals with TRPS2 is typically less severe than in individuals with TRPS3. In addition, an infant with Trichorhinophalangeal Syndrome Type II may also exhibit other abnormalities not associated with TRPS3 such as an unusually small head (microcephaly), excess (redundant) skin, multiple bony growths projecting from the surface of various bones of the body (exostoses), and/or mental retardation. Most cases of Trichorhinophalangeal Syndrome Type II occur randomly (sporadically) as the result of missing genetic material (deletions) on chromosome 8. A few individuals with TRPS II have had children, but the chromosome deletion may be inherited in an autosomal dominant manner. (For more information on this disorder, choose “Trichorhinophalangeal Syndrome Type II” as your search term in the Rare Disease Database.)Ruvalcaba Syndrome is a very rare inherited disorder that is characterized by unusual facial features, abnormalities of the fingers and/or toes, additional skeletal abnormalities, and/or mental retardation. Characteristic abnormalities of the head and facial (craniofacial) area may include an unusually small head (microcephaly), a high forehead, “beaked” nose, small mouth, and/or dental abnormalities. Certain bones of the hands (i.e., metacarpals) and feet (i.e., metatarsals) may be abnormally short, resulting in abnormally short fingers and toes (brachydactyly). In addition, in some cases, fingers may be permanently bent in a fixed position (clinodactyly). Affected individuals may also exhibit short stature, sideways (scoliosis) and/or front-to-back (kyphosis) curvature of the spine, abnormal prominence of the breast bone (pectus carinatum). Ruvalcaba Syndrome has autosomal dominant inheritance. (For more information on this disorder, choose “Ruvalcaba” as your search term in the Rare Disease Database.)
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Related disorders of Trichorhinophalangeal Syndrome Type III. Symptoms of the following disorders can be similar to those of Trichorhinophalangeal Syndrome Type III (TRPS3). Comparisons may be useful for a differential diagnosis:Trichorhinophalangeal Syndrome Type I (TRPS1) is an extremely rare inherited multisystem disorder characterized with symptoms and physical features similar to those associated with TRPS3. These may include fine, thin hair; a rounded (bulbous) “pear-shaped” nose; dental anomalies; multiple abnormalities of the “growing ends” (epiphyses) of bones, particularly in the hands and feet; abnormally short (brachydactyly) and curved fingers and toes; and/or short stature (dwarfism). In most cases, the shortening of the fingers and toes in individuals with TRPS1 is typically much less severe than in individuals with TRPS3. Trichorhinophalangeal Syndrome Type I has autosomal dominant inheritance. (For more information on this disorder, choose “Trichorhinophalangeal Syndrome Type I” as your search term in the Rare Disease Database.)Trichorhinophalangeal Syndrome Type II (TRPS2), also known as Langer-Giedion Syndrome, is an extremely rare inherited disorder with symptoms and physical features similar to those associated with TRPS1 and TRPS3. These may include thin, sparse scalp hair; a rounded (bulbous) nose; a long, prominent groove (philtrum) of the upper lip; abnormally short fingers and toes (brachydactyly); and/or short stature. The shortening of the fingers and toes in individuals with TRPS2 is typically less severe than in individuals with TRPS3. In addition, an infant with Trichorhinophalangeal Syndrome Type II may also exhibit other abnormalities not associated with TRPS3 such as an unusually small head (microcephaly), excess (redundant) skin, multiple bony growths projecting from the surface of various bones of the body (exostoses), and/or mental retardation. Most cases of Trichorhinophalangeal Syndrome Type II occur randomly (sporadically) as the result of missing genetic material (deletions) on chromosome 8. A few individuals with TRPS II have had children, but the chromosome deletion may be inherited in an autosomal dominant manner. (For more information on this disorder, choose “Trichorhinophalangeal Syndrome Type II” as your search term in the Rare Disease Database.)Ruvalcaba Syndrome is a very rare inherited disorder that is characterized by unusual facial features, abnormalities of the fingers and/or toes, additional skeletal abnormalities, and/or mental retardation. Characteristic abnormalities of the head and facial (craniofacial) area may include an unusually small head (microcephaly), a high forehead, “beaked” nose, small mouth, and/or dental abnormalities. Certain bones of the hands (i.e., metacarpals) and feet (i.e., metatarsals) may be abnormally short, resulting in abnormally short fingers and toes (brachydactyly). In addition, in some cases, fingers may be permanently bent in a fixed position (clinodactyly). Affected individuals may also exhibit short stature, sideways (scoliosis) and/or front-to-back (kyphosis) curvature of the spine, abnormal prominence of the breast bone (pectus carinatum). Ruvalcaba Syndrome has autosomal dominant inheritance. (For more information on this disorder, choose “Ruvalcaba” as your search term in the Rare Disease Database.)
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Trichorhinophalangeal Syndrome Type III
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nord_1228_5
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Diagnosis of Trichorhinophalangeal Syndrome Type III
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A diagnosis of trichrhinophalangeal syndome type III may be suspected based upon identification of characteristic physical features (e.g., fine, sparse hair; facial abnormalities; etc.). The diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history, and X-ray studies of the skeleton that reveal severe shortening of bones in the hands and feet (i.e., metacarpals, metatarsals, and phalanges) and the abnormal development of the "growing ends" (epiphyses) of the phalangeal bones (epiphyseal coning).
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Diagnosis of Trichorhinophalangeal Syndrome Type III. A diagnosis of trichrhinophalangeal syndome type III may be suspected based upon identification of characteristic physical features (e.g., fine, sparse hair; facial abnormalities; etc.). The diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history, and X-ray studies of the skeleton that reveal severe shortening of bones in the hands and feet (i.e., metacarpals, metatarsals, and phalanges) and the abnormal development of the "growing ends" (epiphyses) of the phalangeal bones (epiphyseal coning).
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Trichorhinophalangeal Syndrome Type III
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nord_1228_6
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Therapies of Trichorhinophalangeal Syndrome Type III
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TreatmentThe treatment of TRPS3 is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, dental specialists, orthopedic surgeons, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Specific therapies for the treatment of TRPS3 are symptomatic and supportive. Various orthopedic techniques, including surgery, may be used to help treat and/or correct skeletal abnormalities. Physical therapy may be prescribed to help improve the range of motion in the hips and various joints. Additional therapeutic and/or supportive measures may be necessary in some cases.Genetic counseling will be of benefit for affected individuals and their families. Other treatment in symptomatic and supportive.
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Therapies of Trichorhinophalangeal Syndrome Type III. TreatmentThe treatment of TRPS3 is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, dental specialists, orthopedic surgeons, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Specific therapies for the treatment of TRPS3 are symptomatic and supportive. Various orthopedic techniques, including surgery, may be used to help treat and/or correct skeletal abnormalities. Physical therapy may be prescribed to help improve the range of motion in the hips and various joints. Additional therapeutic and/or supportive measures may be necessary in some cases.Genetic counseling will be of benefit for affected individuals and their families. Other treatment in symptomatic and supportive.
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Trichorhinophalangeal Syndrome Type III
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nord_1229_0
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Overview of Trichothiodystrophy
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Summary
Trichothiodystrophy (TTD) is a rare inherited, genetic disease characterized by a broad spectrum of abnormalities. Patients with different symptoms are linked together by the common feature of short, dry, brittle, sulfur-deficient hair which has a characteristic “tiger tail” pattern (alternating light and dark bands) under polarizing microscopy. The signs and symptoms vary widely between patients. Typically, patients are born preterm and with low birth weight. Maternal pregnancy complications are common. Infants may be born with a shiny parchment-like covering on the skin that peels off over several days to weeks (collodion membrane). Through childhood they may have developmental delay or intellectual disability, short stature with poor weight gain, dry, scaly skin (ichthyosis), eye abnormalities (the most common being congenital cataracts), recurrent infections and bone abnormalities. Nearly half (42%) of patients with TTD have extreme sensitivity to ultraviolet radiation (UV) called photosensitivity and develop blistering burns on minimal exposure to UV. Despite the burning on sun exposure, skin cancer has only very rarely been reported in patients with TTD. Introduction
In the past, several names and acronyms such as PIBS, BIBS or IBIBS have been used to describe TTD, however they are not useful for patient healthcare management and do not accurately reflect the multiple features of the condition. TTD is currently described by number (1-9) according to the mutated gene and photosensitivity status of the patient. TTD is generally apparent at birth but can be difficult to diagnose due to the symptom variability and its similarity to other conditions. TTD patients have a reduced life expectancy primarily related to increased risk of infection.
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Overview of Trichothiodystrophy. Summary
Trichothiodystrophy (TTD) is a rare inherited, genetic disease characterized by a broad spectrum of abnormalities. Patients with different symptoms are linked together by the common feature of short, dry, brittle, sulfur-deficient hair which has a characteristic “tiger tail” pattern (alternating light and dark bands) under polarizing microscopy. The signs and symptoms vary widely between patients. Typically, patients are born preterm and with low birth weight. Maternal pregnancy complications are common. Infants may be born with a shiny parchment-like covering on the skin that peels off over several days to weeks (collodion membrane). Through childhood they may have developmental delay or intellectual disability, short stature with poor weight gain, dry, scaly skin (ichthyosis), eye abnormalities (the most common being congenital cataracts), recurrent infections and bone abnormalities. Nearly half (42%) of patients with TTD have extreme sensitivity to ultraviolet radiation (UV) called photosensitivity and develop blistering burns on minimal exposure to UV. Despite the burning on sun exposure, skin cancer has only very rarely been reported in patients with TTD. Introduction
In the past, several names and acronyms such as PIBS, BIBS or IBIBS have been used to describe TTD, however they are not useful for patient healthcare management and do not accurately reflect the multiple features of the condition. TTD is currently described by number (1-9) according to the mutated gene and photosensitivity status of the patient. TTD is generally apparent at birth but can be difficult to diagnose due to the symptom variability and its similarity to other conditions. TTD patients have a reduced life expectancy primarily related to increased risk of infection.
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Trichothiodystrophy
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nord_1229_1
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Symptoms of Trichothiodystrophy
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Pregnancy and newborn The first sign an infant may have TTD can be before birth. Maternal complications during pregnancy such as pre-eclampsia, HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, premature labor and placental abnormalities occur in approximately 80% of TTD pregnancies. TTD infants often have low birthweight (Skin, hair, and nailsWhen the collodion membrane peels off in the newborn period, the skin in many areas of the body may be dry and covered with fine scale called ichthyosis. The scale over time can thicken and darken especially at the waist and flanks; due to the scaly dry nature of their skin, TTD patients can have issues with chronic itching (pruritis). In addition, some children with TTD may not sweat very much and may have issues with hyperthermia in warmer climates. The skin on the palms and soles of the feet is often thickened and dry; painful fissures in flexural areas such as over the knuckles of the hands and instep of the foot can occur. Hyperlinear palms and soles can also be seen in many TTD children and adults. Eczema occurs in a small percentage of patients and increases the problems with the pruritus. The scalp hair is brittle and can be sparse; it breaks easily and, in some patients, will fall out during fever (febrile) illnesses. The hair may be ‘fine’ and feel soft or it may feel more course and dry. It can be fragile and break off after a slight amount of ‘trauma’ such as combing, and for some affected people, hair breaks so easily that there are broken hairs on the pillow after sleeping. TTD patients may have more hair on the top of their heads and little to no hair on the sides or back. Testing of the hair in research laboratories shows low sulfur content and abnormal levels of the amino acid cystine.The scalp skin can be dry, itchy, scaly rough and red (ichthyotic), and this can prevent hair growth. The eyebrows are also sparse and brittle, and the hair of the eyebrows may break off as well. In many patients, the eyelashes may be nearly normal. TTD children often have a smaller receding chin, and larger appearing ears.Onychodystrophy, or abnormal nails, is a common finding in TTD. The nails may be abnormally short, broad and ridged, and may be soft and split easily. They may also be thick, brittle and slow growing. The nails may demonstrate koilynichia, (spoon nails) a turning upward at the tips of the nails. Growth and feeding TTD children have short stature, many have poor weight gain, and will not grow along the standard growth curves. Most children and adults with TTD will be shorter than their peers. People with TTD can have problems with chronic gastroesophageal reflux disease and may need medications and feeding modifications to manage the symptoms. Due to feeding problems and poor weight gain, some TTD children will have feeding tubes (either gastrostomy or nasogastric tubes) placed to augment oral feeding. As TTD children age, they may lose subcutaneous fat and have poor weight gain, resulting in a thinner prematurely aged-looking face.Neurologic Most children and adults with TTD have some form of developmental delay and/or intellectual disability. Small head size (microcephaly) is also a common finding. Often, these children do not walk or talk at the usual ages. Many children with TTD will have MRI scans of the brain for evaluation of the developmental delay. Most TTD children are found to have a reduced amount of myelin (white matter) in the brain and central nervous system. The myelin acts as an ‘insulator’ around nerve sheaths, helping to speed up nerve transmission. In addition, TTD children can have tremors and difficulty coordinating fine and gross muscle coordination. A few patients have developed seizures. Hearing loss can also be seen but it is generally due to recurrent ear infections and not nerve deafness. Despite the developmental delays, individuals with TTD are outgoing and highly social.Minor infections may lead to prolonged illness with hospitalization, sometimes requiring ICU management. This often leads to regression with decline in functional abilities. When recovered from the infections, the children usually improve and regain most of their abilities. However, repeated infections can interfere with normal development over time. This is different from the progressive degeneration typical of patients with xeroderma pigmentosum (XP), a related disorder with mutations in some of the same genes as TTD (see below). In contrast to TTD, XP neurologic degeneration is slow, progressive, and occurs without repeated infections and hospitalizations. TTD patients without repeated infections and hospitalization may develop slowly but generally do not have the progressive loss of function that occurs with XP neurologic degeneration.Hematologic and immune TTD children may also have recurrent infections. The most common infections occur in the gastrointestinal and respiratory tracts. These infections can be life threatening. The children may have low levels of neutrophils, a type of white blood cell important in fighting infections. They may also have lower levels of immunoglobins especially immunoglobin G (IgG) in the blood. This blood protein is also important in fighting infections. EyesTTD patients have a wide variety of ocular abnormalities and ophthalmologic care is an important part of their health monitoring. In some patients, ocular abnormalities are present at birth; however other patients may not develop ocular problems until later in childhood. The most common findings in the newborn period are congenital cataracts and nystagmus (the eyes make repetitive, uncontrolled movements that can affect visual acuity and depth perception). Children with TTD can also develop cataracts at later ages, and identification and surgical removal of the cataracts as soon as they become visually significant is important to preserve eyesight. Other ocular abnormalities include small corneas (microcornea) and small eyeballs (microphthalmia) with decreased best corrected vision. As patients with TTD become older, they can develop dry eyes, leading to corneal surface abnormalities. Normally dry eye is a condition seen in older adults, and this TTD complication is often not identified until the child becomes symptomatic. A few TTD patients may develop macular/retinal degeneration as they age.Skeletal and dental Skeletal and dental abnormalities may also be present. TTD patients have been found to have unusual skeletal findings. They have thick dense bones (osteosclerosis) in the central skeleton including the skull, spine and pelvis. They also have thinner bone (osteopenia) in the peripheral bones of the lower arms, hands and feet. The bone symptoms can vary between people with the condition. Some children with TTD develop debilitating hip degeneration leading to pain, inability to walk and avascular necrosis of the femoral head. The debilitating hip degeneration is seen most commonly in TTD children who also have the combination of osteosclerosis and osteopenia, and mutations in the XPD/ERCC2 gene. TTD patients often have poorly developed teeth. The tooth enamel is often thin and hypoplastic, leading to recurrent cavities (caries). TTD children may need extensive dental care including extractions and tooth caps.Miscellaneous Males with TTD may have cryptorchidism, a condition where the testes fail to descend into the scrotum. They generally require surgery to correct the condition. In females, breast tissue may be sparsely developed despite normal development of the nipples. A few TTD females have developed menstruation and pregnancy may be possible.
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Symptoms of Trichothiodystrophy. Pregnancy and newborn The first sign an infant may have TTD can be before birth. Maternal complications during pregnancy such as pre-eclampsia, HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, premature labor and placental abnormalities occur in approximately 80% of TTD pregnancies. TTD infants often have low birthweight (Skin, hair, and nailsWhen the collodion membrane peels off in the newborn period, the skin in many areas of the body may be dry and covered with fine scale called ichthyosis. The scale over time can thicken and darken especially at the waist and flanks; due to the scaly dry nature of their skin, TTD patients can have issues with chronic itching (pruritis). In addition, some children with TTD may not sweat very much and may have issues with hyperthermia in warmer climates. The skin on the palms and soles of the feet is often thickened and dry; painful fissures in flexural areas such as over the knuckles of the hands and instep of the foot can occur. Hyperlinear palms and soles can also be seen in many TTD children and adults. Eczema occurs in a small percentage of patients and increases the problems with the pruritus. The scalp hair is brittle and can be sparse; it breaks easily and, in some patients, will fall out during fever (febrile) illnesses. The hair may be ‘fine’ and feel soft or it may feel more course and dry. It can be fragile and break off after a slight amount of ‘trauma’ such as combing, and for some affected people, hair breaks so easily that there are broken hairs on the pillow after sleeping. TTD patients may have more hair on the top of their heads and little to no hair on the sides or back. Testing of the hair in research laboratories shows low sulfur content and abnormal levels of the amino acid cystine.The scalp skin can be dry, itchy, scaly rough and red (ichthyotic), and this can prevent hair growth. The eyebrows are also sparse and brittle, and the hair of the eyebrows may break off as well. In many patients, the eyelashes may be nearly normal. TTD children often have a smaller receding chin, and larger appearing ears.Onychodystrophy, or abnormal nails, is a common finding in TTD. The nails may be abnormally short, broad and ridged, and may be soft and split easily. They may also be thick, brittle and slow growing. The nails may demonstrate koilynichia, (spoon nails) a turning upward at the tips of the nails. Growth and feeding TTD children have short stature, many have poor weight gain, and will not grow along the standard growth curves. Most children and adults with TTD will be shorter than their peers. People with TTD can have problems with chronic gastroesophageal reflux disease and may need medications and feeding modifications to manage the symptoms. Due to feeding problems and poor weight gain, some TTD children will have feeding tubes (either gastrostomy or nasogastric tubes) placed to augment oral feeding. As TTD children age, they may lose subcutaneous fat and have poor weight gain, resulting in a thinner prematurely aged-looking face.Neurologic Most children and adults with TTD have some form of developmental delay and/or intellectual disability. Small head size (microcephaly) is also a common finding. Often, these children do not walk or talk at the usual ages. Many children with TTD will have MRI scans of the brain for evaluation of the developmental delay. Most TTD children are found to have a reduced amount of myelin (white matter) in the brain and central nervous system. The myelin acts as an ‘insulator’ around nerve sheaths, helping to speed up nerve transmission. In addition, TTD children can have tremors and difficulty coordinating fine and gross muscle coordination. A few patients have developed seizures. Hearing loss can also be seen but it is generally due to recurrent ear infections and not nerve deafness. Despite the developmental delays, individuals with TTD are outgoing and highly social.Minor infections may lead to prolonged illness with hospitalization, sometimes requiring ICU management. This often leads to regression with decline in functional abilities. When recovered from the infections, the children usually improve and regain most of their abilities. However, repeated infections can interfere with normal development over time. This is different from the progressive degeneration typical of patients with xeroderma pigmentosum (XP), a related disorder with mutations in some of the same genes as TTD (see below). In contrast to TTD, XP neurologic degeneration is slow, progressive, and occurs without repeated infections and hospitalizations. TTD patients without repeated infections and hospitalization may develop slowly but generally do not have the progressive loss of function that occurs with XP neurologic degeneration.Hematologic and immune TTD children may also have recurrent infections. The most common infections occur in the gastrointestinal and respiratory tracts. These infections can be life threatening. The children may have low levels of neutrophils, a type of white blood cell important in fighting infections. They may also have lower levels of immunoglobins especially immunoglobin G (IgG) in the blood. This blood protein is also important in fighting infections. EyesTTD patients have a wide variety of ocular abnormalities and ophthalmologic care is an important part of their health monitoring. In some patients, ocular abnormalities are present at birth; however other patients may not develop ocular problems until later in childhood. The most common findings in the newborn period are congenital cataracts and nystagmus (the eyes make repetitive, uncontrolled movements that can affect visual acuity and depth perception). Children with TTD can also develop cataracts at later ages, and identification and surgical removal of the cataracts as soon as they become visually significant is important to preserve eyesight. Other ocular abnormalities include small corneas (microcornea) and small eyeballs (microphthalmia) with decreased best corrected vision. As patients with TTD become older, they can develop dry eyes, leading to corneal surface abnormalities. Normally dry eye is a condition seen in older adults, and this TTD complication is often not identified until the child becomes symptomatic. A few TTD patients may develop macular/retinal degeneration as they age.Skeletal and dental Skeletal and dental abnormalities may also be present. TTD patients have been found to have unusual skeletal findings. They have thick dense bones (osteosclerosis) in the central skeleton including the skull, spine and pelvis. They also have thinner bone (osteopenia) in the peripheral bones of the lower arms, hands and feet. The bone symptoms can vary between people with the condition. Some children with TTD develop debilitating hip degeneration leading to pain, inability to walk and avascular necrosis of the femoral head. The debilitating hip degeneration is seen most commonly in TTD children who also have the combination of osteosclerosis and osteopenia, and mutations in the XPD/ERCC2 gene. TTD patients often have poorly developed teeth. The tooth enamel is often thin and hypoplastic, leading to recurrent cavities (caries). TTD children may need extensive dental care including extractions and tooth caps.Miscellaneous Males with TTD may have cryptorchidism, a condition where the testes fail to descend into the scrotum. They generally require surgery to correct the condition. In females, breast tissue may be sparsely developed despite normal development of the nipples. A few TTD females have developed menstruation and pregnancy may be possible.
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Trichothiodystrophy
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nord_1229_2
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Causes of Trichothiodystrophy
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TTD is a genetically heterogenous condition. This means that mutations in several different genes may be responsible for the syndrome. Many patients with TTD have abnormalities in genes involved in the nucleotide excision repair pathway which is responsible for repairing DNA damage caused by ultraviolet radiation. The inability to repair DNA damage can lead to excessive sunburn in some patients and skin cancer in a few rare patients. These DNA repair genes also play a role in gene transcription, which is the first step in the process of creating proteins that tell the body how to function.Changes (variants or mutations) in the ERCC2 (XPD) gene are found in the majority of patients with TTD. Mutations in the following genes are also associated with TTD: ERCC3 (XPB), TTDA (GTF2H5), TTDN1 (MPLKIP), TARS, CARS, AARS1, MARS1 and GTF2E2.There is also evidence suggesting that mutations in the X-linked RNF113A gene may also cause TTD.TTD is a genetic disorder that can be passed down through families 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 of having 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.Parents who are close blood 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.
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Causes of Trichothiodystrophy. TTD is a genetically heterogenous condition. This means that mutations in several different genes may be responsible for the syndrome. Many patients with TTD have abnormalities in genes involved in the nucleotide excision repair pathway which is responsible for repairing DNA damage caused by ultraviolet radiation. The inability to repair DNA damage can lead to excessive sunburn in some patients and skin cancer in a few rare patients. These DNA repair genes also play a role in gene transcription, which is the first step in the process of creating proteins that tell the body how to function.Changes (variants or mutations) in the ERCC2 (XPD) gene are found in the majority of patients with TTD. Mutations in the following genes are also associated with TTD: ERCC3 (XPB), TTDA (GTF2H5), TTDN1 (MPLKIP), TARS, CARS, AARS1, MARS1 and GTF2E2.There is also evidence suggesting that mutations in the X-linked RNF113A gene may also cause TTD.TTD is a genetic disorder that can be passed down through families 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 of having 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.Parents who are close blood 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.
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Trichothiodystrophy
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nord_1229_3
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Affects of Trichothiodystrophy
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TTD presents at birth. Males and females are affected in equal numbers. The estimated incidence is about 1 in 1,000,000 newborns in the United States and Europe. Over 100 patients have been reported worldwide. TTD has been reported in all ethnic groups.
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Affects of Trichothiodystrophy. TTD presents at birth. Males and females are affected in equal numbers. The estimated incidence is about 1 in 1,000,000 newborns in the United States and Europe. Over 100 patients have been reported worldwide. TTD has been reported in all ethnic groups.
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Trichothiodystrophy
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nord_1229_4
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Related disorders of Trichothiodystrophy
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Symptoms of the following disorders may resemble those of trichothiodystrophy. Comparisons may be useful for a differential diagnosis.Ichthyoses or “disorders of cornification” are general terms describing a group of scaly skin disorders. (See “ichthyosis” in the Rare Disease Database for more information.)Xeroderma pigmentosum is a disorder in which damage done by ultraviolet light (especially sun light) is not repaired properly leading to dry skin with heavy freckling and development of skin cancer at a young age. Patients may also have progressive neurologic impairment. Xeroderma pigmentosum is also caused by alterations in genes involved in DNA repair. (For more information on this condition, search for “xeroderma pigmentosum” in the Rare Disease Database.)
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Related disorders of Trichothiodystrophy. Symptoms of the following disorders may resemble those of trichothiodystrophy. Comparisons may be useful for a differential diagnosis.Ichthyoses or “disorders of cornification” are general terms describing a group of scaly skin disorders. (See “ichthyosis” in the Rare Disease Database for more information.)Xeroderma pigmentosum is a disorder in which damage done by ultraviolet light (especially sun light) is not repaired properly leading to dry skin with heavy freckling and development of skin cancer at a young age. Patients may also have progressive neurologic impairment. Xeroderma pigmentosum is also caused by alterations in genes involved in DNA repair. (For more information on this condition, search for “xeroderma pigmentosum” in the Rare Disease Database.)
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Trichothiodystrophy
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nord_1229_5
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Diagnosis of Trichothiodystrophy
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An initial evaluation for TTD involves a diagnostic work-up, including obtaining a detailed history of the patient’s prenatal and neonatal history. A thorough physical exam is performed to assess clinical features such as hair abnormalities, short stature, small chin, ichthyosis, intellectual impairment or developmental delay, cataracts, cryptorchidism (in males) and bone and teeth anomalies. Evaluation by a developmental pediatrician or neurologist may determine whether there is any developmental delay or intellectual disability. MRI imaging of the brain to identify abnormal patterns of myelination is often performed. Laboratory testing for immune function, blood count, low red blood cell MCV, elevated hemoglobin A2 level and iron levels can also be performed. TTD is often diagnosed by polarized light microscopy of hair shafts, revealing a tiger-tail pattern. The classical tiger-tail pattern alone usually is enough to diagnose TTD. However, there are other conditions with similar hair shaft abnormalities and often genetic testing is needed to confirm the diagnosis. Some patients with features of TTD will not have mutations in the known genes. They may have mutations in yet to be identified TTD associated genes.
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Diagnosis of Trichothiodystrophy. An initial evaluation for TTD involves a diagnostic work-up, including obtaining a detailed history of the patient’s prenatal and neonatal history. A thorough physical exam is performed to assess clinical features such as hair abnormalities, short stature, small chin, ichthyosis, intellectual impairment or developmental delay, cataracts, cryptorchidism (in males) and bone and teeth anomalies. Evaluation by a developmental pediatrician or neurologist may determine whether there is any developmental delay or intellectual disability. MRI imaging of the brain to identify abnormal patterns of myelination is often performed. Laboratory testing for immune function, blood count, low red blood cell MCV, elevated hemoglobin A2 level and iron levels can also be performed. TTD is often diagnosed by polarized light microscopy of hair shafts, revealing a tiger-tail pattern. The classical tiger-tail pattern alone usually is enough to diagnose TTD. However, there are other conditions with similar hair shaft abnormalities and often genetic testing is needed to confirm the diagnosis. Some patients with features of TTD will not have mutations in the known genes. They may have mutations in yet to be identified TTD associated genes.
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Therapies of Trichothiodystrophy
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Treatment
Many infants with TTD will be discharged from the NICU after several weeks, then require close medical monitoring at home for several months.TTD patients generally have complex health care needs and benefit from a multidisciplinary approach to their medical management. No formal guidelines for the medical management of TTD exist and management is largely based on symptoms.Patients who are sensitive to ultraviolent rays must be protected from exposure to the sun and other sources of ultraviolet radiation to prevent severe burns. Patients should avoid being outside for prolonged periods without protection. They should wear hats, sunglasses and clothing to cover their skin, such as long sleeves and long pants. When going outside during the day, they should have sunscreen applied to uncovered skin such as face, neck, ears and hands. UV can come from other artificial light sources such as halogen and fluorescent light bulbs and mercury vapor lamps. Photosensitive patients should avoid these types of light sources. Despite the burning on sun exposure, skin cancer has only very rarely been reported in patients with TTD, there are a few very rare patients who exhibit symptoms of both xeroderma pigmentosum (XP) and TTD (the XP/TTD syndrome) and may develop skin cancers after UV exposure. These patients require more stringent UV protection. Management of the ichthyosis and dry skin varies with severity. For some patients it is a minor issue but for others management is a daily process of gently removing thickened scale during bathing and followed immediately by moisturizing the skin. Moisturizers or emollient creams and lotions are designed to make the external layers of the skin (epidermis) softer and more pliable. They also increase the skin’s hydration (water content) by reducing evaporation. The moisturizers ideally are fragrance and dye free to avoid allergic reactions. It can be helpful to include the nails when moisturizing the skin of the hands and palms. Applying oil to the scalp and then washing the hair with a gentle shampoo designed for scaling skin conditions can help loosen the scale. Some children with TTD have received IgG infusions to help treat the recurrent infections. Anemia and low iron levels can be treated with dietary iron supplementation.Monitoring is needed for developmental delay and special education services may be required in school. The children should be evaluated for rehabilitation needs. Ongoing physical therapy may be advised for joint stiffness, muscle tightening (contractures), and poor coordination. Genetic counseling is recommended for families of children with trichothiodystrophy.
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Therapies of Trichothiodystrophy. Treatment
Many infants with TTD will be discharged from the NICU after several weeks, then require close medical monitoring at home for several months.TTD patients generally have complex health care needs and benefit from a multidisciplinary approach to their medical management. No formal guidelines for the medical management of TTD exist and management is largely based on symptoms.Patients who are sensitive to ultraviolent rays must be protected from exposure to the sun and other sources of ultraviolet radiation to prevent severe burns. Patients should avoid being outside for prolonged periods without protection. They should wear hats, sunglasses and clothing to cover their skin, such as long sleeves and long pants. When going outside during the day, they should have sunscreen applied to uncovered skin such as face, neck, ears and hands. UV can come from other artificial light sources such as halogen and fluorescent light bulbs and mercury vapor lamps. Photosensitive patients should avoid these types of light sources. Despite the burning on sun exposure, skin cancer has only very rarely been reported in patients with TTD, there are a few very rare patients who exhibit symptoms of both xeroderma pigmentosum (XP) and TTD (the XP/TTD syndrome) and may develop skin cancers after UV exposure. These patients require more stringent UV protection. Management of the ichthyosis and dry skin varies with severity. For some patients it is a minor issue but for others management is a daily process of gently removing thickened scale during bathing and followed immediately by moisturizing the skin. Moisturizers or emollient creams and lotions are designed to make the external layers of the skin (epidermis) softer and more pliable. They also increase the skin’s hydration (water content) by reducing evaporation. The moisturizers ideally are fragrance and dye free to avoid allergic reactions. It can be helpful to include the nails when moisturizing the skin of the hands and palms. Applying oil to the scalp and then washing the hair with a gentle shampoo designed for scaling skin conditions can help loosen the scale. Some children with TTD have received IgG infusions to help treat the recurrent infections. Anemia and low iron levels can be treated with dietary iron supplementation.Monitoring is needed for developmental delay and special education services may be required in school. The children should be evaluated for rehabilitation needs. Ongoing physical therapy may be advised for joint stiffness, muscle tightening (contractures), and poor coordination. Genetic counseling is recommended for families of children with trichothiodystrophy.
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Overview of Trigeminal Neuralgia
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Trigeminal neuralgia (TN), also known as tic douloureux, is a disorder of the fifth cranial nerve (trigeminal nerve). The disorder is sometimes broken down into type 1 and type 2. TN type 1 (TN1) is characterized by attacks of intense, stabbing pain affecting the mouth, cheek, nose, and/or other areas on one side of the face. TN type 2 (TN2) is characterized by less intense pain, but a constant dull aching or burning pain. Both types of pain can occur in the same individual, even at the same time. In some cases, the pain can be excruciating and incapacitating. If untreated, TN can have a profound effect on a person’s quality of life. In most cases, TN1 develops due to a blood vessel pressing against the trigeminal nerve, but sometimes no underlying cause can be identified (idiopathic). TN2 can be idiopathic, due to compression of the trigeminal nerve, or can occur due to a known underlying cause such as a tumor or multiple sclerosis. It is not known why one person gets symptoms of TN1 versus TN2; it may be due to the number of vessels (e.g. arteries, veins) or the degree of compression. TN can usually be managed through medications, surgery or injections.There is no consensus or agreed upon classification system for TN. TN1 is also known as classical trigeminal neuralgia. TN2 was once known as atypical or symptomatic TN. However the term “atypical” trigeminal neuralgia has been inconsistently used for individuals who do not have TN1 and remains a vague, undefined term. Consequently, many researchers and patients have advocated eliminating the term “atypical TN”, which remains a “wastebasket” diagnosis that serves no useful purpose and is often a disservice to patients. Symptomatic TN is often reserved for cases that develop because of multiple sclerosis. The term trigeminal neuropathic facial pain may be used for pain that results from unintentional injury to the trigeminal nerve, which can result from a variety of conditions including facial trauma, oral surgery, ear, nose and throat surgery, or stroke.
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Overview of Trigeminal Neuralgia. Trigeminal neuralgia (TN), also known as tic douloureux, is a disorder of the fifth cranial nerve (trigeminal nerve). The disorder is sometimes broken down into type 1 and type 2. TN type 1 (TN1) is characterized by attacks of intense, stabbing pain affecting the mouth, cheek, nose, and/or other areas on one side of the face. TN type 2 (TN2) is characterized by less intense pain, but a constant dull aching or burning pain. Both types of pain can occur in the same individual, even at the same time. In some cases, the pain can be excruciating and incapacitating. If untreated, TN can have a profound effect on a person’s quality of life. In most cases, TN1 develops due to a blood vessel pressing against the trigeminal nerve, but sometimes no underlying cause can be identified (idiopathic). TN2 can be idiopathic, due to compression of the trigeminal nerve, or can occur due to a known underlying cause such as a tumor or multiple sclerosis. It is not known why one person gets symptoms of TN1 versus TN2; it may be due to the number of vessels (e.g. arteries, veins) or the degree of compression. TN can usually be managed through medications, surgery or injections.There is no consensus or agreed upon classification system for TN. TN1 is also known as classical trigeminal neuralgia. TN2 was once known as atypical or symptomatic TN. However the term “atypical” trigeminal neuralgia has been inconsistently used for individuals who do not have TN1 and remains a vague, undefined term. Consequently, many researchers and patients have advocated eliminating the term “atypical TN”, which remains a “wastebasket” diagnosis that serves no useful purpose and is often a disservice to patients. Symptomatic TN is often reserved for cases that develop because of multiple sclerosis. The term trigeminal neuropathic facial pain may be used for pain that results from unintentional injury to the trigeminal nerve, which can result from a variety of conditions including facial trauma, oral surgery, ear, nose and throat surgery, or stroke.
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Symptoms of Trigeminal Neuralgia
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The most significant symptom of trigeminal neuralgia is recurring episodes of intense, short-lived spasms of pain of the lower portion of the face and the jaw. The nose is not infrequently affected. Much less often, the eyes and forehead are affected. In most cases, pain is limited to one side of the face (unilateral). The pain has been compared to a series of “electrical shocks” followed by a steady dull ache. The pain often starts and stops rapidly. Intense pain usually lessens rapidly (usually within several seconds), but the following dull aching pain may persist for as much as one to two minutes. For many individuals, pain is completely gone in between episodes. However, for some individuals, even some individuals with TN1, some degree of pain may persist.Pain may be triggered by mild tactile stimuli including brushing one’s teeth, washing one’s face, shaving, drinking hot or cold drinks, chewing, talking, blowing one’s nose, a cool breeze, or a light touch to the face. Some episodes may occur without an apparent trigger (spontaneously). Consequently, episodes can occur repeatedly throughout the day. Episodes rarely occur during sleep. The frequency and severity of TN can vary dramatically from one person to another. One person may have as many as one hundred attacks in one day while another person may only have an occasional episode. Attacks typically stop for a period of time and then return. Over time, the pain tends to grow worse with fewer pain-free periods.Pain may cause affected individuals to grimace, wince, or contort their heads. Skin on the affected side of the face may become flushed and the eye may tear. Some individuals also experience excessive salivation.With TN2, facial pain is a constant dull or burning sensation and tends to affect a more widespread portion of the face than TN1. In some individuals, the pain will not go away even for short periods of time. The symptoms of TN2 tend to be more difficult to treat.The pain associated with TN can be so severe that affected individuals avoid simple activities such as brushing one’s teeth and/or avoid social situations for fear of an impending attack. The disorder can cause profound psychological effects such as depression and anxiety.
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Symptoms of Trigeminal Neuralgia. The most significant symptom of trigeminal neuralgia is recurring episodes of intense, short-lived spasms of pain of the lower portion of the face and the jaw. The nose is not infrequently affected. Much less often, the eyes and forehead are affected. In most cases, pain is limited to one side of the face (unilateral). The pain has been compared to a series of “electrical shocks” followed by a steady dull ache. The pain often starts and stops rapidly. Intense pain usually lessens rapidly (usually within several seconds), but the following dull aching pain may persist for as much as one to two minutes. For many individuals, pain is completely gone in between episodes. However, for some individuals, even some individuals with TN1, some degree of pain may persist.Pain may be triggered by mild tactile stimuli including brushing one’s teeth, washing one’s face, shaving, drinking hot or cold drinks, chewing, talking, blowing one’s nose, a cool breeze, or a light touch to the face. Some episodes may occur without an apparent trigger (spontaneously). Consequently, episodes can occur repeatedly throughout the day. Episodes rarely occur during sleep. The frequency and severity of TN can vary dramatically from one person to another. One person may have as many as one hundred attacks in one day while another person may only have an occasional episode. Attacks typically stop for a period of time and then return. Over time, the pain tends to grow worse with fewer pain-free periods.Pain may cause affected individuals to grimace, wince, or contort their heads. Skin on the affected side of the face may become flushed and the eye may tear. Some individuals also experience excessive salivation.With TN2, facial pain is a constant dull or burning sensation and tends to affect a more widespread portion of the face than TN1. In some individuals, the pain will not go away even for short periods of time. The symptoms of TN2 tend to be more difficult to treat.The pain associated with TN can be so severe that affected individuals avoid simple activities such as brushing one’s teeth and/or avoid social situations for fear of an impending attack. The disorder can cause profound psychological effects such as depression and anxiety.
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Causes of Trigeminal Neuralgia
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The exact cause of trigeminal neuralgia is not fully understood. In most cases, the disorder results from a blood vessel pressing against the trigeminal nerve near the base of the brain. This compression may damage the nerve and cause excess bursts of neurological activity. The reason a blood vessel ends up pressing against the trigeminal nerve is not fully understood.Some researchers believe that the specific injury to the trigeminal nerve involves damage to, or loss of, the myelin sheath from nerve fibers (demyelination) causes the symptoms. The myelin sheath is the fatty covering of nerve cells and fibers. Some researchers believe that damage to the myelin sheath results in increased electrical activity in the trigeminal nerve, which triggers the pain regions of the brain.In rare cases, tumors may press against the trigeminal nerve. Multiple sclerosis is also sometimes cited as a cause of TN due to deterioration of the myelin sheath. In many cases, no underlying cause of TN can be identified (idiopathic).The trigeminal nerve is one of the 12 pairs of nerves that arise from the underside of the brain. The trigeminal nerve has three main branches. Each of these three branches further splits into multiple smaller branches. The ophthalmic or upper branch provides sensation to the area of the eyes, forehead, front of the head and the scalp. The maxillary or middle branch provides sensation to cheeks, around the nose, top lip, upper jaw, and teeth and gums. The mandibular or lower branch provides sensation to the bottom lip, lower jaw, and teeth and gums. TN pain can result from one or more of these three branches. However, the middle or lower branches are affected more often than the upper branch.
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Causes of Trigeminal Neuralgia. The exact cause of trigeminal neuralgia is not fully understood. In most cases, the disorder results from a blood vessel pressing against the trigeminal nerve near the base of the brain. This compression may damage the nerve and cause excess bursts of neurological activity. The reason a blood vessel ends up pressing against the trigeminal nerve is not fully understood.Some researchers believe that the specific injury to the trigeminal nerve involves damage to, or loss of, the myelin sheath from nerve fibers (demyelination) causes the symptoms. The myelin sheath is the fatty covering of nerve cells and fibers. Some researchers believe that damage to the myelin sheath results in increased electrical activity in the trigeminal nerve, which triggers the pain regions of the brain.In rare cases, tumors may press against the trigeminal nerve. Multiple sclerosis is also sometimes cited as a cause of TN due to deterioration of the myelin sheath. In many cases, no underlying cause of TN can be identified (idiopathic).The trigeminal nerve is one of the 12 pairs of nerves that arise from the underside of the brain. The trigeminal nerve has three main branches. Each of these three branches further splits into multiple smaller branches. The ophthalmic or upper branch provides sensation to the area of the eyes, forehead, front of the head and the scalp. The maxillary or middle branch provides sensation to cheeks, around the nose, top lip, upper jaw, and teeth and gums. The mandibular or lower branch provides sensation to the bottom lip, lower jaw, and teeth and gums. TN pain can result from one or more of these three branches. However, the middle or lower branches are affected more often than the upper branch.
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Affects of Trigeminal Neuralgia
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Trigeminal neuralgia affects females slightly more often than males. Although the exact incidence is unknown, approximately 10,000-15,000 new cases occur each year in the United States. The disorder most frequently affects individuals more than 50 years of age. However, cases can occur in younger adults as well. In younger individuals, the cause is often idiopathic, but when compared to older adult cases are more likely to be caused by damage to the central nervous system as in individuals with multiple sclerosis. Although extremely rare, TN can occur in children.
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Affects of Trigeminal Neuralgia. Trigeminal neuralgia affects females slightly more often than males. Although the exact incidence is unknown, approximately 10,000-15,000 new cases occur each year in the United States. The disorder most frequently affects individuals more than 50 years of age. However, cases can occur in younger adults as well. In younger individuals, the cause is often idiopathic, but when compared to older adult cases are more likely to be caused by damage to the central nervous system as in individuals with multiple sclerosis. Although extremely rare, TN can occur in children.
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Related disorders of Trigeminal Neuralgia
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Symptoms of the following disorders can be similar to those of trigeminal neuralgia. Comparisons may be useful for a differential diagnosis.A variety of conditions can cause symptoms similar to those seen in TN. Such conditions include cluster headaches, migraines, dental pain, giant cell arteritis, glossopharyngeal neuralgia, postherpetic neuralgia, occipital neuralgia, sinus infections (sinusitis), middle ear infections (otitis media), and temporomandibular joint syndrome.
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Related disorders of Trigeminal Neuralgia. Symptoms of the following disorders can be similar to those of trigeminal neuralgia. Comparisons may be useful for a differential diagnosis.A variety of conditions can cause symptoms similar to those seen in TN. Such conditions include cluster headaches, migraines, dental pain, giant cell arteritis, glossopharyngeal neuralgia, postherpetic neuralgia, occipital neuralgia, sinus infections (sinusitis), middle ear infections (otitis media), and temporomandibular joint syndrome.
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Diagnosis of Trigeminal Neuralgia
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A diagnosis of trigeminal neuralgia is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. TN should be suspected in individuals with facial pain affecting one side of the face. Because there is no specific diagnostic test for TN, physicians rely on individual’s personal history and description of symptoms when considering a diagnosis of TN.One published set of guidelines for diagnosing TN is from the International Headache Society.For classical TN:For symptomatic TN:Certain imaging techniques such as magnetic resonance imaging (MRI) can be used to assess for or rule out underlying causes of TN including tumors or multiple sclerosis. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. However, it is difficult to see a blood vessel pressing against the trigeminal nerve root through a “routine” MRI.Facial pain experts may order a “targeted” MRI, which usually means using a high resolution MR(3T), with special attention paid to the trigeminal nerve. This test may be performed with or without gadolinium, a contrast agent that is used to enhance the scanning results and supply a more detailed picture of tissues such as the brain or blood vessels. On some MR machines this is called FIESTA sequences. This means that 1 millimeter thin sections are taken, in a coronal plane, without any skips in between images, through the entire course of the trigeminal nerve. This results in a high likelihood of finding the offending vessel. This targeted method often yields an identified cause even in individuals who have been told that they have a normal MRI (routine study).
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Diagnosis of Trigeminal Neuralgia. A diagnosis of trigeminal neuralgia is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. TN should be suspected in individuals with facial pain affecting one side of the face. Because there is no specific diagnostic test for TN, physicians rely on individual’s personal history and description of symptoms when considering a diagnosis of TN.One published set of guidelines for diagnosing TN is from the International Headache Society.For classical TN:For symptomatic TN:Certain imaging techniques such as magnetic resonance imaging (MRI) can be used to assess for or rule out underlying causes of TN including tumors or multiple sclerosis. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. However, it is difficult to see a blood vessel pressing against the trigeminal nerve root through a “routine” MRI.Facial pain experts may order a “targeted” MRI, which usually means using a high resolution MR(3T), with special attention paid to the trigeminal nerve. This test may be performed with or without gadolinium, a contrast agent that is used to enhance the scanning results and supply a more detailed picture of tissues such as the brain or blood vessels. On some MR machines this is called FIESTA sequences. This means that 1 millimeter thin sections are taken, in a coronal plane, without any skips in between images, through the entire course of the trigeminal nerve. This results in a high likelihood of finding the offending vessel. This targeted method often yields an identified cause even in individuals who have been told that they have a normal MRI (routine study).
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Therapies of Trigeminal Neuralgia
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TreatmentSpecific therapeutic procedures and interventions for TN may vary, depending upon numerous factors, such as disease severity; underlying cause (if known); the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens, surgical therapies, and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.The initial therapy for individuals with TN is usually the use of medications, particularly the anti-seizure medications (anti-convulsants), carbamazepine or oxycarbazepine. When used in the early stages, these drugs are generally effective in reducing pain of affected individuals. Most people begin with a low dose that is gradually increased until the pain goes away. The exact dosage needed for each individual will vary. Despite its initial effectiveness, the benefits of these drugs may lessen over time. As with most drugs, carbamazepine can be associated with side effects. Oxycarbazepine, which is a newer medication that is related to carbamazepine, is generally associated with fewer side effects than carbamazepine.Additional anti-seizure medications that have been used to treat TN in smaller studies or case reports include topiramate, gabapentin, pregabalin, clonazepam, phenytoin, lamotrigine, and valproic acid.Over time, in many cases, these drugs may become less effective or ineffective. When one anti-seizure drug loses effectiveness, another anti-seizure medication may be tried. More than one anti-seizure medication may be necessary to control pain in an affected individual. Eventually, anti-seizure medications may stop providing relief.Muscle relaxants, such as baclofen, may also be used. Such medications may be used alone or in conjunction with anti-seizure medication. Tricyclic antidepressant medications such as amitriptyline and nortriptyline can dampen pain transmission in individuals with TN2. Common pain relievers such as opioids are generally ineffective in TN1, but may provide some relief in TN2.If medications fail to control pain or become ineffective, surgery is recommended. There are several different surgical techniques that have been used to treat individuals with TN. Surgical techniques are generally not used unless other therapies have failed or become ineffective. The decision to undergo surgery to treat TN can depend on several factors. Some physicians and individuals in the TN community believe that surgical interventions should occur sooner rather than later. There is evidence that affected individuals have a better response to microvascular decompression if the surgery is done within seven years of the initial diagnosis rather than later. Surgery should be considered early in an individual who does not have an adequate response to the two front-line medications, whether these medications are used in succession or in combination. An inadequate response can be defined as incomplete pain relief affecting activities of daily living or requiring such high doses of medication to relieve the pain that the side effects limit functioning.Decisions concerning the use of a particular surgery, drug regimens, and/or other treatments should be made by physicians and other members of the health care team in careful consultation with parents or a patient based upon the specifics of the individual case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.One of the most common procedures to treat TN1 is microvascular decompression, also known as the Janetta procedure. This procedure involves moving the blood vessel that is pressing against the trigeminal nerve and inserting a soft cushion between the nerve and the vessel. This allows the trigeminal nerve to recover, eventually relieving the pain. Microvascular decompression can result in sustained pain relief of greater than 10 years in some cases. This procedure is the only non-destructive one that will leave trigeminal nerve function intact, but the procedure is the most invasive and carries a small risk of serious complications. During the procedure, the physician makes a small incision behind the ear on the same side of the head where the pain is located and creates a small hole in the skull to gain access the trigeminal nerve and the blood vessels that are compressing it.Another possible treatment is stereotactic surgery, which includes procedures known as Gamma Knife and CyberKnife. These procedures employ a highly concentrated beam of ionizing radiation that is delivered to a specific target at the root of the trigeminal nerve. The radiation creates a lesion near the nerve root that disrupts the transmission of pain signals to the brain. Pain relief may be delayed, however, by up to several weeks or months. Additionally, in approximately 50% of individuals, pain returns within three years. These procedures are the least invasive surgical techniques for treating individuals with TN and can be repeated if pain recurs.Three additional procedures involve damaging the trigeminal nerve to interrupt the transmission of pain signals to the brain. These procedures are percutaneous balloon compression, percutaneous glycerol rhizotomy, and percutaneous stereotactic rhizotomy. They involve the insertion of a needle through the cheek and into the trigeminal nerve. Percutaneous balloon compression involves inserting a tiny balloon in the trigeminal nerve near the area where the pain fibers are located. The balloon is inflated, damaging the nerve fibers. Then the balloon is deflated and removed. Percutaneous glycerol rhizotomy involves injecting glycerol, a chemical compound, into the trigeminal nerve to damage the nerve. Percutaneous stereotactic rhizotomy, also known as radiofrequency lesioning, involves uses an electrode to apply heat to damage nerve fibers.
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Therapies of Trigeminal Neuralgia. TreatmentSpecific therapeutic procedures and interventions for TN may vary, depending upon numerous factors, such as disease severity; underlying cause (if known); the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens, surgical therapies, and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.The initial therapy for individuals with TN is usually the use of medications, particularly the anti-seizure medications (anti-convulsants), carbamazepine or oxycarbazepine. When used in the early stages, these drugs are generally effective in reducing pain of affected individuals. Most people begin with a low dose that is gradually increased until the pain goes away. The exact dosage needed for each individual will vary. Despite its initial effectiveness, the benefits of these drugs may lessen over time. As with most drugs, carbamazepine can be associated with side effects. Oxycarbazepine, which is a newer medication that is related to carbamazepine, is generally associated with fewer side effects than carbamazepine.Additional anti-seizure medications that have been used to treat TN in smaller studies or case reports include topiramate, gabapentin, pregabalin, clonazepam, phenytoin, lamotrigine, and valproic acid.Over time, in many cases, these drugs may become less effective or ineffective. When one anti-seizure drug loses effectiveness, another anti-seizure medication may be tried. More than one anti-seizure medication may be necessary to control pain in an affected individual. Eventually, anti-seizure medications may stop providing relief.Muscle relaxants, such as baclofen, may also be used. Such medications may be used alone or in conjunction with anti-seizure medication. Tricyclic antidepressant medications such as amitriptyline and nortriptyline can dampen pain transmission in individuals with TN2. Common pain relievers such as opioids are generally ineffective in TN1, but may provide some relief in TN2.If medications fail to control pain or become ineffective, surgery is recommended. There are several different surgical techniques that have been used to treat individuals with TN. Surgical techniques are generally not used unless other therapies have failed or become ineffective. The decision to undergo surgery to treat TN can depend on several factors. Some physicians and individuals in the TN community believe that surgical interventions should occur sooner rather than later. There is evidence that affected individuals have a better response to microvascular decompression if the surgery is done within seven years of the initial diagnosis rather than later. Surgery should be considered early in an individual who does not have an adequate response to the two front-line medications, whether these medications are used in succession or in combination. An inadequate response can be defined as incomplete pain relief affecting activities of daily living or requiring such high doses of medication to relieve the pain that the side effects limit functioning.Decisions concerning the use of a particular surgery, drug regimens, and/or other treatments should be made by physicians and other members of the health care team in careful consultation with parents or a patient based upon the specifics of the individual case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.One of the most common procedures to treat TN1 is microvascular decompression, also known as the Janetta procedure. This procedure involves moving the blood vessel that is pressing against the trigeminal nerve and inserting a soft cushion between the nerve and the vessel. This allows the trigeminal nerve to recover, eventually relieving the pain. Microvascular decompression can result in sustained pain relief of greater than 10 years in some cases. This procedure is the only non-destructive one that will leave trigeminal nerve function intact, but the procedure is the most invasive and carries a small risk of serious complications. During the procedure, the physician makes a small incision behind the ear on the same side of the head where the pain is located and creates a small hole in the skull to gain access the trigeminal nerve and the blood vessels that are compressing it.Another possible treatment is stereotactic surgery, which includes procedures known as Gamma Knife and CyberKnife. These procedures employ a highly concentrated beam of ionizing radiation that is delivered to a specific target at the root of the trigeminal nerve. The radiation creates a lesion near the nerve root that disrupts the transmission of pain signals to the brain. Pain relief may be delayed, however, by up to several weeks or months. Additionally, in approximately 50% of individuals, pain returns within three years. These procedures are the least invasive surgical techniques for treating individuals with TN and can be repeated if pain recurs.Three additional procedures involve damaging the trigeminal nerve to interrupt the transmission of pain signals to the brain. These procedures are percutaneous balloon compression, percutaneous glycerol rhizotomy, and percutaneous stereotactic rhizotomy. They involve the insertion of a needle through the cheek and into the trigeminal nerve. Percutaneous balloon compression involves inserting a tiny balloon in the trigeminal nerve near the area where the pain fibers are located. The balloon is inflated, damaging the nerve fibers. Then the balloon is deflated and removed. Percutaneous glycerol rhizotomy involves injecting glycerol, a chemical compound, into the trigeminal nerve to damage the nerve. Percutaneous stereotactic rhizotomy, also known as radiofrequency lesioning, involves uses an electrode to apply heat to damage nerve fibers.
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Overview of Trimethylaminuria
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Trimethylaminuria is a rare disorder in which the body's metabolic processes fail to alter the chemical trimethylamine. Trimethylamine is notable for its unpleasant smell. It is the chemical that gives rotten fish a bad smell. When the normal metabolic process fails, trimethylamine accumulates in the body, and its odor is detected in the person's sweat, urine and breath. The consequences of emitting a foul odor can be socially and psychologically damaging among adolescents and adults.The genetic or primary form of this disorder is transmitted in an autosomal recessive pattern. The metabolic deficiency occurs as a result of a failure in the cell to make a specific protein, in this case the enzyme flavin-containing monooxygenase 3 (FMO3). Enzymes are nature's catalysts and act to speed up biochemical processes. Without this enzyme, foods containing carnitine, choline and/or trimethylamine N-oxide are processed to trimethylamine and no further, causing a strong fishy odor.A secondary form of trimethylaminuria may result from the side effects of treatment with large doses of the amino-acid derivative L-carnitine (levocarnitine) or choline. This secondary form of the disorder is a result of an overload of trimethylamine. In this case, there is not enough of the enzyme to get rid of the excess trimethylamine.
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Overview of Trimethylaminuria. Trimethylaminuria is a rare disorder in which the body's metabolic processes fail to alter the chemical trimethylamine. Trimethylamine is notable for its unpleasant smell. It is the chemical that gives rotten fish a bad smell. When the normal metabolic process fails, trimethylamine accumulates in the body, and its odor is detected in the person's sweat, urine and breath. The consequences of emitting a foul odor can be socially and psychologically damaging among adolescents and adults.The genetic or primary form of this disorder is transmitted in an autosomal recessive pattern. The metabolic deficiency occurs as a result of a failure in the cell to make a specific protein, in this case the enzyme flavin-containing monooxygenase 3 (FMO3). Enzymes are nature's catalysts and act to speed up biochemical processes. Without this enzyme, foods containing carnitine, choline and/or trimethylamine N-oxide are processed to trimethylamine and no further, causing a strong fishy odor.A secondary form of trimethylaminuria may result from the side effects of treatment with large doses of the amino-acid derivative L-carnitine (levocarnitine) or choline. This secondary form of the disorder is a result of an overload of trimethylamine. In this case, there is not enough of the enzyme to get rid of the excess trimethylamine.
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Symptoms of Trimethylaminuria
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The fish-odor smell is the obvious symptom; otherwise affected individuals appear normal and healthy.Trimethylamine is normally formed by bacterial action in the intestine on choline (found in foods such as soy, liver, kidneys, wheat germ, brewer’s yeast, and egg yolk), or on trimethylamine N-oxide (found in salt water fish). The trimethylamine is then carried to the liver where it is converted to trimethylamine N-oxide, a metabolic product that has no odor.When secondary trimethylaminuria develops as a result of large oral doses of L-carnitine, choline or lecithin, the symptoms disappear as the dosage is lowered. L-carnitine is used in the treatment of carnitine-deficiency syndromes and is sometimes used by athletes who believe it enhances physical strength. (For more information on this disorder, choose “carnitine” as your search words in the Rare Disease Database). Choline is used in the treatment of Huntington disease and Alzheimer disease. Choline and lecithin are present in certain food supplements and ‘health’ foods.
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Symptoms of Trimethylaminuria. The fish-odor smell is the obvious symptom; otherwise affected individuals appear normal and healthy.Trimethylamine is normally formed by bacterial action in the intestine on choline (found in foods such as soy, liver, kidneys, wheat germ, brewer’s yeast, and egg yolk), or on trimethylamine N-oxide (found in salt water fish). The trimethylamine is then carried to the liver where it is converted to trimethylamine N-oxide, a metabolic product that has no odor.When secondary trimethylaminuria develops as a result of large oral doses of L-carnitine, choline or lecithin, the symptoms disappear as the dosage is lowered. L-carnitine is used in the treatment of carnitine-deficiency syndromes and is sometimes used by athletes who believe it enhances physical strength. (For more information on this disorder, choose “carnitine” as your search words in the Rare Disease Database). Choline is used in the treatment of Huntington disease and Alzheimer disease. Choline and lecithin are present in certain food supplements and ‘health’ foods.
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Causes of Trimethylaminuria
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Primary trimethylaminuria is a rare metabolic disorder caused by changes (mutations) in the FMO3 gene. Humans have several FMO genes, but only mutations in FMO3 cause trimethylaminuria. For reasons that are unclear, many different mutations of the FMO3 gene exist.Primary trimethylaminuria is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one 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 altered gene and, therefore, have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents of both carrying the same abnormal gene, which increases the risk of having children with a recessive genetic disorder.Secondary trimethylaminuria occurs as the result of treatment with large doses of dietary precursors of the offending chemical. Symptoms develop when the ability of the liver enzyme (flavin-containing monooxygenase 3) is insufficient to break down (metabolize) the excess trimethylamine.
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Causes of Trimethylaminuria. Primary trimethylaminuria is a rare metabolic disorder caused by changes (mutations) in the FMO3 gene. Humans have several FMO genes, but only mutations in FMO3 cause trimethylaminuria. For reasons that are unclear, many different mutations of the FMO3 gene exist.Primary trimethylaminuria is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one 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 altered gene and, therefore, have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents of both carrying the same abnormal gene, which increases the risk of having children with a recessive genetic disorder.Secondary trimethylaminuria occurs as the result of treatment with large doses of dietary precursors of the offending chemical. Symptoms develop when the ability of the liver enzyme (flavin-containing monooxygenase 3) is insufficient to break down (metabolize) the excess trimethylamine.
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Affects of Trimethylaminuria
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Trimethylaminuria is a rare metabolic disorder. More than 100 cases have been reported in the medical literature. Some clinicians believe that the disorder is under-diagnosed since many people with mild symptoms do not seek help. However, some physicians do not recognize the symptoms of trimethylaminuria when a person with body odor seeks a diagnosis.
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Affects of Trimethylaminuria. Trimethylaminuria is a rare metabolic disorder. More than 100 cases have been reported in the medical literature. Some clinicians believe that the disorder is under-diagnosed since many people with mild symptoms do not seek help. However, some physicians do not recognize the symptoms of trimethylaminuria when a person with body odor seeks a diagnosis.
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Related disorders of Trimethylaminuria
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Related disorders of Trimethylaminuria.
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Diagnosis of Trimethylaminuria
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The presence of the rotten-fish odor is indicative, especially in severe cases. However, diagnosis based on smell is unreliable because the odor is often episodic and not everyone can detect the smell of trimethylamine. In addition, on the basis of smell, trimethylaminuria can be difficult to distinguish from other conditions that give rise to an unpleasant body odor. Diagnosis is based on urinary analysis of trimethylamine and trimethylamine N-oxide, which can distinguish between severe and mild cases. Urine analysis after the administration of large doses of trimethylamine can distinguish carriers of the condition from unaffected individuals. Genetic testing is available to distinguish between primary genetic trimethylaminuria, which will result in severe symptoms, and secondary, non-genetic forms of the disorder.
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Diagnosis of Trimethylaminuria. The presence of the rotten-fish odor is indicative, especially in severe cases. However, diagnosis based on smell is unreliable because the odor is often episodic and not everyone can detect the smell of trimethylamine. In addition, on the basis of smell, trimethylaminuria can be difficult to distinguish from other conditions that give rise to an unpleasant body odor. Diagnosis is based on urinary analysis of trimethylamine and trimethylamine N-oxide, which can distinguish between severe and mild cases. Urine analysis after the administration of large doses of trimethylamine can distinguish carriers of the condition from unaffected individuals. Genetic testing is available to distinguish between primary genetic trimethylaminuria, which will result in severe symptoms, and secondary, non-genetic forms of the disorder.
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Therapies of Trimethylaminuria
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Treatment
In mild cases, symptoms are relieved when foods containing choline and lecithin are restricted. Some severe cases may require the administration of a gut-sterilizing antibiotic such as metronidazole. This treatment reduces the number of intestinal bacteria that break down choline and trimethylamine N-oxide into trimethylamine. In the case of mutations that do not completely abolish FMO3 activity, supplements of riboflavin might help maximize residual enzyme activity. Dietary supplements such as activated charcoal and copper chlorophyllin can bind trimethylamine in the gut and hence reduce the amount available for absorption. The use of slightly acidic soaps and body lotions can convert trimethylamine on the skin into a less volatile form that can be removed by washing. If the disorder is acquired due to excessive doses of L-carnitine, choline or lecithin, symptoms disappear with reduction of dosage.Genetic counseling may be helpful for patients and their families.
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Therapies of Trimethylaminuria. Treatment
In mild cases, symptoms are relieved when foods containing choline and lecithin are restricted. Some severe cases may require the administration of a gut-sterilizing antibiotic such as metronidazole. This treatment reduces the number of intestinal bacteria that break down choline and trimethylamine N-oxide into trimethylamine. In the case of mutations that do not completely abolish FMO3 activity, supplements of riboflavin might help maximize residual enzyme activity. Dietary supplements such as activated charcoal and copper chlorophyllin can bind trimethylamine in the gut and hence reduce the amount available for absorption. The use of slightly acidic soaps and body lotions can convert trimethylamine on the skin into a less volatile form that can be removed by washing. If the disorder is acquired due to excessive doses of L-carnitine, choline or lecithin, symptoms disappear with reduction of dosage.Genetic counseling may be helpful for patients and their families.
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Overview of Triosephosphate Isomerase Deficiency
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Triosephosphate isomerase (TPI) deficiency is a rare genetic multisystem disorder. It is characterized by lack or reduced activity of the enzyme triosephosphate isomerase, an enzyme necessary for the breakdown (metabolism) of certain sugars in the body. Affected individuals experience low levels of circulating red blood cells due to premature destruction of red blood cells (hemolytic anemia) and severe, progressive neurological symptoms. Specific symptoms vary from case to case. Intellectual disability is a variable finding. Additional symptoms may develop including disease of the heart muscle (cardiomyopathy) and a susceptibility to developing chronic infections. Affected individuals usually develop life-threatening complications early during childhood. TPI deficiency is inherited as an autosomal recessive trait.
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Overview of Triosephosphate Isomerase Deficiency. Triosephosphate isomerase (TPI) deficiency is a rare genetic multisystem disorder. It is characterized by lack or reduced activity of the enzyme triosephosphate isomerase, an enzyme necessary for the breakdown (metabolism) of certain sugars in the body. Affected individuals experience low levels of circulating red blood cells due to premature destruction of red blood cells (hemolytic anemia) and severe, progressive neurological symptoms. Specific symptoms vary from case to case. Intellectual disability is a variable finding. Additional symptoms may develop including disease of the heart muscle (cardiomyopathy) and a susceptibility to developing chronic infections. Affected individuals usually develop life-threatening complications early during childhood. TPI deficiency is inherited as an autosomal recessive trait.
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Symptoms of Triosephosphate Isomerase Deficiency
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The symptoms of TPI deficiency vary from case to case. The disorder is characterized by hemolytic anemia and progressive neurological findings. Hemolytic anemia occurs before birth (neonatally) in approximately half of the cases.Hemolytic anemia is a condition characterized by low levels of circulating red blood cells (erythrocytes) that occurs because red blood cells are prematurely destroyed and the bone marrow cannot compensate for the loss. Hemolytic anemia may cause fatigue, lightheadedness, yellowing of the skin and whites of the eyes (jaundice), pale skin color, and difficulty breathing.Additional symptoms associated with TPI deficiency include increased susceptibility to infections, an abnormally enlarged spleen (splenomegaly), breathing difficulties due to paralysis of the muscle that separates the stomach and the chest cavity (diaphragm), and disease of the heart muscle (cardiomyopathy).In most cases, life-threatening complications such as respiratory or heart (cardiac) failure occur during childhood. However, adults with TPI deficiency with less severe symptoms have been reported.Progressive neurological symptoms are seen in infants with TPI deficiency usually between 6 and 30 months of age. Such symptoms include diminished muscle tone (hypotonia), weakness, muscular wasting or degeneration (amyotrophy), lack of deep tendon reflexes, and involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs.Some individuals do not develop any additional neurological symptoms and intelligence is unaffected. In other cases, intellectual disability occurs along with tremors and dystonia. Dystonia is the name for a group of movement disorders that is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures).
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Symptoms of Triosephosphate Isomerase Deficiency. The symptoms of TPI deficiency vary from case to case. The disorder is characterized by hemolytic anemia and progressive neurological findings. Hemolytic anemia occurs before birth (neonatally) in approximately half of the cases.Hemolytic anemia is a condition characterized by low levels of circulating red blood cells (erythrocytes) that occurs because red blood cells are prematurely destroyed and the bone marrow cannot compensate for the loss. Hemolytic anemia may cause fatigue, lightheadedness, yellowing of the skin and whites of the eyes (jaundice), pale skin color, and difficulty breathing.Additional symptoms associated with TPI deficiency include increased susceptibility to infections, an abnormally enlarged spleen (splenomegaly), breathing difficulties due to paralysis of the muscle that separates the stomach and the chest cavity (diaphragm), and disease of the heart muscle (cardiomyopathy).In most cases, life-threatening complications such as respiratory or heart (cardiac) failure occur during childhood. However, adults with TPI deficiency with less severe symptoms have been reported.Progressive neurological symptoms are seen in infants with TPI deficiency usually between 6 and 30 months of age. Such symptoms include diminished muscle tone (hypotonia), weakness, muscular wasting or degeneration (amyotrophy), lack of deep tendon reflexes, and involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs.Some individuals do not develop any additional neurological symptoms and intelligence is unaffected. In other cases, intellectual disability occurs along with tremors and dystonia. Dystonia is the name for a group of movement disorders that is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures).
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Causes of Triosephosphate Isomerase Deficiency
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TPI deficiency is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one 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 defective gene and 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 normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Investigators have determined that TPI deficiency occurs due to disruption or changes (mutations) of a gene located on the short arm of chromosome 12 (12p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
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Causes of Triosephosphate Isomerase Deficiency. TPI deficiency is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one 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 defective gene and 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 normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Investigators have determined that TPI deficiency occurs due to disruption or changes (mutations) of a gene located on the short arm of chromosome 12 (12p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
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Affects of Triosephosphate Isomerase Deficiency
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TPI deficiency affects males and females in equal numbers. Approximately 30 to 50 cases have been reported in the medical literature since the disorder initial description in 1965.
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Affects of Triosephosphate Isomerase Deficiency. TPI deficiency affects males and females in equal numbers. Approximately 30 to 50 cases have been reported in the medical literature since the disorder initial description in 1965.
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Related disorders of Triosephosphate Isomerase Deficiency
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Symptoms of the following disorders can be similar to those of TPI deficiency. Comparisons may be useful for a differential diagnosis.Red cell pyruvate kinase deficiency is a hereditary blood disorder characterized by a deficiency of the enzyme pyruvate kinase. Physical findings associated with the disorder may include reduced levels of oxygen-carrying hemoglobulin in the blood due to premature destruction of red blood cells (hemolytic anemia); abnormally increased levels of bilirubin in the blood (hyperbilirubinemia); abnormal enlargement of the spleen (splenomegaly); and/or other abnormalities. Pyruvate kinase deficiency is inherited as an autosomal recessive genetic trait. It is one of a group of diseases known as hereditary nonspherocytic hemolytic anemias. Nonspherocytic refers to the fact that the red blood cells do not assume a spherical shape, as they do with some blood disorders. (For more information on this disorder, choose “pyruvate kinase deficiency” as your search term in the Rare Disease Database.)Phosphoglycerate kinase deficiency is an extremely rare inherited metabolic disorder characterized by deficiency of the enzyme phosphoglycerate kinase. This enzyme is essential for the breakdown of glycogen, resulting in the release of energy. Symptoms and findings associated with the disorder may include low levels of circulating red blood cells (hemolytic anemia); varying degrees of mental retardation; rapidly changing emotions (emotional lability); an impaired ability to communicate through and/or to comprehend speech or writing (aphasia); exercise-induced pain, stiffness, or cramps; enlargement of the spleen (splenomegaly); and/or paralysis of one side of the body (hemiplegia). In most cases, phosphoglycerate kinase deficiency is inherited as an X-linked trait. In such cases, the disorder is fully expressed in males only; however, some females who carry one copy of the disease gene (heterozygotes) may have hemolytic anemia. (For more information on this disorder, choose “phosphoglycerate kinase deficiency” as your search term in the Rare Disease Database.)
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Related disorders of Triosephosphate Isomerase Deficiency. Symptoms of the following disorders can be similar to those of TPI deficiency. Comparisons may be useful for a differential diagnosis.Red cell pyruvate kinase deficiency is a hereditary blood disorder characterized by a deficiency of the enzyme pyruvate kinase. Physical findings associated with the disorder may include reduced levels of oxygen-carrying hemoglobulin in the blood due to premature destruction of red blood cells (hemolytic anemia); abnormally increased levels of bilirubin in the blood (hyperbilirubinemia); abnormal enlargement of the spleen (splenomegaly); and/or other abnormalities. Pyruvate kinase deficiency is inherited as an autosomal recessive genetic trait. It is one of a group of diseases known as hereditary nonspherocytic hemolytic anemias. Nonspherocytic refers to the fact that the red blood cells do not assume a spherical shape, as they do with some blood disorders. (For more information on this disorder, choose “pyruvate kinase deficiency” as your search term in the Rare Disease Database.)Phosphoglycerate kinase deficiency is an extremely rare inherited metabolic disorder characterized by deficiency of the enzyme phosphoglycerate kinase. This enzyme is essential for the breakdown of glycogen, resulting in the release of energy. Symptoms and findings associated with the disorder may include low levels of circulating red blood cells (hemolytic anemia); varying degrees of mental retardation; rapidly changing emotions (emotional lability); an impaired ability to communicate through and/or to comprehend speech or writing (aphasia); exercise-induced pain, stiffness, or cramps; enlargement of the spleen (splenomegaly); and/or paralysis of one side of the body (hemiplegia). In most cases, phosphoglycerate kinase deficiency is inherited as an X-linked trait. In such cases, the disorder is fully expressed in males only; however, some females who carry one copy of the disease gene (heterozygotes) may have hemolytic anemia. (For more information on this disorder, choose “phosphoglycerate kinase deficiency” as your search term in the Rare Disease Database.)
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Diagnosis of Triosephosphate Isomerase Deficiency
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A diagnosis of TPI deficiency is suspected based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic findings. A diagnosis may be confirmed by molecular genetic testing that identifies the characteristic genetic mutation associated with TPI deficiency.Prenatal diagnosis is possible by measuring TPI enzyme activity in amniotic fluid cells and fetal blood cells. A procedure known as chorionic villus sampling (CVS) has also been used for prenatal diagnosis. This procedure involves the removal and study of tissue samples from the placenta.
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Diagnosis of Triosephosphate Isomerase Deficiency. A diagnosis of TPI deficiency is suspected based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic findings. A diagnosis may be confirmed by molecular genetic testing that identifies the characteristic genetic mutation associated with TPI deficiency.Prenatal diagnosis is possible by measuring TPI enzyme activity in amniotic fluid cells and fetal blood cells. A procedure known as chorionic villus sampling (CVS) has also been used for prenatal diagnosis. This procedure involves the removal and study of tissue samples from the placenta.
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Therapies of Triosephosphate Isomerase Deficiency
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TreatmentNo specific therapy exists for of TPI deficiency. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, cardiologists, neurologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.Specific therapies may include blood transfusions to treat hemolytic anemia during episodes of red blood cell destruction (hemolysis) and assisted ventilation to treat paralysis of the diaphragm. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Triosephosphate Isomerase Deficiency. TreatmentNo specific therapy exists for of TPI deficiency. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, cardiologists, neurologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.Specific therapies may include blood transfusions to treat hemolytic anemia during episodes of red blood cell destruction (hemolysis) and assisted ventilation to treat paralysis of the diaphragm. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Overview of Triploidy
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Summary Triploidy is a rare chromosomal abnormality. Triploidy is the presence of an additional set of chromosomes in the cell for a total of 69 chromosomes rather than the normal 46 chromosomes per cell. The extra set of chromosomes originates either from the father or the mother during fertilization. Pregnancies with triploidy are usually miscarried early in the pregnancy. If the pregnancy continues to term, the infant dies within the first days of life. A few affected individuals have been reported to have survived to adulthood, but suffered from developmental delay, learning difficulties, seizures, hearing loss and other abnormalities. Those that survive have mosaic triploidy, meaning that some cells have the normal number of 46 chromosomes and other cells have 69 chromosomes per cell. Infants affected with complete triploidy suffer from growth restriction and multiple birth defects.
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Overview of Triploidy. Summary Triploidy is a rare chromosomal abnormality. Triploidy is the presence of an additional set of chromosomes in the cell for a total of 69 chromosomes rather than the normal 46 chromosomes per cell. The extra set of chromosomes originates either from the father or the mother during fertilization. Pregnancies with triploidy are usually miscarried early in the pregnancy. If the pregnancy continues to term, the infant dies within the first days of life. A few affected individuals have been reported to have survived to adulthood, but suffered from developmental delay, learning difficulties, seizures, hearing loss and other abnormalities. Those that survive have mosaic triploidy, meaning that some cells have the normal number of 46 chromosomes and other cells have 69 chromosomes per cell. Infants affected with complete triploidy suffer from growth restriction and multiple birth defects.
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Symptoms of Triploidy
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Infants affected with triploidy have heart defects, abnormal brain development, adrenal and kidney defects (cystic kidneys), spinal cord malformations (neural tube defects) and abnormal facial features (widely spaced eyes, low nasal bridge, low-set malformed ears, small jaw, absent/small eye, and cleft lip and palate). The third and fourth fingers of the hands and the second and third toes of the feet may be united and the hands may have unusual simian creases. There may also be liver and gallbladder defects, twisted intestines and deformities of the fingers and toes. The placenta in triploidy may be immature, large, and filled with cysts. Individuals who are mosaic will survive longer than those with complete triploidy but usually have intellectual disability, developmental delay, depression, seizures, short stature, obesity and other abnormalities.The pregnant mother carrying a triploidy fetus sometimes experiences increase in blood pressure (hypertension), swelling (edema), and excretion of albumin in the urine (albuminuria). This condition is called toxemia or preeclampsia.
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Symptoms of Triploidy. Infants affected with triploidy have heart defects, abnormal brain development, adrenal and kidney defects (cystic kidneys), spinal cord malformations (neural tube defects) and abnormal facial features (widely spaced eyes, low nasal bridge, low-set malformed ears, small jaw, absent/small eye, and cleft lip and palate). The third and fourth fingers of the hands and the second and third toes of the feet may be united and the hands may have unusual simian creases. There may also be liver and gallbladder defects, twisted intestines and deformities of the fingers and toes. The placenta in triploidy may be immature, large, and filled with cysts. Individuals who are mosaic will survive longer than those with complete triploidy but usually have intellectual disability, developmental delay, depression, seizures, short stature, obesity and other abnormalities.The pregnant mother carrying a triploidy fetus sometimes experiences increase in blood pressure (hypertension), swelling (edema), and excretion of albumin in the urine (albuminuria). This condition is called toxemia or preeclampsia.
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Causes of Triploidy
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Triploidy is the presence of a complete additional set of chromosomes. The triplication of the chromosomes is caused by the fertilization of an egg by two sperms, or the fertilization of an egg by a sperm that has an extra set of chromosomes or by the fertilization of an egg that has an extra set of chromosomes by a normal sperm. This disorder does not run in families and is not associated with maternal or paternal age.
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Causes of Triploidy. Triploidy is the presence of a complete additional set of chromosomes. The triplication of the chromosomes is caused by the fertilization of an egg by two sperms, or the fertilization of an egg by a sperm that has an extra set of chromosomes or by the fertilization of an egg that has an extra set of chromosomes by a normal sperm. This disorder does not run in families and is not associated with maternal or paternal age.
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Affects of Triploidy
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Triploidy accounts for 1-3 percent of all pregnancies. 2/3 of triploid pregnancies are male.
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Affects of Triploidy. Triploidy accounts for 1-3 percent of all pregnancies. 2/3 of triploid pregnancies are male.
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Related disorders of Triploidy
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Symptoms of the following disorders are caused by duplication, triplication or deletion of chromosomes:Tetraploidy is a condition in which there are four sets of chromosomes in a single cell instead of the normal two sets. The total number of chromosomes per cell in tetraploidy is 92 instead of 46. The affected babies are usually miscarried early in the pregnancy or die within the first days of life. Affected babies have been reported to have multiple birth defects such as abnormal facial features (small head and jaw, cleft lip and palate, small or absent eye ball, abnormal ears), heart defects, brain defects, abnormal genitals and feet abnormalities (clubfoot). Tetraploidy can be suspected during pregnancy by the detection of birth defects on ultrasound. The final diagnosis can be made by cytogenetic analysis of cells taken during pregnancy through amniocentesis or chorionic villus sampling (CVS).Trisomies, such as trisomy 21 (Down syndrome), are characterized by a triple chromosome. The most common symptom of the trisomies is intellectual disability. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. People with a trisomy have an extra chromosome added to one of the normal pairs. The triplication of the chromosome may be partial, either an extra short arm (p+) or an extra long arm (q+). Conditions are classified by the name of the abnormal chromosome pair and which portion of the chromosome is affected. (For more information on this disorder, choose “Trisomy” as your search term in the Rare Disease Database.)Down syndrome (trisomy 21) is the most common and readily identifiable genetic condition caused by a chromosomal abnormality. One additional chromosome is present. Children with Down syndrome have some degree of intellectual disability that can range from mild to profound. However, most children with Down syndrome function in the mild to moderate range.Chromosome 11q-syndrome (Jacobsen syndrome) is a rare genetic disorder caused by lack of the long arm of chromosome 11. The disorder may be characterized by a narrow protruding forehead, eye problems, abnormally shaped nose and mouth and intellectual disability. The severity and type of abnormality depends upon the size and location of the missing chromosome piece. The cause of the chromosome break itself is unknown. (For more information on this disorder, choose “Chromosome 11, Partial Monosomy 11q” as your search term in the Rare Disease Database.)Chromosome 18p-syndrome is a deletion of the short arm (p) of chromosome 18. It is characterized by unusual facial features and mild to severe intellectual disability. This syndrome may also include growth deficiency, diminished muscle tension and a smaller than normal sized brain. There may also be behavior problems and delayed speech. (For more information on this disorder, choose “Chromosome 18p-Syndrome” as your search term in the Rare Disease Database.)
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Related disorders of Triploidy. Symptoms of the following disorders are caused by duplication, triplication or deletion of chromosomes:Tetraploidy is a condition in which there are four sets of chromosomes in a single cell instead of the normal two sets. The total number of chromosomes per cell in tetraploidy is 92 instead of 46. The affected babies are usually miscarried early in the pregnancy or die within the first days of life. Affected babies have been reported to have multiple birth defects such as abnormal facial features (small head and jaw, cleft lip and palate, small or absent eye ball, abnormal ears), heart defects, brain defects, abnormal genitals and feet abnormalities (clubfoot). Tetraploidy can be suspected during pregnancy by the detection of birth defects on ultrasound. The final diagnosis can be made by cytogenetic analysis of cells taken during pregnancy through amniocentesis or chorionic villus sampling (CVS).Trisomies, such as trisomy 21 (Down syndrome), are characterized by a triple chromosome. The most common symptom of the trisomies is intellectual disability. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. People with a trisomy have an extra chromosome added to one of the normal pairs. The triplication of the chromosome may be partial, either an extra short arm (p+) or an extra long arm (q+). Conditions are classified by the name of the abnormal chromosome pair and which portion of the chromosome is affected. (For more information on this disorder, choose “Trisomy” as your search term in the Rare Disease Database.)Down syndrome (trisomy 21) is the most common and readily identifiable genetic condition caused by a chromosomal abnormality. One additional chromosome is present. Children with Down syndrome have some degree of intellectual disability that can range from mild to profound. However, most children with Down syndrome function in the mild to moderate range.Chromosome 11q-syndrome (Jacobsen syndrome) is a rare genetic disorder caused by lack of the long arm of chromosome 11. The disorder may be characterized by a narrow protruding forehead, eye problems, abnormally shaped nose and mouth and intellectual disability. The severity and type of abnormality depends upon the size and location of the missing chromosome piece. The cause of the chromosome break itself is unknown. (For more information on this disorder, choose “Chromosome 11, Partial Monosomy 11q” as your search term in the Rare Disease Database.)Chromosome 18p-syndrome is a deletion of the short arm (p) of chromosome 18. It is characterized by unusual facial features and mild to severe intellectual disability. This syndrome may also include growth deficiency, diminished muscle tension and a smaller than normal sized brain. There may also be behavior problems and delayed speech. (For more information on this disorder, choose “Chromosome 18p-Syndrome” as your search term in the Rare Disease Database.)
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Diagnosis of Triploidy
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The presence of multiple major malformations, low amniotic fluid and/or growth restriction on fetal ultrasound during pregnancy raises the suspicion of triploidy. The diagnosis can be made during pregnancy by chromosome analysis (karyotyping) of cells obtained by amniocentesis or chorionic villus sampling (CVS). The diagnosis can be confirmed after birth by chromosome analysis of tissue (skin) obtained from the affected infant. Triploidy cannot be diagnosed by chromosome microarray testing. The accuracy of non-invasive prenatal testing using cell-free fetal (cff) DNA in the diagnosis of triploidy is still being studied. Abnormal levels of specific maternal blood proteins such as alpha-fetoprotein, human chorionic gonadotropin, estriol and pregnancy-assisted plasma protein-A have been associated with an increased risk for triploidy.
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Diagnosis of Triploidy. The presence of multiple major malformations, low amniotic fluid and/or growth restriction on fetal ultrasound during pregnancy raises the suspicion of triploidy. The diagnosis can be made during pregnancy by chromosome analysis (karyotyping) of cells obtained by amniocentesis or chorionic villus sampling (CVS). The diagnosis can be confirmed after birth by chromosome analysis of tissue (skin) obtained from the affected infant. Triploidy cannot be diagnosed by chromosome microarray testing. The accuracy of non-invasive prenatal testing using cell-free fetal (cff) DNA in the diagnosis of triploidy is still being studied. Abnormal levels of specific maternal blood proteins such as alpha-fetoprotein, human chorionic gonadotropin, estriol and pregnancy-assisted plasma protein-A have been associated with an increased risk for triploidy.
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Therapies of Triploidy
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TreatmentTreatment of triploid syndrome is symptomatic and supportive.
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Therapies of Triploidy. TreatmentTreatment of triploid syndrome is symptomatic and supportive.
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Overview of Trismus-Pseudocamptodactyly Syndrome
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SummaryTrismus-pseudocamptodactyly syndrome (TPS) is a rare inherited disorder characterized by short muscles and tendons that result in limited mobility of the hands, legs, and mouth. The most serious complication of this condition is the inability to completely open the mouth (trismus), which causes difficulty with chewing. Short muscles and tendons in the fingers cause the fingers to bend or curve (camptodactyly) when the hand is bent back at the wrist. However, the fingers are not permanently bent or curved, so this particular finding is called “pseudocamptodactyly” (pseudo meaning false). This condition can also result in limited movement and various malformations of the feet. Many of the symptoms of TPS manifest during infancy. As an affected child ages, abnormalities associated with shortened muscle-tendons units (e.g., difficulty with coordinated hand movements) may become apparent. There is currently no cure for this condition, however, a team of specialist can help treat and manage the symptoms. The severity of these physical findings varies from individual to individual.
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Overview of Trismus-Pseudocamptodactyly Syndrome. SummaryTrismus-pseudocamptodactyly syndrome (TPS) is a rare inherited disorder characterized by short muscles and tendons that result in limited mobility of the hands, legs, and mouth. The most serious complication of this condition is the inability to completely open the mouth (trismus), which causes difficulty with chewing. Short muscles and tendons in the fingers cause the fingers to bend or curve (camptodactyly) when the hand is bent back at the wrist. However, the fingers are not permanently bent or curved, so this particular finding is called “pseudocamptodactyly” (pseudo meaning false). This condition can also result in limited movement and various malformations of the feet. Many of the symptoms of TPS manifest during infancy. As an affected child ages, abnormalities associated with shortened muscle-tendons units (e.g., difficulty with coordinated hand movements) may become apparent. There is currently no cure for this condition, however, a team of specialist can help treat and manage the symptoms. The severity of these physical findings varies from individual to individual.
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Symptoms of Trismus-Pseudocamptodactyly Syndrome
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TPS is a rare genetic disorder of muscle development and function. It is characterized by the inability to fully open the mouth (trismus), often resulting in problems with chewing. Although this is one of the most significant findings, it may not be as severe in some affected individuals. In those whom this abnormality is severe, limited and/or impaired chewing may cause difficulties with eating and proper digestion.Other major physical findings associated with TPS involve the fibrous cords that connect muscles to bones (tendons). Tendons work together with nearby muscles (muscle-tendon unit) and bones to produce movement of various parts of the body. If tendons are unusually short, this may result in certain physical abnormalities. In TPS, the muscle-tendon units in the fingers are unusually short, resulting in curved or bent fingers (camptodactyly) when the hand is bent backward at the wrist. However, if the hand is bent forward at the wrist, the fingers can then be completely extended. The fingers are not permanently fixed in the bent or curved position, therefore this finding is called “pseudocamptodactyly”.In addition, individuals with this syndrome have shortened muscle-tendon units in the forearms and legs. Short muscle-tendon units in the leg may cause various foot problems. These may include a permanent flexing of the toe or toes (hammer or claw toes), abnormal inward bending of the foot (clubfoot), flatfoot, and/or pigeon-toe. In some cases, shortened muscles and tendons may result in an unusual tilt of the pelvis, which can lead to hip dislocation. Abnormal positioning or slight twist of the head is also seen in some individuals. Many people with TPS often have difficulty with fine motor skills of the hands (i.e. holding small objects) and walking. Some individuals with TPS may be slightly shorter than would otherwise be expected. Those with TPS have a normal life expectancy and normal intelligence. It is important to note that the severity of the physical findings associated with this disorder may vary from individual to individual.
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Symptoms of Trismus-Pseudocamptodactyly Syndrome. TPS is a rare genetic disorder of muscle development and function. It is characterized by the inability to fully open the mouth (trismus), often resulting in problems with chewing. Although this is one of the most significant findings, it may not be as severe in some affected individuals. In those whom this abnormality is severe, limited and/or impaired chewing may cause difficulties with eating and proper digestion.Other major physical findings associated with TPS involve the fibrous cords that connect muscles to bones (tendons). Tendons work together with nearby muscles (muscle-tendon unit) and bones to produce movement of various parts of the body. If tendons are unusually short, this may result in certain physical abnormalities. In TPS, the muscle-tendon units in the fingers are unusually short, resulting in curved or bent fingers (camptodactyly) when the hand is bent backward at the wrist. However, if the hand is bent forward at the wrist, the fingers can then be completely extended. The fingers are not permanently fixed in the bent or curved position, therefore this finding is called “pseudocamptodactyly”.In addition, individuals with this syndrome have shortened muscle-tendon units in the forearms and legs. Short muscle-tendon units in the leg may cause various foot problems. These may include a permanent flexing of the toe or toes (hammer or claw toes), abnormal inward bending of the foot (clubfoot), flatfoot, and/or pigeon-toe. In some cases, shortened muscles and tendons may result in an unusual tilt of the pelvis, which can lead to hip dislocation. Abnormal positioning or slight twist of the head is also seen in some individuals. Many people with TPS often have difficulty with fine motor skills of the hands (i.e. holding small objects) and walking. Some individuals with TPS may be slightly shorter than would otherwise be expected. Those with TPS have a normal life expectancy and normal intelligence. It is important to note that the severity of the physical findings associated with this disorder may vary from individual to individual.
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Causes of Trismus-Pseudocamptodactyly Syndrome
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TPS is an autosomal dominant disorder caused by changes in the MYH8 gene. All cases of TPS studied to date were found to have the same change in the MYH8 gene. This gene is involved in making the instructions for the development of the limb skeletal muscles and the muscles in the face.Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular 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 an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
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Causes of Trismus-Pseudocamptodactyly Syndrome. TPS is an autosomal dominant disorder caused by changes in the MYH8 gene. All cases of TPS studied to date were found to have the same change in the MYH8 gene. This gene is involved in making the instructions for the development of the limb skeletal muscles and the muscles in the face.Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular 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 an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
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Trismus-Pseudocamptodactyly Syndrome
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Affects of Trismus-Pseudocamptodactyly Syndrome
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TPS affects females and males equally. However, twice as many affected females have been reported. The current prevalence rate of TPS is unknown. Approximately 11 families and over 300 individual cases have been reported since the disorder was first described in 1969. Of those cases, some have been traced to a Dutch female who came to the United States and settled in Tennessee during the eighteenth century. In addition, other reported cases have included five affected individuals in three generations of one Japanese family, six affected members of a German family. Affected individuals of families from the Netherlands, Canada, United Kingdom, Belgium, and Taiwan have also been reported.
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Affects of Trismus-Pseudocamptodactyly Syndrome. TPS affects females and males equally. However, twice as many affected females have been reported. The current prevalence rate of TPS is unknown. Approximately 11 families and over 300 individual cases have been reported since the disorder was first described in 1969. Of those cases, some have been traced to a Dutch female who came to the United States and settled in Tennessee during the eighteenth century. In addition, other reported cases have included five affected individuals in three generations of one Japanese family, six affected members of a German family. Affected individuals of families from the Netherlands, Canada, United Kingdom, Belgium, and Taiwan have also been reported.
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Related disorders of Trismus-Pseudocamptodactyly Syndrome
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Symptoms of the following genetic disorders can be similar to those of Trismus-Pseudocamptodactyly syndrome. Comparisons may be useful for a differential diagnosis:Freeman-Sheldon syndrome, is a rare, autosomal dominant disorder genetic condition that is apparent at birth (congenital). It is characterized by abnormal skeletal development and an unusual expressionless face with full cheeks and a small mouth, giving a typical “whistling” facial appearance. Symptoms may include permanent fixation of the fingers in a flexed position (camptodactyly), unusual outward positioning of the fingers (ulnar deviation of the fingers), and/or abnormal inward bending of the foot (clubfoot). In addition, affected individuals may have deep set and widely-spaced eyes, small nose and nostrils, small mouth, vertical folds in the jaw skin, and/or other facial features. In some cases, sideways curvature of the spine (scoliosis) may be present. Other skeletal malformations may become clear during X-ray or other imaging procedures. Individuals with Freeman-Sheldon syndrome are of normal height. (For more information on this disorder, search “Freeman Sheldon syndrome” in the Rare Disease Database.)Distal arthrogryposis multiplex congenita, type 2B, is a rare, autosomal dominant disorder that is apparent at birth and is characterized by stiffness or immobility of the joints (contractures) with deformities of the hands and/or feet. Symptoms may include a permanent flexing of the fingers (camptodactyly), unusual positioning of the fingers and/or feet, abnormal bending inward of the foot (clubfoot), and other irregularities of the arms and legs. Other features of this disorder may include an inability to completely open the mouth (trismus), an underdeveloped jaw, a receding jaw, an abnormal split (cleft) on the upper lip and/or the roof of the mouth (palate), droopy eyelids, and/or a webbed neck. In addition, affected individuals may exhibit abnormalities of the bones of the spine (vertebrae). People with distal arthrogryposis multiplex congenita, type 2B are shorter than would otherwise be expected. (For more information on this disorder, search “arthrogryposis multiplex congenita” in the Rare Disease Database.)
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Related disorders of Trismus-Pseudocamptodactyly Syndrome. Symptoms of the following genetic disorders can be similar to those of Trismus-Pseudocamptodactyly syndrome. Comparisons may be useful for a differential diagnosis:Freeman-Sheldon syndrome, is a rare, autosomal dominant disorder genetic condition that is apparent at birth (congenital). It is characterized by abnormal skeletal development and an unusual expressionless face with full cheeks and a small mouth, giving a typical “whistling” facial appearance. Symptoms may include permanent fixation of the fingers in a flexed position (camptodactyly), unusual outward positioning of the fingers (ulnar deviation of the fingers), and/or abnormal inward bending of the foot (clubfoot). In addition, affected individuals may have deep set and widely-spaced eyes, small nose and nostrils, small mouth, vertical folds in the jaw skin, and/or other facial features. In some cases, sideways curvature of the spine (scoliosis) may be present. Other skeletal malformations may become clear during X-ray or other imaging procedures. Individuals with Freeman-Sheldon syndrome are of normal height. (For more information on this disorder, search “Freeman Sheldon syndrome” in the Rare Disease Database.)Distal arthrogryposis multiplex congenita, type 2B, is a rare, autosomal dominant disorder that is apparent at birth and is characterized by stiffness or immobility of the joints (contractures) with deformities of the hands and/or feet. Symptoms may include a permanent flexing of the fingers (camptodactyly), unusual positioning of the fingers and/or feet, abnormal bending inward of the foot (clubfoot), and other irregularities of the arms and legs. Other features of this disorder may include an inability to completely open the mouth (trismus), an underdeveloped jaw, a receding jaw, an abnormal split (cleft) on the upper lip and/or the roof of the mouth (palate), droopy eyelids, and/or a webbed neck. In addition, affected individuals may exhibit abnormalities of the bones of the spine (vertebrae). People with distal arthrogryposis multiplex congenita, type 2B are shorter than would otherwise be expected. (For more information on this disorder, search “arthrogryposis multiplex congenita” in the Rare Disease Database.)
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Diagnosis of Trismus-Pseudocamptodactyly Syndrome
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TPS may be diagnosed during infancy, based on a thorough clinical evaluation, characteristic physical findings, and/or a variety of specialized tests, including X-rays studies. Individuals with this condition may be born with their hands clenched, but the hands usually loosen shortly after birth. Genetic testing can be performed to confirm a clinical suspicion of TPS. The identification of one abnormal copy of the MYH8 gene can help confirm a diagnosis of TPS.
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Diagnosis of Trismus-Pseudocamptodactyly Syndrome. TPS may be diagnosed during infancy, based on a thorough clinical evaluation, characteristic physical findings, and/or a variety of specialized tests, including X-rays studies. Individuals with this condition may be born with their hands clenched, but the hands usually loosen shortly after birth. Genetic testing can be performed to confirm a clinical suspicion of TPS. The identification of one abnormal copy of the MYH8 gene can help confirm a diagnosis of TPS.
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Therapies of Trismus-Pseudocamptodactyly Syndrome
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Treatment
The treatment of this disorder is directed toward the specific symptoms seen in each individual. Treatment may require the efforts of a team of specialists who work together to plan a child's care. Such specialists may include pediatricians, those who diagnose and treat skeletal disorders (orthopedists), orthopedic surgeons, dentists, anesthesiologists, physicians who specialize in disorders of the digestive tract (gastroenterologists), nutritionists, and physical and occupational therapists.In some people, jaw surgery may be performed to help increase the opening of their mouth. Genetic counseling is recommended for affected individuals and their families.
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Therapies of Trismus-Pseudocamptodactyly Syndrome. Treatment
The treatment of this disorder is directed toward the specific symptoms seen in each individual. Treatment may require the efforts of a team of specialists who work together to plan a child's care. Such specialists may include pediatricians, those who diagnose and treat skeletal disorders (orthopedists), orthopedic surgeons, dentists, anesthesiologists, physicians who specialize in disorders of the digestive tract (gastroenterologists), nutritionists, and physical and occupational therapists.In some people, jaw surgery may be performed to help increase the opening of their mouth. Genetic counseling is recommended for affected individuals and their families.
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Overview of Trisomy 13 Syndrome
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Trisomy 13 Syndrome is a rare chromosomal disorder in which all or a portion of chromosome 13 appears three times (trisomy) rather than twice in cells of the body. In some affected individuals, only a percentage of cells may contain the extra 13th chromosome (mosaicism), whereas other cells contain the normal chromosomal pair.In individuals with Trisomy 13 Syndrome, the range and severity of associated symptoms and findings may depend on the specific location of the duplicated (trisomic) portion of chromosome 13, as well as the percentage of cells containing the abnormality. However, in many affected infants and children, such abnormalities may include developmental delays, profound mental retardation, unusually small eyes (microphthalmia), an abnormal groove in the upper lip (cleft lip), incomplete closure of the roof of the mouth (cleft palate), undescended testes (cryptorchidism) in affected males, and extra (supernumerary) fingers and toes (polydactyly). Additional malformations of the head and facial (craniofacial) area may also be present, such as a relatively small head (microcephaly) with a sloping forehead; a broad, flat nose; widely set eyes (ocular hypertelorism); vertical skin folds covering the eyes; inner corners (epicanthal folds); scalp defects; and malformed, low-set ears. Affected infants may also have incomplete development of certain regions of the brain (e.g., the forebrain); kidney (renal) malformations; and structural heart (cardiac) defects at birth (congenital). For example, characteristic heart defects may include an abnormal opening in the partition dividing the upper or lower chambers of the heart (atrial or ventricular septal defects) or persistence of the fetal opening between the two major arteries (aorta, pulmonary artery) emerging from the heart (patent ductus arteriosus). Many infants with Trisomy 13 Syndrome fail to grow and gain weight at the expected rate (failure to thrive) and have severe feeding difficulties, diminished muscle tone (hypotonia), and episodes in which there is temporary cessation of spontaneous berathing (apnea). Life-threatening complications may develop during infancy or early childhood.
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Overview of Trisomy 13 Syndrome. Trisomy 13 Syndrome is a rare chromosomal disorder in which all or a portion of chromosome 13 appears three times (trisomy) rather than twice in cells of the body. In some affected individuals, only a percentage of cells may contain the extra 13th chromosome (mosaicism), whereas other cells contain the normal chromosomal pair.In individuals with Trisomy 13 Syndrome, the range and severity of associated symptoms and findings may depend on the specific location of the duplicated (trisomic) portion of chromosome 13, as well as the percentage of cells containing the abnormality. However, in many affected infants and children, such abnormalities may include developmental delays, profound mental retardation, unusually small eyes (microphthalmia), an abnormal groove in the upper lip (cleft lip), incomplete closure of the roof of the mouth (cleft palate), undescended testes (cryptorchidism) in affected males, and extra (supernumerary) fingers and toes (polydactyly). Additional malformations of the head and facial (craniofacial) area may also be present, such as a relatively small head (microcephaly) with a sloping forehead; a broad, flat nose; widely set eyes (ocular hypertelorism); vertical skin folds covering the eyes; inner corners (epicanthal folds); scalp defects; and malformed, low-set ears. Affected infants may also have incomplete development of certain regions of the brain (e.g., the forebrain); kidney (renal) malformations; and structural heart (cardiac) defects at birth (congenital). For example, characteristic heart defects may include an abnormal opening in the partition dividing the upper or lower chambers of the heart (atrial or ventricular septal defects) or persistence of the fetal opening between the two major arteries (aorta, pulmonary artery) emerging from the heart (patent ductus arteriosus). Many infants with Trisomy 13 Syndrome fail to grow and gain weight at the expected rate (failure to thrive) and have severe feeding difficulties, diminished muscle tone (hypotonia), and episodes in which there is temporary cessation of spontaneous berathing (apnea). Life-threatening complications may develop during infancy or early childhood.
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Trisomy 13 Syndrome
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Symptoms of Trisomy 13 Syndrome
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Associated symptoms and findings may vary in range and severity from case to case. However, Trisomy 13 Syndrome is often characterized by craniofacial, neurologic, heart (cardiac), and/or other defects.Affected infants typically are unusually small and have feeding difficulties. Various craniofacial malformations are frequently present, such as an abnormally small head (microcephaly) and a sloping forehead; unusual wideness of the soft spots (fontanelles) at the front and back of the skull; incomplete closure of the roof of the mouth (palate); a small jaw; scalp ulceration at the top of the head; and/or low-set, malformed ears. Other characteristics may include a short neck; loose skin folds over the back of the neck; and/or the presence of a benign lesion or birthmark consisting of abnormal clusters of blood vessels (capillary hemangiomas), most frequently on the center of the forehead. In addition, eye (ocular) abnormalities may include unusually small eyes (microphthalmia); partial absence of ocular tissue from the iris (iris coloboma); abnormal development of the retina (retinal dysplasia); vertical skin folds over the inner corners of the eyes (epicanthal folds); and/or other ocular defects. In addition, the eyebrows may be sparse or absent.Trisomy 13 Syndrome is also frequently characterized by variable degrees of holoprosencephaly, a condition in which the forebrain fails to divide properly during embryonic development. In those with Trisomy 13 Syndrome, holoprosencephaly may result in various associated, midline facial defects, including closely set eyes (hypotelorism); an abnormal groove in the middle and side of the upper lip (median and lateral cleft lip); abnormalities of the nose; and/or other features. Associated cyclopia has occurred infrequently, characterized by fusion of the eye cavities (orbits) into a single cavity containing one eye. Affected infants may also have additional abnormalities of the central nervous system (i.e., brain and spinal cord). Holoprosencephaly may be associated with episodes characterized by temporary cessation of spontaneous breathing (apnea) or sudden uncontrolled electrical activity in the brain (seizures). Many infants are thought to be deaf, and profound mental retardation is usually present. In addition, in some cases, additional features may include abnormal tone of voluntary (skeletal) muscles; absence of the band of nerve fibers that joins the two hemispheres of the brain (agenesis of the corpus callosum); underdevelopment of the cerebellum (cerebellar hypoplasia); hydrocephalus; and/or myelomeningocele. Hydrocephalus is a condition in which obstructed flow or impaired absorption of cerebrospinal fluid (CSF) results in an abnormal accumulation of CSF in the skull, usually under increased pressure. CSF is the protective fluid that circulates through the cavities (ventricles) of the brain, the canal containing the spinal cord (spinal canal), and the space between layers of the protective membranes (meninges) surrounding the brain and spinal cord (i.e., subarachnoid space). Myelomeningocele is characterized by protrusion of a membranous sac containing a portion of the spinal cord, its meninges, and CSF through a defect in the spinal column.About 80 percent of infants with Trisomy 13 Syndrome also have congenital heart defects, such as atrial or ventricular septal defects or patent ductus arteriosus (PDA). In infants with PDA, the channel that is present between the pulmonary artery and the aorta during fetal development fails to close after birth. (The pulmonary artery carries oxygen-depleted blood from the right ventricle to the lungs, where the exchange of oxygen and carbon dioxide occurs. The aorta, the major artery of the body, arises from the left ventricle and supplies oxygen-rich blood to most arteries.) In some cases, other defects may be present involving the pulmonary artery and aorta, certain heart valves, and/or heart chambers. In addition, the heart may be located in the right side of the chest, instead of its normal location in the left side of the chest (dextrocardia).Kidney (renal) defects may also occur. These may include multiple cysts in the kidneys; abnormal union of the two kidneys at the base (horseshoe kidney); and/or swelling of the kidneys with urine due to blockage or narrowing of the ureters (hydronephrosis), which carry urine into the bladder. Abnormalities of the genitals are also associated with Trisomy 13 Syndrome, including undescended testes (cryptorchidism) and an abnormally formed scrotum in affected males and underdeveloped ovaries and malformed uterus (bicornuate uterus) in affected females.Infants with Trisomy 13 Syndrome also frequently have certain abnormalities of the hands and feet. These may include more than the normal number of fingers and/or toes (polydactyly); abnormal bending (flexion) and possible overlapping of fingers; and unusually rounded (hyperconvex) nails. The heels of the feet may be abnormally prominent. In addition, Trisomy 13 Syndrome may be associated with abnormal skin ridge patterns (dermatoglyphics), including a single deep crease across the palms of the hands (simian crease). In some cases, other abnormalities may also be present. Such features may include thin ribs, an underdeveloped pelvis, certain muscle abnormalities, hernias, abnormal development of the pancreas, and/or other anomalies.
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Symptoms of Trisomy 13 Syndrome. Associated symptoms and findings may vary in range and severity from case to case. However, Trisomy 13 Syndrome is often characterized by craniofacial, neurologic, heart (cardiac), and/or other defects.Affected infants typically are unusually small and have feeding difficulties. Various craniofacial malformations are frequently present, such as an abnormally small head (microcephaly) and a sloping forehead; unusual wideness of the soft spots (fontanelles) at the front and back of the skull; incomplete closure of the roof of the mouth (palate); a small jaw; scalp ulceration at the top of the head; and/or low-set, malformed ears. Other characteristics may include a short neck; loose skin folds over the back of the neck; and/or the presence of a benign lesion or birthmark consisting of abnormal clusters of blood vessels (capillary hemangiomas), most frequently on the center of the forehead. In addition, eye (ocular) abnormalities may include unusually small eyes (microphthalmia); partial absence of ocular tissue from the iris (iris coloboma); abnormal development of the retina (retinal dysplasia); vertical skin folds over the inner corners of the eyes (epicanthal folds); and/or other ocular defects. In addition, the eyebrows may be sparse or absent.Trisomy 13 Syndrome is also frequently characterized by variable degrees of holoprosencephaly, a condition in which the forebrain fails to divide properly during embryonic development. In those with Trisomy 13 Syndrome, holoprosencephaly may result in various associated, midline facial defects, including closely set eyes (hypotelorism); an abnormal groove in the middle and side of the upper lip (median and lateral cleft lip); abnormalities of the nose; and/or other features. Associated cyclopia has occurred infrequently, characterized by fusion of the eye cavities (orbits) into a single cavity containing one eye. Affected infants may also have additional abnormalities of the central nervous system (i.e., brain and spinal cord). Holoprosencephaly may be associated with episodes characterized by temporary cessation of spontaneous breathing (apnea) or sudden uncontrolled electrical activity in the brain (seizures). Many infants are thought to be deaf, and profound mental retardation is usually present. In addition, in some cases, additional features may include abnormal tone of voluntary (skeletal) muscles; absence of the band of nerve fibers that joins the two hemispheres of the brain (agenesis of the corpus callosum); underdevelopment of the cerebellum (cerebellar hypoplasia); hydrocephalus; and/or myelomeningocele. Hydrocephalus is a condition in which obstructed flow or impaired absorption of cerebrospinal fluid (CSF) results in an abnormal accumulation of CSF in the skull, usually under increased pressure. CSF is the protective fluid that circulates through the cavities (ventricles) of the brain, the canal containing the spinal cord (spinal canal), and the space between layers of the protective membranes (meninges) surrounding the brain and spinal cord (i.e., subarachnoid space). Myelomeningocele is characterized by protrusion of a membranous sac containing a portion of the spinal cord, its meninges, and CSF through a defect in the spinal column.About 80 percent of infants with Trisomy 13 Syndrome also have congenital heart defects, such as atrial or ventricular septal defects or patent ductus arteriosus (PDA). In infants with PDA, the channel that is present between the pulmonary artery and the aorta during fetal development fails to close after birth. (The pulmonary artery carries oxygen-depleted blood from the right ventricle to the lungs, where the exchange of oxygen and carbon dioxide occurs. The aorta, the major artery of the body, arises from the left ventricle and supplies oxygen-rich blood to most arteries.) In some cases, other defects may be present involving the pulmonary artery and aorta, certain heart valves, and/or heart chambers. In addition, the heart may be located in the right side of the chest, instead of its normal location in the left side of the chest (dextrocardia).Kidney (renal) defects may also occur. These may include multiple cysts in the kidneys; abnormal union of the two kidneys at the base (horseshoe kidney); and/or swelling of the kidneys with urine due to blockage or narrowing of the ureters (hydronephrosis), which carry urine into the bladder. Abnormalities of the genitals are also associated with Trisomy 13 Syndrome, including undescended testes (cryptorchidism) and an abnormally formed scrotum in affected males and underdeveloped ovaries and malformed uterus (bicornuate uterus) in affected females.Infants with Trisomy 13 Syndrome also frequently have certain abnormalities of the hands and feet. These may include more than the normal number of fingers and/or toes (polydactyly); abnormal bending (flexion) and possible overlapping of fingers; and unusually rounded (hyperconvex) nails. The heels of the feet may be abnormally prominent. In addition, Trisomy 13 Syndrome may be associated with abnormal skin ridge patterns (dermatoglyphics), including a single deep crease across the palms of the hands (simian crease). In some cases, other abnormalities may also be present. Such features may include thin ribs, an underdeveloped pelvis, certain muscle abnormalities, hernias, abnormal development of the pancreas, and/or other anomalies.
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Causes of Trisomy 13 Syndrome
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In individuals with Trisomy 13 Syndrome, all or a relatively large region of chromosome 13 is present three times (trisomy) rather than twice in cells. In about five percent of cases, only a percentage of cells contains the extra 13th chromosome (mosaicism). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. Trisomy (or “duplication”) of a particular region or regions of chromosome 13 is responsible for the symptoms and findings that characterize the disorder. The severity and range of symptoms may depend on the length and location of the duplicated portion of the chromosome. In addition, those with trisomy 13 mosaicism typically have less severe symptoms; however, in such cases, disease manifestations may be extremely variable, ranging from near normal to the full spectrum of malformations.In most individuals with Trisomy 13 Syndrome, duplication of chromosome 13 is caused by spontaneous (de novo) errors during the division of reproductive cells in one of the parents (e.g., nondisjunction during meiosis). Evidence suggests that the risk of such errors may increase with advanced parental age. In cases in which only a percentage of cells contains the trisomy 13 abnormality (mosaicism), errors may also occur during cellular division after fertilization (mitosis). In about 20 percent of affected individuals, trisomy 13 results from a translocation involving chromosome 13 and another chromosome. Translocations occur when regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. For most individuals with Trisomy 13 Syndrome, such translocations occur spontaneously for unknown reasons (de novo); less commonly, they are transmitted by a parent who is a carrier of a “balanced” translocation. (If a chromosomal rearrangement is balanced–i.e., consists of an altered but balanced set of chromosomes–it is usually harmless to the carrier. However, balanced translocations are sometimes associated with a higher risk of abnormal chromosomal development in the carrier's offspring. Chromosomal testing may determine whether a parent has a balanced translocation.)Investigators suggest that certain symptoms and findings associated with Trisomy 13 Syndrome may result from overexpression of developmentally important genes on chromosome 13. For example, the gene that regulates production of an enzyme known as esterase D (ESD) has been located on the long arm (q) of chromosome 13 (13q14.11). Elevated levels of esterase D have been found in the kidney tissues of some affected infants. Further investigations are required to learn more about the specific underlying causes of Trisomy 13 Syndrome and the potential role of esterase D.
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Causes of Trisomy 13 Syndrome. In individuals with Trisomy 13 Syndrome, all or a relatively large region of chromosome 13 is present three times (trisomy) rather than twice in cells. In about five percent of cases, only a percentage of cells contains the extra 13th chromosome (mosaicism). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. Trisomy (or “duplication”) of a particular region or regions of chromosome 13 is responsible for the symptoms and findings that characterize the disorder. The severity and range of symptoms may depend on the length and location of the duplicated portion of the chromosome. In addition, those with trisomy 13 mosaicism typically have less severe symptoms; however, in such cases, disease manifestations may be extremely variable, ranging from near normal to the full spectrum of malformations.In most individuals with Trisomy 13 Syndrome, duplication of chromosome 13 is caused by spontaneous (de novo) errors during the division of reproductive cells in one of the parents (e.g., nondisjunction during meiosis). Evidence suggests that the risk of such errors may increase with advanced parental age. In cases in which only a percentage of cells contains the trisomy 13 abnormality (mosaicism), errors may also occur during cellular division after fertilization (mitosis). In about 20 percent of affected individuals, trisomy 13 results from a translocation involving chromosome 13 and another chromosome. Translocations occur when regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. For most individuals with Trisomy 13 Syndrome, such translocations occur spontaneously for unknown reasons (de novo); less commonly, they are transmitted by a parent who is a carrier of a “balanced” translocation. (If a chromosomal rearrangement is balanced–i.e., consists of an altered but balanced set of chromosomes–it is usually harmless to the carrier. However, balanced translocations are sometimes associated with a higher risk of abnormal chromosomal development in the carrier's offspring. Chromosomal testing may determine whether a parent has a balanced translocation.)Investigators suggest that certain symptoms and findings associated with Trisomy 13 Syndrome may result from overexpression of developmentally important genes on chromosome 13. For example, the gene that regulates production of an enzyme known as esterase D (ESD) has been located on the long arm (q) of chromosome 13 (13q14.11). Elevated levels of esterase D have been found in the kidney tissues of some affected infants. Further investigations are required to learn more about the specific underlying causes of Trisomy 13 Syndrome and the potential role of esterase D.
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Affects of Trisomy 13 Syndrome
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Trisomy 13 Syndrome is sometimes called Patau Syndrome, after one of the researchers (Patau K) who identified the syndrome's trisomic origin in 1960. The syndrome appears to affect females slightly more frequently than males and occurs in about one in 5,000 to 12,000 live births. Evidence suggests that approximately one percent of all recognized miscarriages occur in association with Trisomy 13 Syndrome. In addition, as noted above, the frequency of Trisomy 13 increases with advancing age of the mother.Investigators have also suggested a possible association between preeclampsia and Trisomy 13. Preeclampsia is an abnormal condition of pregnancy characterized by the rapid onset of high blood pressure (hypertension), abnormal amounts of protein in the urine (proteinuria), and/or excessive retention of fluids (edema). According to researchers, the number of cases of preeclampsia appears to be significantly higher in women who are carrying a fetus with Trisomy 13 Syndrome than would be otherwise expected in the general population. In addition, the incidence appears significantly higher than when compared with pregnancies complicated by certain other chromosomal abnormalities (e.g., trisomy 18, trisomy 21 [Down Syndrome]). Such researchers suggest the possibility that a gene or genes on fetal chromosome 13 may influence the development of preeclampsia.
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Affects of Trisomy 13 Syndrome. Trisomy 13 Syndrome is sometimes called Patau Syndrome, after one of the researchers (Patau K) who identified the syndrome's trisomic origin in 1960. The syndrome appears to affect females slightly more frequently than males and occurs in about one in 5,000 to 12,000 live births. Evidence suggests that approximately one percent of all recognized miscarriages occur in association with Trisomy 13 Syndrome. In addition, as noted above, the frequency of Trisomy 13 increases with advancing age of the mother.Investigators have also suggested a possible association between preeclampsia and Trisomy 13. Preeclampsia is an abnormal condition of pregnancy characterized by the rapid onset of high blood pressure (hypertension), abnormal amounts of protein in the urine (proteinuria), and/or excessive retention of fluids (edema). According to researchers, the number of cases of preeclampsia appears to be significantly higher in women who are carrying a fetus with Trisomy 13 Syndrome than would be otherwise expected in the general population. In addition, the incidence appears significantly higher than when compared with pregnancies complicated by certain other chromosomal abnormalities (e.g., trisomy 18, trisomy 21 [Down Syndrome]). Such researchers suggest the possibility that a gene or genes on fetal chromosome 13 may influence the development of preeclampsia.
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Related disorders of Trisomy 13 Syndrome
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Symptoms of the following disorders may be similar to those of Trisomy 13 Syndrome. Comparisons may be useful for a differential diagnosis:Pseudo-trisomy 13 Syndrome is a rare disorder characterized by holoprosencephaly; associated midline facial abnormalities; extra fingers and/or toes (polydactyly); and/or heart defects, such as atrial or ventricular septal defects. In some cases, additional abnormalities may also be present, including genital defects; absence of the band of nerve fibers joining the two hemispheres of the brain (agenesis of corpus callosum); hydrocephalus; and/or other features. Although symptoms and findings are similar to those potentially associated with Trisomy 13 Syndrome, infants with this disorder do not have an extra chromosome 13 and their chromosomal studies appear normal. Evidence suggests that this disorder may be inherited as an autosomal recessive trait.There are a number of other disorders, including other chromosomal syndromes, that may be characterized by symptoms and findings similar to those associated with Trisomy 13 Syndrome. Chromosomal testing is necessary to confirm whether a specific chromosomal abnormality is present. (For further information on such disorders, choose the name of the specific disorder in question or use “chromosome” as your search term in the Rare Disease Database.)
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Related disorders of Trisomy 13 Syndrome. Symptoms of the following disorders may be similar to those of Trisomy 13 Syndrome. Comparisons may be useful for a differential diagnosis:Pseudo-trisomy 13 Syndrome is a rare disorder characterized by holoprosencephaly; associated midline facial abnormalities; extra fingers and/or toes (polydactyly); and/or heart defects, such as atrial or ventricular septal defects. In some cases, additional abnormalities may also be present, including genital defects; absence of the band of nerve fibers joining the two hemispheres of the brain (agenesis of corpus callosum); hydrocephalus; and/or other features. Although symptoms and findings are similar to those potentially associated with Trisomy 13 Syndrome, infants with this disorder do not have an extra chromosome 13 and their chromosomal studies appear normal. Evidence suggests that this disorder may be inherited as an autosomal recessive trait.There are a number of other disorders, including other chromosomal syndromes, that may be characterized by symptoms and findings similar to those associated with Trisomy 13 Syndrome. Chromosomal testing is necessary to confirm whether a specific chromosomal abnormality is present. (For further information on such disorders, choose the name of the specific disorder in question or use “chromosome” as your search term in the Rare Disease Database.)
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Diagnosis of Trisomy 13 Syndrome
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In some instances, a diagnosis of Trisomy 13 Syndrome may be suggested before birth (prenatally) by specialized tests, such as fetal ultrasonography, amniocentesis, and/or chorionic villus sampling (CVS). During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing findings that may suggest a chromosomal disorder or other abnormalities. For example, ultrasound findings that may be suggestive of Trisomy 13 may include holoprosencephaly, polydactyly, and growth retardation.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 samples may reveal the presence of an extra chromosome 13.The diagnosis of Trisomy 13 Syndrome may be made or confirmed after birth (postnatally) by a thorough clinical evaluation, detection of characteristic physical findings, and chromosomal analysis. Testing may also reveal unusual persistence of embryonic and/or fetal hemoglobin in the blood of newborns and infants with Trisomy 13 Syndrome. (Hemoglobin is the oxygen-carrying component of red blood cells.)For infants diagnosed with the syndrome, careful monitoring and various specialized tests may be conducted to ensure early detection and appropriate management of conditions potentially associated with Trisomy 13 Syndrome.
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Diagnosis of Trisomy 13 Syndrome. In some instances, a diagnosis of Trisomy 13 Syndrome may be suggested before birth (prenatally) by specialized tests, such as fetal ultrasonography, amniocentesis, and/or chorionic villus sampling (CVS). During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing findings that may suggest a chromosomal disorder or other abnormalities. For example, ultrasound findings that may be suggestive of Trisomy 13 may include holoprosencephaly, polydactyly, and growth retardation.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 samples may reveal the presence of an extra chromosome 13.The diagnosis of Trisomy 13 Syndrome may be made or confirmed after birth (postnatally) by a thorough clinical evaluation, detection of characteristic physical findings, and chromosomal analysis. Testing may also reveal unusual persistence of embryonic and/or fetal hemoglobin in the blood of newborns and infants with Trisomy 13 Syndrome. (Hemoglobin is the oxygen-carrying component of red blood cells.)For infants diagnosed with the syndrome, careful monitoring and various specialized tests may be conducted to ensure early detection and appropriate management of conditions potentially associated with Trisomy 13 Syndrome.
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Therapies of Trisomy 13 Syndrome
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TreatmentThe treatment of Trisomy 13 Syndrome is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a multidisciplinary team of medical professionals.In some cases, recommended treatment may include surgical correction of certain abnormalities associated with the disorder. The surgical procedures performed will depend upon the nature and severity of the anatomical abnormalities, their associated symptoms, and other factors.A supportive team approach for children with this disorder may be of benefit and may include physical therapy, medical, and/or social services. Genetic counseling will also be of benefit for families of children with Trisomy 13 Syndrome. Other treatment for this disorder is symptomatic and supportive.
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Therapies of Trisomy 13 Syndrome. TreatmentThe treatment of Trisomy 13 Syndrome is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a multidisciplinary team of medical professionals.In some cases, recommended treatment may include surgical correction of certain abnormalities associated with the disorder. The surgical procedures performed will depend upon the nature and severity of the anatomical abnormalities, their associated symptoms, and other factors.A supportive team approach for children with this disorder may be of benefit and may include physical therapy, medical, and/or social services. Genetic counseling will also be of benefit for families of children with Trisomy 13 Syndrome. Other treatment for this disorder is symptomatic and supportive.
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Overview of Trisomy 18
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Trisomy 18 is a rare chromosomal disorder in which all or a critical region of chromosome 18 appears three times (trisomy) rather than twice in cells of the body. In some children, the chromosomal abnormality may be present in only a percentage of cells, whereas other cells contain the typical chromosomal pair (mosaicism).Trisomy 18 may be a life-threatening condition; some affected die before birth or within the first month of life. Some individuals have survived to their teenage years and beyond, with a range of medical and developmental needs. Trisomy 18 is usually not inherited but occurs by chance.Depending on the specific location of the duplicated (trisomic) portion of chromosome 18 and the percentage of cells, symptoms and findings can be extremely variable from person to person. The majority of affected infants experience growth deficiency, feeding and breathing difficulties, and developmental delays. Individuals with trisomy 18 also have distinctive malformations of the head and facial (craniofacial) area as well as of the hands and feet, possible skeletal deformities, genitourinary issues and heart defects present at birth (congenital). Congenital heart defects and associated respiratory difficulties may lead to potentially life-threatening complications during infancy or childhood. Treatment is dependent upon the specific symptoms present, recommendations from the medical team and parent/family preference.
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Overview of Trisomy 18. Trisomy 18 is a rare chromosomal disorder in which all or a critical region of chromosome 18 appears three times (trisomy) rather than twice in cells of the body. In some children, the chromosomal abnormality may be present in only a percentage of cells, whereas other cells contain the typical chromosomal pair (mosaicism).Trisomy 18 may be a life-threatening condition; some affected die before birth or within the first month of life. Some individuals have survived to their teenage years and beyond, with a range of medical and developmental needs. Trisomy 18 is usually not inherited but occurs by chance.Depending on the specific location of the duplicated (trisomic) portion of chromosome 18 and the percentage of cells, symptoms and findings can be extremely variable from person to person. The majority of affected infants experience growth deficiency, feeding and breathing difficulties, and developmental delays. Individuals with trisomy 18 also have distinctive malformations of the head and facial (craniofacial) area as well as of the hands and feet, possible skeletal deformities, genitourinary issues and heart defects present at birth (congenital). Congenital heart defects and associated respiratory difficulties may lead to potentially life-threatening complications during infancy or childhood. Treatment is dependent upon the specific symptoms present, recommendations from the medical team and parent/family preference.
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Symptoms of Trisomy 18
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The symptoms associated with trisomy 18 are extremely variable. Severity is dependent upon the percentage of cells that contain the third copy of the chromosome (mosaicism). Certain findings before birth (prenatally) and during infancy are considered characteristic of trisomy 18. In many patients, there is decreased movement in utero. Affected infants may have poor suckling ability and associated feeding difficulties that can be supported with tube feeding, failure to grow and gain weight at the expected rate (failure to thrive), and distinctive malformations of the head and facial (craniofacial) area. Many infants with trisomy 18 also have malformations of the hands and feet, additional skeletal defects, and structural abnormalities of the heart (congenital heart defects) and undescended testes in affected males (cryptorchidism). Skeletal muscles and underlying connective and fatty tissues (subcutaneous and adipose tissue) may be underdeveloped (hypoplastic). Additional characteristics during infancy may include diminished muscle tone (hypotonia) followed by unusually increased tone (hypertonia) and muscle stiffness (rigidity) that is often due to tremors or seizures; a weak cry; decreased response to environmental sounds due to anatomical abnormities of the ear; and/or repeated episodes in which there is a temporary cessation of breathing (apneic episodes).Many infants with trisomy 18 also have distinctive characteristics of the craniofacial region. These may include a small head (microcephaly) that appears unusually long and narrow (dolichocephaly); a prominent back region of the head (occiput); a small mouth (microstomia); incomplete closure of the roof of the mouth (cleft palate) and/or an abnormal groove in the upper lip (cleft lip); a small jaw (micrognathia); or a short, webbed neck. Affected infants may also have an upturned nose; low-set, malformed ears; widely spaced eyes (ocular hypertelorism) with slanted or narrow eyelid folds (palpebral folds); and vertical skin folds covering the eyes’ inner corners (epicanthal folds).Trisomy 18 may also be characterized by additional eye (ocular) malformations. For example, there may be drooping of the upper eyelids (ptosis) and an inability to completely close the eyes. Some affected infants also have clouding of the normally transparent front regions of the eyes (corneas); loss of transparency of the lenses (cataracts); or unusual smallness of the eyes (microphthalmia). Additional ocular malformations may include abnormal deviation of one eye in relation to the other (strabismus); inequality in the diameter of the pupils (anisocoria); rapid involuntary eye movements (nystagmus); and/or a decreased response to visual stimuli.Many infants with trisomy 18 also have characteristic malformations of the hands and feet. The hands are typically clenched, with overlapping of the index finger (second finger) over the third finger and the “pinky” (fifth finger) over the fourth. Frequent findings also include unusual skin ridge patterns (dermatoglyphics) on the fingers and palms; underdeveloped (hypoplastic) nails, particularly those of the fifth fingers and toes; and abnormal deviation of the great toes (hallux) in an upwardly bent position (dorsiflexion). In some children, additional irregularities may be present such as the presence of extra fingers or toes (polydactyly); webbing (syndactyly) of one or more toes; or the feet appear shaped like the rocker of a rocking chair (“rocker-bottom feet”) with abnormal prominence of the heel bones (calcaneus). Some infants also have a foot deformity in which the heels are turned inward and the soles are flexed or clubfeet (talipes equinovarus).Many infants with trisomy 18 also have skeletal malformations such as a short breastbone (sternum); a small pelvis with limited outward movements (abduction) of the hips; or abnormalities of the ribs. There may be defects of certain bones of the spinal column (vertebrae), including sideways curvature of the spine (scoliosis); underdevelopment of one half of certain vertebrae (hemivertebrae); or abnormal fusion of vertebrae.As mentioned above, in males with the disorder, the testes may fail to descend into the scrotum (cryptorchidism). Trisomy 18 may also be associated with additional genital malformations. In some affected males, there may be division of the scrotum into two parts (bifid scrotum) and/or abnormal placement of the urinary opening (hypospadias), such as on the underside of the penis. In some females with the disorder, there is underdevelopment (hypoplasia) of the outer skin folds (labia majora) surrounding the vaginal opening and abnormal prominence of the relatively small, sensitive protrusion (clitoris) that forms part of the female external genitalia.Trisomy 18 is also often characterized by structural heart (cardiac) defects that are present at birth (congenital heart defects). Many affected infants have an abnormal opening in the fibrous partition (septum) that separates the lower chambers of the heart (ventricular septal defect; VSD). Another common finding is abnormal persistence of the fetal opening between the two major arteries (aorta, pulmonary artery) that emerge from the heart (patent ductus arteriosus; PDA). Additional cardiac defects may be present including narrowing (stenosis) of the opening between the right ventricle and the artery that carries oxygen-deficient blood to the lungs (pulmonary artery); narrowing of the major artery that transports oxygen-rich blood from the heart to all parts of the body (coarctation of the aorta); and/or abnormalities of heart valves.Some infants with trisomy 18 have malformations of the abdominal wall and the kidneys. For example, there may be protrusion of portions of the intestine through an abnormal opening in muscles of the groin (inguinal hernia) or the abdominal wall near the navel (umbilical hernia). Some infants with trisomy 18 have an omphalocele, a birth defect in which varying amounts of intestines or other abdominal organs (viscera), covered by a membrane-like sac, protrude through an opening in the abdominal wall near the navel. Some affected infants may have kidneys that are abnormally positioned (ectopic) or joined together (horseshoe kidneys) or contain multiple cysts (polycystic kidneys). There may also be swelling of the kidneys with urine due to narrowing or blockage of the tubes that carry urine from the kidneys to the bladder (hydronephrosis).Some affected infants may also have malformations of the brain and spinal cord (central nervous system; CNS). These may include absence (agenesis) or underdevelopment (hypoplasia) of the thick band of nerve fibers connecting the two hemispheres of the brain (corpus callosum); protrusion of part of the spinal cord and its surrounding membranes (meninges) through an abnormal opening in the spinal column (myelomeningocele); or other malformations. Congenital heart defects, respiratory difficulties (e.g., apneic episodes, aspiration), or other abnormalities associated with the disorder may lead to potentially life-threatening complications during infancy or childhood.Trisomy 18 is also typically characterized by intellectual disability, along with delayed verbal, and motor development. Yet, children do communicate through facial expressions, gestures and vocalizations. Some are able to use augmentative communication devices and systems. Mobility needs can be addressed through orthotics, gait trainers and other assistive devices as tolerated. Individuals with trisomy 18 recognize family members and caregivers and can display a range of emotions including indicating preferences for items and people in their environment.
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Symptoms of Trisomy 18. The symptoms associated with trisomy 18 are extremely variable. Severity is dependent upon the percentage of cells that contain the third copy of the chromosome (mosaicism). Certain findings before birth (prenatally) and during infancy are considered characteristic of trisomy 18. In many patients, there is decreased movement in utero. Affected infants may have poor suckling ability and associated feeding difficulties that can be supported with tube feeding, failure to grow and gain weight at the expected rate (failure to thrive), and distinctive malformations of the head and facial (craniofacial) area. Many infants with trisomy 18 also have malformations of the hands and feet, additional skeletal defects, and structural abnormalities of the heart (congenital heart defects) and undescended testes in affected males (cryptorchidism). Skeletal muscles and underlying connective and fatty tissues (subcutaneous and adipose tissue) may be underdeveloped (hypoplastic). Additional characteristics during infancy may include diminished muscle tone (hypotonia) followed by unusually increased tone (hypertonia) and muscle stiffness (rigidity) that is often due to tremors or seizures; a weak cry; decreased response to environmental sounds due to anatomical abnormities of the ear; and/or repeated episodes in which there is a temporary cessation of breathing (apneic episodes).Many infants with trisomy 18 also have distinctive characteristics of the craniofacial region. These may include a small head (microcephaly) that appears unusually long and narrow (dolichocephaly); a prominent back region of the head (occiput); a small mouth (microstomia); incomplete closure of the roof of the mouth (cleft palate) and/or an abnormal groove in the upper lip (cleft lip); a small jaw (micrognathia); or a short, webbed neck. Affected infants may also have an upturned nose; low-set, malformed ears; widely spaced eyes (ocular hypertelorism) with slanted or narrow eyelid folds (palpebral folds); and vertical skin folds covering the eyes’ inner corners (epicanthal folds).Trisomy 18 may also be characterized by additional eye (ocular) malformations. For example, there may be drooping of the upper eyelids (ptosis) and an inability to completely close the eyes. Some affected infants also have clouding of the normally transparent front regions of the eyes (corneas); loss of transparency of the lenses (cataracts); or unusual smallness of the eyes (microphthalmia). Additional ocular malformations may include abnormal deviation of one eye in relation to the other (strabismus); inequality in the diameter of the pupils (anisocoria); rapid involuntary eye movements (nystagmus); and/or a decreased response to visual stimuli.Many infants with trisomy 18 also have characteristic malformations of the hands and feet. The hands are typically clenched, with overlapping of the index finger (second finger) over the third finger and the “pinky” (fifth finger) over the fourth. Frequent findings also include unusual skin ridge patterns (dermatoglyphics) on the fingers and palms; underdeveloped (hypoplastic) nails, particularly those of the fifth fingers and toes; and abnormal deviation of the great toes (hallux) in an upwardly bent position (dorsiflexion). In some children, additional irregularities may be present such as the presence of extra fingers or toes (polydactyly); webbing (syndactyly) of one or more toes; or the feet appear shaped like the rocker of a rocking chair (“rocker-bottom feet”) with abnormal prominence of the heel bones (calcaneus). Some infants also have a foot deformity in which the heels are turned inward and the soles are flexed or clubfeet (talipes equinovarus).Many infants with trisomy 18 also have skeletal malformations such as a short breastbone (sternum); a small pelvis with limited outward movements (abduction) of the hips; or abnormalities of the ribs. There may be defects of certain bones of the spinal column (vertebrae), including sideways curvature of the spine (scoliosis); underdevelopment of one half of certain vertebrae (hemivertebrae); or abnormal fusion of vertebrae.As mentioned above, in males with the disorder, the testes may fail to descend into the scrotum (cryptorchidism). Trisomy 18 may also be associated with additional genital malformations. In some affected males, there may be division of the scrotum into two parts (bifid scrotum) and/or abnormal placement of the urinary opening (hypospadias), such as on the underside of the penis. In some females with the disorder, there is underdevelopment (hypoplasia) of the outer skin folds (labia majora) surrounding the vaginal opening and abnormal prominence of the relatively small, sensitive protrusion (clitoris) that forms part of the female external genitalia.Trisomy 18 is also often characterized by structural heart (cardiac) defects that are present at birth (congenital heart defects). Many affected infants have an abnormal opening in the fibrous partition (septum) that separates the lower chambers of the heart (ventricular septal defect; VSD). Another common finding is abnormal persistence of the fetal opening between the two major arteries (aorta, pulmonary artery) that emerge from the heart (patent ductus arteriosus; PDA). Additional cardiac defects may be present including narrowing (stenosis) of the opening between the right ventricle and the artery that carries oxygen-deficient blood to the lungs (pulmonary artery); narrowing of the major artery that transports oxygen-rich blood from the heart to all parts of the body (coarctation of the aorta); and/or abnormalities of heart valves.Some infants with trisomy 18 have malformations of the abdominal wall and the kidneys. For example, there may be protrusion of portions of the intestine through an abnormal opening in muscles of the groin (inguinal hernia) or the abdominal wall near the navel (umbilical hernia). Some infants with trisomy 18 have an omphalocele, a birth defect in which varying amounts of intestines or other abdominal organs (viscera), covered by a membrane-like sac, protrude through an opening in the abdominal wall near the navel. Some affected infants may have kidneys that are abnormally positioned (ectopic) or joined together (horseshoe kidneys) or contain multiple cysts (polycystic kidneys). There may also be swelling of the kidneys with urine due to narrowing or blockage of the tubes that carry urine from the kidneys to the bladder (hydronephrosis).Some affected infants may also have malformations of the brain and spinal cord (central nervous system; CNS). These may include absence (agenesis) or underdevelopment (hypoplasia) of the thick band of nerve fibers connecting the two hemispheres of the brain (corpus callosum); protrusion of part of the spinal cord and its surrounding membranes (meninges) through an abnormal opening in the spinal column (myelomeningocele); or other malformations. Congenital heart defects, respiratory difficulties (e.g., apneic episodes, aspiration), or other abnormalities associated with the disorder may lead to potentially life-threatening complications during infancy or childhood.Trisomy 18 is also typically characterized by intellectual disability, along with delayed verbal, and motor development. Yet, children do communicate through facial expressions, gestures and vocalizations. Some are able to use augmentative communication devices and systems. Mobility needs can be addressed through orthotics, gait trainers and other assistive devices as tolerated. Individuals with trisomy 18 recognize family members and caregivers and can display a range of emotions including indicating preferences for items and people in their environment.
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Trisomy 18
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Causes of Trisomy 18
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Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered.In individuals with trisomy 18, all or a particular region of chromosome 18 is present three times (trisomy) rather than twice within cells. This extra genetic material from the third copy of the chromosome disrupts typical development and causes characteristic features of the condition. In about 5% of patients, only some cells in the body contain the extra 18th chromosome (mosaicism). Very rarely, an extra piece of chromosome 18 is attached to another chromosome (translocation trisomy 18 or partial trisomy 18). If only part of the long (q) arm of chromosome 18 is present in three copies, the symptoms may be less severe than in people with full trisomy 18. Duplication of a specific region or regions of chromosome 18 is responsible for the symptoms and findings that characterize the condition. The severity and range of symptoms may depend on the length and location of the duplicated portion of the chromosome as well as the percentage of cells with the duplication. In individuals with partial trisomy of chromosome 18 who have characteristic symptoms of the disorder, evidence suggests that a critical region associated with trisomy 18 is duplication at band 18q11.In most individuals with the disorder, duplication of chromosome 18 is caused by spontaneous (de novo) errors during the division of reproductive cells in one of the parents (e.g., nondisjunction during meiosis). Reports suggest that the risk of such errors may increase with advanced parental age. In cases in which only a percentage of cells contain three copies (mosaicism), errors may also occur during cellular division after fertilization (mitosis).In some individuals, trisomy 18 may result from a translocation involving chromosome 18 and another chromosome. Translocations occur when regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. Such translocations may occur spontaneously for unknown reasons (de novo) or be transmitted by a parent who is a carrier of a “balanced” translocation. (If a chromosomal rearrangement is balanced–i.e., consists of an altered but balanced set of chromosomes–it is usually harmless to the carrier. However, balanced translocations are sometimes associated with a higher risk of abnormal chromosomal development in the carrier’s offspring. Chromosomal testing may determine whether a parent has a balanced translocation.) A person with a balanced translocation had an increased risk with each pregnancy to have a child with trisomy 18.
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Causes of Trisomy 18. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered.In individuals with trisomy 18, all or a particular region of chromosome 18 is present three times (trisomy) rather than twice within cells. This extra genetic material from the third copy of the chromosome disrupts typical development and causes characteristic features of the condition. In about 5% of patients, only some cells in the body contain the extra 18th chromosome (mosaicism). Very rarely, an extra piece of chromosome 18 is attached to another chromosome (translocation trisomy 18 or partial trisomy 18). If only part of the long (q) arm of chromosome 18 is present in three copies, the symptoms may be less severe than in people with full trisomy 18. Duplication of a specific region or regions of chromosome 18 is responsible for the symptoms and findings that characterize the condition. The severity and range of symptoms may depend on the length and location of the duplicated portion of the chromosome as well as the percentage of cells with the duplication. In individuals with partial trisomy of chromosome 18 who have characteristic symptoms of the disorder, evidence suggests that a critical region associated with trisomy 18 is duplication at band 18q11.In most individuals with the disorder, duplication of chromosome 18 is caused by spontaneous (de novo) errors during the division of reproductive cells in one of the parents (e.g., nondisjunction during meiosis). Reports suggest that the risk of such errors may increase with advanced parental age. In cases in which only a percentage of cells contain three copies (mosaicism), errors may also occur during cellular division after fertilization (mitosis).In some individuals, trisomy 18 may result from a translocation involving chromosome 18 and another chromosome. Translocations occur when regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. Such translocations may occur spontaneously for unknown reasons (de novo) or be transmitted by a parent who is a carrier of a “balanced” translocation. (If a chromosomal rearrangement is balanced–i.e., consists of an altered but balanced set of chromosomes–it is usually harmless to the carrier. However, balanced translocations are sometimes associated with a higher risk of abnormal chromosomal development in the carrier’s offspring. Chromosomal testing may determine whether a parent has a balanced translocation.) A person with a balanced translocation had an increased risk with each pregnancy to have a child with trisomy 18.
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Trisomy 18
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Affects of Trisomy 18
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Trisomy 18 affects females more frequently than males by a ratio of three or four to one. Large population surveys indicate that it occurs in about one in 5,000 to 7,000 live births. The frequency of trisomy 18 appears to increase with advancing maternal age. Reports indicate mean maternal age is 32.5 years. There are also reports of mothers in their late teens and early 20’s.
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Affects of Trisomy 18. Trisomy 18 affects females more frequently than males by a ratio of three or four to one. Large population surveys indicate that it occurs in about one in 5,000 to 7,000 live births. The frequency of trisomy 18 appears to increase with advancing maternal age. Reports indicate mean maternal age is 32.5 years. There are also reports of mothers in their late teens and early 20’s.
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Trisomy 18
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Related disorders of Trisomy 18
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Symptoms of the following disorder may be similar to those of trisomy 18. Comparisons may be useful for a differential diagnosis:Trisomy 13 is a chromosomal disorder in which all or a portion of chromosome 13 is present three times rather than twice in all or some cells of the body. Associated symptoms and findings may vary in range and severity. These infants have some similar characteristics with trisomy 18 infants, but in general the signs and symptoms are different. Affected infants typically are small for gestational age, have feeding difficulties, and have various craniofacial malformations. These may include an abnormally small head (microcephaly) and a sloping forehead; unusual wideness of the soft spots (fontanelles) at the front and back of the skull; incomplete closure of the roof of the mouth (palate); a small jaw; scalp ulceration at the top of the head; low-set, malformed ears; unusually small eyes (microphthalmia); and/or other eye defects such as colobomas. The disorder may also be associated with extra fingers and toes (polydactyly); failure of the forebrain to divide properly during embryonic development (holoprosencephaly); additional defects of the central nervous system; renal malformations; and/or cardiac defects. In most cases, trisomy 13 is due to errors during the division of reproductive cells in one of the parents. (For further information, choose “trisomy 13” as your search term in the Rare Disease Database.)There are a number of other disorders that are characterized by symptoms and findings similar to trisomy 18 such as trisomy 9 mosaicism. Chromosomal testing is necessary to confirm whether a specific chromosomal abnormality is present. (For further information on such disorders, choose the name of the specific disorder in question or use “chromosome” as your search term in the Rare Disease Database.)
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Related disorders of Trisomy 18. Symptoms of the following disorder may be similar to those of trisomy 18. Comparisons may be useful for a differential diagnosis:Trisomy 13 is a chromosomal disorder in which all or a portion of chromosome 13 is present three times rather than twice in all or some cells of the body. Associated symptoms and findings may vary in range and severity. These infants have some similar characteristics with trisomy 18 infants, but in general the signs and symptoms are different. Affected infants typically are small for gestational age, have feeding difficulties, and have various craniofacial malformations. These may include an abnormally small head (microcephaly) and a sloping forehead; unusual wideness of the soft spots (fontanelles) at the front and back of the skull; incomplete closure of the roof of the mouth (palate); a small jaw; scalp ulceration at the top of the head; low-set, malformed ears; unusually small eyes (microphthalmia); and/or other eye defects such as colobomas. The disorder may also be associated with extra fingers and toes (polydactyly); failure of the forebrain to divide properly during embryonic development (holoprosencephaly); additional defects of the central nervous system; renal malformations; and/or cardiac defects. In most cases, trisomy 13 is due to errors during the division of reproductive cells in one of the parents. (For further information, choose “trisomy 13” as your search term in the Rare Disease Database.)There are a number of other disorders that are characterized by symptoms and findings similar to trisomy 18 such as trisomy 9 mosaicism. Chromosomal testing is necessary to confirm whether a specific chromosomal abnormality is present. (For further information on such disorders, choose the name of the specific disorder in question or use “chromosome” as your search term in the Rare Disease Database.)
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Trisomy 18
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Diagnosis of Trisomy 18
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A diagnosis of trisomy 18 may be suspected before birth based upon specialized testing such as fetal ultrasonography and maternal serum screening. During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing findings that may suggest a chromosomal disorder or other abnormalities. In addition, screening tests that reveal abnormal levels of certain “markers” in the mother's blood may suggest an increased risk of trisomy 18 or other chromosomal abnormalities (e.g., Down syndrome). Such tests measure the levels of specific substances in the blood, including alpha-fetoprotein (AFP); human chorionic gonadotropin (hCG); unconjugated estriol; or other markers. If such screening studies reveal abnormal levels of these markers, additional testing may be recommended, such as amniocentesis or chorionic villus sampling (CVS) for chromosomal analysis. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed. CVS involves the removal of tissue samples from a portion of the placenta.The diagnosis of trisomy 18 may also be confirmed after birth based on a thorough clinical evaluation, detection of characteristic physical findings, and chromosomal analysis. For infants diagnosed with trisomy 18, careful monitoring and specialized testing may be conducted to ensure early detection and appropriate management of conditions associated with trisomy 18 such as cardiac defects and kidney concerns.
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Diagnosis of Trisomy 18. A diagnosis of trisomy 18 may be suspected before birth based upon specialized testing such as fetal ultrasonography and maternal serum screening. During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing findings that may suggest a chromosomal disorder or other abnormalities. In addition, screening tests that reveal abnormal levels of certain “markers” in the mother's blood may suggest an increased risk of trisomy 18 or other chromosomal abnormalities (e.g., Down syndrome). Such tests measure the levels of specific substances in the blood, including alpha-fetoprotein (AFP); human chorionic gonadotropin (hCG); unconjugated estriol; or other markers. If such screening studies reveal abnormal levels of these markers, additional testing may be recommended, such as amniocentesis or chorionic villus sampling (CVS) for chromosomal analysis. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed. CVS involves the removal of tissue samples from a portion of the placenta.The diagnosis of trisomy 18 may also be confirmed after birth based on a thorough clinical evaluation, detection of characteristic physical findings, and chromosomal analysis. For infants diagnosed with trisomy 18, careful monitoring and specialized testing may be conducted to ensure early detection and appropriate management of conditions associated with trisomy 18 such as cardiac defects and kidney concerns.
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Trisomy 18
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Therapies of Trisomy 18
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Treatment
The treatment of trisomy 18 is directed toward the specific symptoms in each affected individual. Treatment often requires the coordinated efforts of a multidisciplinary team of medical professionals. For many affected infants, supportive measures may be required to improve feeding and the intake of necessary nutrients. Such measures may include the delivery of liquid nutrients to the stomach through a tube inserted through the nose (nasogastric tube feeding) or stomach (gastrostomy). In addition, oxygen therapy may be required to ensure sufficient oxygen supply to bodily tissues or placement of a tracheostomy. Some individuals need support from a ventilator after invasive procedures or surgeries and most can be successfully weaned. Recommended treatment may include surgical correction of certain abnormalities associated with the disorder which may help to improve quantity and quality of life. The surgical procedures performed will depend upon the nature and severity of the anatomical malformations, their associated symptoms, and other unique factors. Individuals have received palliative and more aggressive interventions for cardiac malformations. For example, in recent years, many individuals have had successful cardiac surgery to correct VSD. A prevalent symptom among individuals with trisomy 18 is the presence of malignancies. It is recommended to have early imaging and lab exams done at specific intervals. For example, monitoring for Wilms tumor (a rare kidney cancer) is recommended every three months by abdominal ultrasound for children over one year of age. Nephroblastomatosis is commonly seen as a precursor to Wilms tumor. The possibility of hepatoblastoma (liver cancer) has also been reported in children with trisomy 18. Chemotherapy and surgical resection for patients with stable cardiac function can prolong life. A team approach for children with this disorder may include early intervention (birth to age three services) special education, physical therapy, occupational therapy, speech therapy in addition to necessary medical professionals and social services including in home nursing care and respite care as feasible. Coordinated treatment for this disorder is symptomatic and supportive.Genetic counseling is recommended for families with children with trisomy 18. This resource suggests a shared decision making model to help families and physicians provide the most optimal patient care.
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Therapies of Trisomy 18. Treatment
The treatment of trisomy 18 is directed toward the specific symptoms in each affected individual. Treatment often requires the coordinated efforts of a multidisciplinary team of medical professionals. For many affected infants, supportive measures may be required to improve feeding and the intake of necessary nutrients. Such measures may include the delivery of liquid nutrients to the stomach through a tube inserted through the nose (nasogastric tube feeding) or stomach (gastrostomy). In addition, oxygen therapy may be required to ensure sufficient oxygen supply to bodily tissues or placement of a tracheostomy. Some individuals need support from a ventilator after invasive procedures or surgeries and most can be successfully weaned. Recommended treatment may include surgical correction of certain abnormalities associated with the disorder which may help to improve quantity and quality of life. The surgical procedures performed will depend upon the nature and severity of the anatomical malformations, their associated symptoms, and other unique factors. Individuals have received palliative and more aggressive interventions for cardiac malformations. For example, in recent years, many individuals have had successful cardiac surgery to correct VSD. A prevalent symptom among individuals with trisomy 18 is the presence of malignancies. It is recommended to have early imaging and lab exams done at specific intervals. For example, monitoring for Wilms tumor (a rare kidney cancer) is recommended every three months by abdominal ultrasound for children over one year of age. Nephroblastomatosis is commonly seen as a precursor to Wilms tumor. The possibility of hepatoblastoma (liver cancer) has also been reported in children with trisomy 18. Chemotherapy and surgical resection for patients with stable cardiac function can prolong life. A team approach for children with this disorder may include early intervention (birth to age three services) special education, physical therapy, occupational therapy, speech therapy in addition to necessary medical professionals and social services including in home nursing care and respite care as feasible. Coordinated treatment for this disorder is symptomatic and supportive.Genetic counseling is recommended for families with children with trisomy 18. This resource suggests a shared decision making model to help families and physicians provide the most optimal patient care.
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Trisomy 18
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Overview of Trisomy 9p (Multiple Variants)
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Trisomy 9p is a rare chromosomal syndrome in which a portion of the 9th chromosome appears three times (trisomy) rather than twice in cells of the body. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p,” a long arm identified by the letter “q,” and a narrowed region at which the two arms are joined (centromere). Chromosomes are further subdivided into bands that are numbered outward from the centromere. For example, the short arm of chromosome 9 includes bands 9p11 to 9p24, and the long arm includes bands 9q11 to 9q34.In trisomy 9p, the trisomy (or duplicated material) may involve a portion of the short arm (9p), the entire short arm, or the short arm and a portion of the long arm (9q) of chromosome 9. Evidence suggests that, in many cases, associated symptoms and findings may be relatively similar among affected infants despite differing lengths of the trisomic (duplicated) segment of 9p. However, in those with larger trisomies (e.g., extending to middle or end [distal] regions of 9q), additional features may also be present that appear to correlate with the extent of the duplication.
Additionally, certain individuals with duplications of specific areas of chromosome 9p have not developed any symptoms or only very mild or subtle symptoms.Children with trisomy 9p are affected by delays in reaching developmental milestones including crawling or walking (developmental delays), growth deficiency, and distinctive malformations of the skull and facial (craniofacial) region. As children grow older, intellectual disability may become apparent.In some instances, additional physical abnormalities may also be present, such as other skeletal defects and/or structural malformations of the heart that are present at birth (congenital heart defects). In some cases, the trisomy appears to result from a balanced chromosomal rearrangement in one of the parents; in others, it is thought to arise from spontaneous (de novo) errors very early in embryonic development that occur for unknown reasons (sporadically).The chromosomal abnormality was originally reported in the medical literature in1970. Trisomy 9p was first proposed as a distinct syndrome with characteristic symptoms and findings in 1975.
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Overview of Trisomy 9p (Multiple Variants). Trisomy 9p is a rare chromosomal syndrome in which a portion of the 9th chromosome appears three times (trisomy) rather than twice in cells of the body. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p,” a long arm identified by the letter “q,” and a narrowed region at which the two arms are joined (centromere). Chromosomes are further subdivided into bands that are numbered outward from the centromere. For example, the short arm of chromosome 9 includes bands 9p11 to 9p24, and the long arm includes bands 9q11 to 9q34.In trisomy 9p, the trisomy (or duplicated material) may involve a portion of the short arm (9p), the entire short arm, or the short arm and a portion of the long arm (9q) of chromosome 9. Evidence suggests that, in many cases, associated symptoms and findings may be relatively similar among affected infants despite differing lengths of the trisomic (duplicated) segment of 9p. However, in those with larger trisomies (e.g., extending to middle or end [distal] regions of 9q), additional features may also be present that appear to correlate with the extent of the duplication.
Additionally, certain individuals with duplications of specific areas of chromosome 9p have not developed any symptoms or only very mild or subtle symptoms.Children with trisomy 9p are affected by delays in reaching developmental milestones including crawling or walking (developmental delays), growth deficiency, and distinctive malformations of the skull and facial (craniofacial) region. As children grow older, intellectual disability may become apparent.In some instances, additional physical abnormalities may also be present, such as other skeletal defects and/or structural malformations of the heart that are present at birth (congenital heart defects). In some cases, the trisomy appears to result from a balanced chromosomal rearrangement in one of the parents; in others, it is thought to arise from spontaneous (de novo) errors very early in embryonic development that occur for unknown reasons (sporadically).The chromosomal abnormality was originally reported in the medical literature in1970. Trisomy 9p was first proposed as a distinct syndrome with characteristic symptoms and findings in 1975.
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Trisomy 9p (Multiple Variants)
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Symptoms of Trisomy 9p (Multiple Variants)
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The specific symptoms of trisomy 9p can vary greatly from one person to another due, in part, to the specific length of the duplicated material on chromosome 9p.Trisomy 9p is often characterized by low muscle tone (hypotonia) as well as growth deficiency and delayed bone maturation, which means that the rate of growth and development of the bones is slower than in individuals with 46 chromosomes. Hypotonia can affect infants, most often related to difficulty feeding, resulting in the failure to gain weight and grow at the expected rate (failure to thrive). In general, growth deficiency primarily begins after birth (postnatally). Some infants may also experience oropharyngeal dysphagia, in which there is difficulty emptying food or drink from the back of the throat at the back of the mouth (oropharynx) into the esophagus. However, reports indicate that, in those with larger trisomic segments (e.g., through bands 9q22 or 9q32), growth deficiency may begin before birth (intrauterine growth retardation). Microcephaly, a condition indicates that the head circumference is smaller than would be expected based upon an infant’s age and gender, is also apparent in infancy.In many cases, trisomy 9p is also associated with varying degrees of intellectual disability, ranging from moderate to severe, and delays in the acquisition of skills requiring the coordination of mental and physical activities (developmental coordination disorder). According to reports in the medical literature, language development appears to be most severely delayed. Learning disabilities, ranging from mild to severe, also occur. Intellectual and learning issues go hand in hand. Intellectual and learning disabilities represent a broad range, especially when the children with partial trisomy 9p are considered as well. The gap with typically developing peers will often widen with age.Many infants and children with trisomy 9p also have a characteristic facial appearance. Most individuals with this condition present with a short and broad head (brachycephaly); a wide mouth with downturned corners; a prominent, relatively bulbous nose; large, low-set, “cup-shaped” ears; and/or a short vertical groove in the center of the upper lip (philtrum). Characteristic eye abnormalities may also be present, such as deeply set, widely spaced eyes; downwardly slanting eyelid folds (palpebral fissures); vertical skin folds that may cover the eyes’ inner corners (epicanthal folds); and/or abnormal deviation of one eye in relation to the other (strabismus). Some affected infants may also have a short, webbed neck; a highly arched roof of the mouth (palate); and/or widely spaced nipples. Teeth may erupt later than expected and may emerge crooked. In addition, in those with larger trisomic segments, additional craniofacial features may include a small jaw (micrognathia), incomplete closure (clefting) of the roof of the mouth (cleft palate), and/or an abnormal groove or gap in the upper lip (cleft lip).Many individuals with trisomy 9p may also have various anomalies of the hands and feet. These may include decreased length of specific bones of the fingers and toes (phalanges) and within the hands (metacarpals) and feet (metatarsals); short fingers and toes (digits) with small nails; and/or the pinkies may be fixed or ‘locked’ in a bent position (clinodactyly). The syndrome may also be associated with unusual, distinctive skin ridge patterns of the fingers and hands (abnormal dermatoglyphics), including a single flexion crease on the fifth fingers and a reduced total finger ridge count. Less often, a single crease across the palms may also be present.In some cases, trisomy 9p may be associated with skeletal defects including delayed closure of the “soft spots” (fontanels) and the fibrous joints (cranial sutures) between certain? bones of the skull; a deformity in which the foot is twisted out of shape or position (clubfoot); and/or abnormal front-to-back or side-to-side curvature of the spine (kyphoscoliosis) that may develop during the second decade of life. Less commonly, partial webbing (syndactyly) of certain fingers and toes and dislocation of the hips at birth have been noted.Approximately five to 25% of children with may also have congenital heart defects, particularly an abnormal opening in the partition (septum) that separates the two lower chambers (ventricles) of the heart (ventricular septal defects [VSDs]). In those with cardiac defects, associated symptoms and findings may vary, depending upon the size, nature, and/or combination of heart malformations present. For example, in some cases, such as those with small, isolated VSDs, no symptoms may be apparent (asymptomatic). However, in other instances, such as children with larger VSDs and/or other cardiac defects, associated symptoms and findings may include difficulties feeding, shortness of breath, profuse sweating, irritability, fatigue, bluish discoloration of the skin and/or mucous membranes (cyanosis. In severe cases, congenital heart disease may lead to potentially life-threatening complications. Surgery may be necessary to remedy heart defects along with follow-up care and monitoring.In some instances, additional physical abnormalities have been reported. These have included genital malformations in affected males, such as undescended testes (cryptorchidism) and/or abnormal placement of the urinary opening (hypospadias); kidney (renal) malformations; protrusion of part of the intestine and the fold of fatty membrane in front of the intestine (omentum) through a defect in the abdominal wall at the navel (umbilical hernia); and/or hydrocephalus, in which blockage of the normal flow of spinal fluid leads to excessive amounts of cerebrospinal (CSF) fluid accumulating in and around the brain. This leads to abnormally high pressure within the skull and swelling of the head, and can result in neurological impairment. CSF is the watery protective fluid that circulates through the cavities (ventricles) of the brain, the canal containing the spinal cord (spinal canal), and the space between layers of the protective membranes (meninges) surrounding the brain and spinal cord (i.e., subarachnoid space). Depending upon the age at symptom onset and other factors, associated symptoms may include sudden episodes of uncontrolled electrical activity in the brain (seizures), irritability, vomiting, headache, loss of coordination, deteriorating mental functioning, and/or other findings.Some individuals may also develop a brain malformation known as Dandy-Walker malformation (DWM). DWM occurs during embryonic development of the cerebellum and 4th ventricle. The cerebellum is an area at the back of the brain that helps coordinate movement, and, to a lesser extent, may be involved with some cognitive and behavioral functions. The 4th ventricle is a space around the cerebellum that channels fluid from inside to around the outside of the brain. DWM is characterized by improper development (e.g. small size and abnormal position) of the middle part of the cerebellum known as the cerebellar vermis, cystic enlargement of the 4th ventricle and enlargement of the base of the skull (posterior fossa). DWM may be associated with hydrocephalus. (For more information on this condition, Search for “DWM’ in the Rare Disease Database.) Affected children may be below average height for their age (short stature). In some cases, affected children have been diagnosed with growth hormone deficiency.
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Symptoms of Trisomy 9p (Multiple Variants). The specific symptoms of trisomy 9p can vary greatly from one person to another due, in part, to the specific length of the duplicated material on chromosome 9p.Trisomy 9p is often characterized by low muscle tone (hypotonia) as well as growth deficiency and delayed bone maturation, which means that the rate of growth and development of the bones is slower than in individuals with 46 chromosomes. Hypotonia can affect infants, most often related to difficulty feeding, resulting in the failure to gain weight and grow at the expected rate (failure to thrive). In general, growth deficiency primarily begins after birth (postnatally). Some infants may also experience oropharyngeal dysphagia, in which there is difficulty emptying food or drink from the back of the throat at the back of the mouth (oropharynx) into the esophagus. However, reports indicate that, in those with larger trisomic segments (e.g., through bands 9q22 or 9q32), growth deficiency may begin before birth (intrauterine growth retardation). Microcephaly, a condition indicates that the head circumference is smaller than would be expected based upon an infant’s age and gender, is also apparent in infancy.In many cases, trisomy 9p is also associated with varying degrees of intellectual disability, ranging from moderate to severe, and delays in the acquisition of skills requiring the coordination of mental and physical activities (developmental coordination disorder). According to reports in the medical literature, language development appears to be most severely delayed. Learning disabilities, ranging from mild to severe, also occur. Intellectual and learning issues go hand in hand. Intellectual and learning disabilities represent a broad range, especially when the children with partial trisomy 9p are considered as well. The gap with typically developing peers will often widen with age.Many infants and children with trisomy 9p also have a characteristic facial appearance. Most individuals with this condition present with a short and broad head (brachycephaly); a wide mouth with downturned corners; a prominent, relatively bulbous nose; large, low-set, “cup-shaped” ears; and/or a short vertical groove in the center of the upper lip (philtrum). Characteristic eye abnormalities may also be present, such as deeply set, widely spaced eyes; downwardly slanting eyelid folds (palpebral fissures); vertical skin folds that may cover the eyes’ inner corners (epicanthal folds); and/or abnormal deviation of one eye in relation to the other (strabismus). Some affected infants may also have a short, webbed neck; a highly arched roof of the mouth (palate); and/or widely spaced nipples. Teeth may erupt later than expected and may emerge crooked. In addition, in those with larger trisomic segments, additional craniofacial features may include a small jaw (micrognathia), incomplete closure (clefting) of the roof of the mouth (cleft palate), and/or an abnormal groove or gap in the upper lip (cleft lip).Many individuals with trisomy 9p may also have various anomalies of the hands and feet. These may include decreased length of specific bones of the fingers and toes (phalanges) and within the hands (metacarpals) and feet (metatarsals); short fingers and toes (digits) with small nails; and/or the pinkies may be fixed or ‘locked’ in a bent position (clinodactyly). The syndrome may also be associated with unusual, distinctive skin ridge patterns of the fingers and hands (abnormal dermatoglyphics), including a single flexion crease on the fifth fingers and a reduced total finger ridge count. Less often, a single crease across the palms may also be present.In some cases, trisomy 9p may be associated with skeletal defects including delayed closure of the “soft spots” (fontanels) and the fibrous joints (cranial sutures) between certain? bones of the skull; a deformity in which the foot is twisted out of shape or position (clubfoot); and/or abnormal front-to-back or side-to-side curvature of the spine (kyphoscoliosis) that may develop during the second decade of life. Less commonly, partial webbing (syndactyly) of certain fingers and toes and dislocation of the hips at birth have been noted.Approximately five to 25% of children with may also have congenital heart defects, particularly an abnormal opening in the partition (septum) that separates the two lower chambers (ventricles) of the heart (ventricular septal defects [VSDs]). In those with cardiac defects, associated symptoms and findings may vary, depending upon the size, nature, and/or combination of heart malformations present. For example, in some cases, such as those with small, isolated VSDs, no symptoms may be apparent (asymptomatic). However, in other instances, such as children with larger VSDs and/or other cardiac defects, associated symptoms and findings may include difficulties feeding, shortness of breath, profuse sweating, irritability, fatigue, bluish discoloration of the skin and/or mucous membranes (cyanosis. In severe cases, congenital heart disease may lead to potentially life-threatening complications. Surgery may be necessary to remedy heart defects along with follow-up care and monitoring.In some instances, additional physical abnormalities have been reported. These have included genital malformations in affected males, such as undescended testes (cryptorchidism) and/or abnormal placement of the urinary opening (hypospadias); kidney (renal) malformations; protrusion of part of the intestine and the fold of fatty membrane in front of the intestine (omentum) through a defect in the abdominal wall at the navel (umbilical hernia); and/or hydrocephalus, in which blockage of the normal flow of spinal fluid leads to excessive amounts of cerebrospinal (CSF) fluid accumulating in and around the brain. This leads to abnormally high pressure within the skull and swelling of the head, and can result in neurological impairment. CSF is the watery protective fluid that circulates through the cavities (ventricles) of the brain, the canal containing the spinal cord (spinal canal), and the space between layers of the protective membranes (meninges) surrounding the brain and spinal cord (i.e., subarachnoid space). Depending upon the age at symptom onset and other factors, associated symptoms may include sudden episodes of uncontrolled electrical activity in the brain (seizures), irritability, vomiting, headache, loss of coordination, deteriorating mental functioning, and/or other findings.Some individuals may also develop a brain malformation known as Dandy-Walker malformation (DWM). DWM occurs during embryonic development of the cerebellum and 4th ventricle. The cerebellum is an area at the back of the brain that helps coordinate movement, and, to a lesser extent, may be involved with some cognitive and behavioral functions. The 4th ventricle is a space around the cerebellum that channels fluid from inside to around the outside of the brain. DWM is characterized by improper development (e.g. small size and abnormal position) of the middle part of the cerebellum known as the cerebellar vermis, cystic enlargement of the 4th ventricle and enlargement of the base of the skull (posterior fossa). DWM may be associated with hydrocephalus. (For more information on this condition, Search for “DWM’ in the Rare Disease Database.) Affected children may be below average height for their age (short stature). In some cases, affected children have been diagnosed with growth hormone deficiency.
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Causes of Trisomy 9p (Multiple Variants)
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In many cases, the trisomy appears to result from spontaneous (de novo) errors very early in embryonic development that occur for unknown reasons (sporadically). In such de novo cases, the parents of the affected child usually have normal chromosomes and a relatively low risk of having another child with the chromosomal abnormality.In approximately 50% of cases, trisomy 9p may be due to a balanced chromosomal rearrangement in one of the parents. In most cases, the parental rearrangement is described as a “balanced translocation.” Translocations occur when portions of a chromosome break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. However, no genetic material is gained or lost, only rearranged. If a chromosomal rearrangement is balanced, meaning that it consists of an altered but balanced set of chromosomes, it is usually harmless to the carrier. However, such a chromosomal rearrangement may be associated with an increased risk of abnormal chromosomal development in the carrier’s offspring. Such children may inherit an unaltered set of chromosomes, the same balanced translocation as the parent, or an unbalanced translocation, in which a chromosome has extra (trisomic) or missing (monosomic) genetic material.Rare cases have also been reported in which the parental chromosomal rearrangement has been an inversion. An inversion is characterized by breakage of a chromosome in two places and reunion of the segment in reverse order from the original arrangement.Chromosomal analysis and genetic counseling are typically recommended for parents of an affected child to help confirm or exclude the presence of a balanced translocation or other chromosomal rearrangement involving chromosome 9 in one of the parents.Specific Breakpoints and a “Critical Region”
In individuals with trisomy 9p, all or a portion of the short arm (p) of chromosome 9 (9p) appears three times (trisomy) rather than twice in the cells of the body. In addition, in some cases, a portion of the long arm of chromosome 9 (9q) may also be trisomic (duplicated). In extremely rare cases, individuals with a trisomic portion of 9p may also have a deleted or missing (monosomic) portion.Evidence indicates that, in many cases, clinical features may be relatively similar among affected individuals despite differing lengths of the duplicated segment of 9p. According to some researchers, such findings suggest that certain characteristic abnormalities associated with the syndrome may result from trisomy of the end (distal) portion of 9p. (“Distal” indicates away or farthest from a particular point of reference, meaning the chromosome’s centromere. The distal region of 9p is sometimes referred to as “9p2” and includes bands 9p21 through 9p24, the latter of which is the end or “terminal” band of 9p [also known as “9pter”].) However, in individuals with larger trisomies, such as those that extend through bands 9p22, additional clinical findings may also be present that appear to correlate with the extent of the duplication.Generally, according to investigators, trisomies involving part or all of 9p and, in some cases, extending to 9q11-13 may be characterized by intellectual disability and distinctive craniofacial malformations already described. However, in addition to such features, intrauterine growth retardation, congenital heart defects, other skeletal abnormalities (e.g., congenital hip dislocation), and additional craniofacial malformations (e.g., micrognathia, cleft lip and cleft palate) are more common with trisomies extending to or including band 9p21.3-p24. Researchers believe that 9p22 is a “critical” region responsible for most of the classic symptoms of trisomy 9p. However, there are individuals reported in the medical literature who have duplications involving this region and exhibit only mild symptoms. More research is necessary to determine the specific correlation between the duplicated segment of 9p and the associated symptoms and whether additional factors such as modifier genes play a role in the development of specific symptoms in each individual case. twice in the cells of the body. In addition, in some cases, a portion of the long arm of chromosome 9 (9q) may also be trisomic (duplicated). In extremely rare cases, individuals with a trisomic portion of 9p may also have a deleted or missing (monosomic) portion.
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Causes of Trisomy 9p (Multiple Variants). In many cases, the trisomy appears to result from spontaneous (de novo) errors very early in embryonic development that occur for unknown reasons (sporadically). In such de novo cases, the parents of the affected child usually have normal chromosomes and a relatively low risk of having another child with the chromosomal abnormality.In approximately 50% of cases, trisomy 9p may be due to a balanced chromosomal rearrangement in one of the parents. In most cases, the parental rearrangement is described as a “balanced translocation.” Translocations occur when portions of a chromosome break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. However, no genetic material is gained or lost, only rearranged. If a chromosomal rearrangement is balanced, meaning that it consists of an altered but balanced set of chromosomes, it is usually harmless to the carrier. However, such a chromosomal rearrangement may be associated with an increased risk of abnormal chromosomal development in the carrier’s offspring. Such children may inherit an unaltered set of chromosomes, the same balanced translocation as the parent, or an unbalanced translocation, in which a chromosome has extra (trisomic) or missing (monosomic) genetic material.Rare cases have also been reported in which the parental chromosomal rearrangement has been an inversion. An inversion is characterized by breakage of a chromosome in two places and reunion of the segment in reverse order from the original arrangement.Chromosomal analysis and genetic counseling are typically recommended for parents of an affected child to help confirm or exclude the presence of a balanced translocation or other chromosomal rearrangement involving chromosome 9 in one of the parents.Specific Breakpoints and a “Critical Region”
In individuals with trisomy 9p, all or a portion of the short arm (p) of chromosome 9 (9p) appears three times (trisomy) rather than twice in the cells of the body. In addition, in some cases, a portion of the long arm of chromosome 9 (9q) may also be trisomic (duplicated). In extremely rare cases, individuals with a trisomic portion of 9p may also have a deleted or missing (monosomic) portion.Evidence indicates that, in many cases, clinical features may be relatively similar among affected individuals despite differing lengths of the duplicated segment of 9p. According to some researchers, such findings suggest that certain characteristic abnormalities associated with the syndrome may result from trisomy of the end (distal) portion of 9p. (“Distal” indicates away or farthest from a particular point of reference, meaning the chromosome’s centromere. The distal region of 9p is sometimes referred to as “9p2” and includes bands 9p21 through 9p24, the latter of which is the end or “terminal” band of 9p [also known as “9pter”].) However, in individuals with larger trisomies, such as those that extend through bands 9p22, additional clinical findings may also be present that appear to correlate with the extent of the duplication.Generally, according to investigators, trisomies involving part or all of 9p and, in some cases, extending to 9q11-13 may be characterized by intellectual disability and distinctive craniofacial malformations already described. However, in addition to such features, intrauterine growth retardation, congenital heart defects, other skeletal abnormalities (e.g., congenital hip dislocation), and additional craniofacial malformations (e.g., micrognathia, cleft lip and cleft palate) are more common with trisomies extending to or including band 9p21.3-p24. Researchers believe that 9p22 is a “critical” region responsible for most of the classic symptoms of trisomy 9p. However, there are individuals reported in the medical literature who have duplications involving this region and exhibit only mild symptoms. More research is necessary to determine the specific correlation between the duplicated segment of 9p and the associated symptoms and whether additional factors such as modifier genes play a role in the development of specific symptoms in each individual case. twice in the cells of the body. In addition, in some cases, a portion of the long arm of chromosome 9 (9q) may also be trisomic (duplicated). In extremely rare cases, individuals with a trisomic portion of 9p may also have a deleted or missing (monosomic) portion.
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Affects of Trisomy 9p (Multiple Variants)
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In observed cases, trisomy 9p has appeared to affect females approximately twice as frequently as males. As of 2013, more than 150 cases have been reported in the medical literature since the disorder was first described in 1970. Trisomy 9p is the fourth most common type of trisomy after trisomy 21 (Down syndrome), trisomy 18 (Edwards’s syndrome) and trisomy 13 (Patau syndrome).
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Affects of Trisomy 9p (Multiple Variants). In observed cases, trisomy 9p has appeared to affect females approximately twice as frequently as males. As of 2013, more than 150 cases have been reported in the medical literature since the disorder was first described in 1970. Trisomy 9p is the fourth most common type of trisomy after trisomy 21 (Down syndrome), trisomy 18 (Edwards’s syndrome) and trisomy 13 (Patau syndrome).
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Related disorders of Trisomy 9p (Multiple Variants)
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Symptoms of the following disorders may be similar to those of trisomy 9p. Comparisons may be useful for a differential diagnosis:Chromosome 9, tetrasomy 9p is a rare chromosomal disorder in which the short arm of chromosome 9 (9p) is present four times (tetrasomy) rather than twice in all or some cells of the body. Although many associated symptoms and findings may be similar to those seen in individuals with trisomy 9p, researchers suggest that such features may be more variable or severe in some cases. Characteristic abnormalities associated with tetrasomy 9p may include growth deficiency; developmental coordination disorder; moderate to severe intellectual disability; and various craniofacial, skeletal, heart (cardiac), kidney (renal), and/or other physical defects. Craniofacial abnormalities may resemble those associated with trisomy 9p, such as a bulbous nose; low-set, malformed ears; a down-slanted mouth; deeply set, widely spaced eyes; a short neck; and/or other features. Microcephaly, a condition indicates that the head circumference is smaller than would be expected based upon an infant’s age and gender, is also apparent in infancy. Tetrasomy 9p appears to result from spontaneous (de novo) errors very early in embryonic development that randomly occur for unknown reasons. (For more information, choose “Tetrasomy 9p” as your search term in the Rare Disease Database.)Chromosome 9, trisomy mosaic is a chromosomal disorder characterized by trisomy of the entire 9th chromosome in some cells of the body (mosaicism). The term “mosaicism” indicates that a percentage of an affected individual’s cells has the chromosomal abnormality, while other cells may have the typical chromosomal makeup. The range and severity of associated symptoms and findings may depend on the percentage of cells with the extra chromosome. Characteristic features may include growth deficiency before birth (intrauterine growth retardation); congenital heart defects; skeletal, genital, renal, and/or neurologic abnormalities; and/or variable craniofacial defects, such as a bulbous nose, short eyelid folds (palpebral fissures), deeply set eyes, a small jaw (micrognathia), low-set and malformed ears, a short neck, and/or other abnormalities. Chromosome 9, trisomy mosaic may be caused by errors during the division of a parent’s reproductive cells (meiosis) or during the division of body tissue cells (somatic cells) early in the development of the embryo (mitosis); the reason for such errors is not known. (For more information on this disorder, choose “Chromosome 9, Trisomy Mosaic” as your search term in the Rare Disease Database.)
Additional chromosomal disorders may be characterized by symptoms and findings similar to those associated with trisomy 9p. Chromosomal testing is necessary to confirm the specific chromosomal abnormality present. (For further information on such disorders, choose the name of the specific chromosomal disorder in question or use “chromosome” as your search term in the Rare Disease Database.)
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Related disorders of Trisomy 9p (Multiple Variants). Symptoms of the following disorders may be similar to those of trisomy 9p. Comparisons may be useful for a differential diagnosis:Chromosome 9, tetrasomy 9p is a rare chromosomal disorder in which the short arm of chromosome 9 (9p) is present four times (tetrasomy) rather than twice in all or some cells of the body. Although many associated symptoms and findings may be similar to those seen in individuals with trisomy 9p, researchers suggest that such features may be more variable or severe in some cases. Characteristic abnormalities associated with tetrasomy 9p may include growth deficiency; developmental coordination disorder; moderate to severe intellectual disability; and various craniofacial, skeletal, heart (cardiac), kidney (renal), and/or other physical defects. Craniofacial abnormalities may resemble those associated with trisomy 9p, such as a bulbous nose; low-set, malformed ears; a down-slanted mouth; deeply set, widely spaced eyes; a short neck; and/or other features. Microcephaly, a condition indicates that the head circumference is smaller than would be expected based upon an infant’s age and gender, is also apparent in infancy. Tetrasomy 9p appears to result from spontaneous (de novo) errors very early in embryonic development that randomly occur for unknown reasons. (For more information, choose “Tetrasomy 9p” as your search term in the Rare Disease Database.)Chromosome 9, trisomy mosaic is a chromosomal disorder characterized by trisomy of the entire 9th chromosome in some cells of the body (mosaicism). The term “mosaicism” indicates that a percentage of an affected individual’s cells has the chromosomal abnormality, while other cells may have the typical chromosomal makeup. The range and severity of associated symptoms and findings may depend on the percentage of cells with the extra chromosome. Characteristic features may include growth deficiency before birth (intrauterine growth retardation); congenital heart defects; skeletal, genital, renal, and/or neurologic abnormalities; and/or variable craniofacial defects, such as a bulbous nose, short eyelid folds (palpebral fissures), deeply set eyes, a small jaw (micrognathia), low-set and malformed ears, a short neck, and/or other abnormalities. Chromosome 9, trisomy mosaic may be caused by errors during the division of a parent’s reproductive cells (meiosis) or during the division of body tissue cells (somatic cells) early in the development of the embryo (mitosis); the reason for such errors is not known. (For more information on this disorder, choose “Chromosome 9, Trisomy Mosaic” as your search term in the Rare Disease Database.)
Additional chromosomal disorders may be characterized by symptoms and findings similar to those associated with trisomy 9p. Chromosomal testing is necessary to confirm the specific chromosomal abnormality present. (For further information on such disorders, choose the name of the specific chromosomal disorder in question or use “chromosome” as your search term in the Rare Disease Database.)
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Diagnosis of Trisomy 9p (Multiple Variants)
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In some cases, the diagnosis of trisomy 9p may be suggested before birth (prenatally) by specialized tests such as ultrasound, amniocentesis, and/or chorionic villus sampling (CVS). During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing characteristic findings that suggest a chromosomal disorder or other developmental abnormalities. 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 trisomy of part or all of the short arm of chromosome 9 (9p) and, in some cases, a portion of the long arm (9q).Trisomy 9p may also be diagnosed and/or confirmed after birth (postnatally) by a thorough clinical evaluation, identification of characteristic physical findings, chromosomal analysis, and other specialized tests. Chromosomes can be obtained from a blood sample.
Clinical Testing and Workup
There are different tests that can be performed on sample tissue for chromosomal analysis. Chromosomes obtained from sample tissue are stained so that they can be viewed more easily and are then examined under a microscope where the duplicated segment of chromosome 9p can be detected (high resolution karyotype). To determine the precise breakpoint on 9p, a more sensitive test may be necessary such as fluorescent in situ hybridization (FISH), a diagnostic test in which probes marked by a specific color of fluorescent dye attach to a specific chromosome allowing researchers to better view that specific region of a chromosome; m-array comparative genomic hybridization (CGH) a method in which a normal DNA is mixed to patient’s DNA in order to analyze gains (duplications) or losses (deletions) of chromosomal regions. M-array CGH allows for improved definition of breakpoint(s) in trisomy 9p, but it cannot detect balanced rearrangements (such as balanced translocation that sometimes can be diagnosed in one parent of the affected child).In some cases, diagnostic evaluation may include enzyme tests to detect elevated activity of the galactose-1-phosphate uridyltransferase (GALT) enzyme or the nucleoside triphosphate adenylatekinase (AK3) enzyme, both of which are known to be regulated by genes on the short arm of chromosome 9. In addition, in those diagnosed with trisomy 9p, various specialized tests may be performed to help detect and/or characterize certain abnormalities (e.g., certain skeletal malformations, congenital heart defects, etc.) that may be associated with the syndrome.
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Diagnosis of Trisomy 9p (Multiple Variants). In some cases, the diagnosis of trisomy 9p may be suggested before birth (prenatally) by specialized tests such as ultrasound, amniocentesis, and/or chorionic villus sampling (CVS). During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing characteristic findings that suggest a chromosomal disorder or other developmental abnormalities. 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 trisomy of part or all of the short arm of chromosome 9 (9p) and, in some cases, a portion of the long arm (9q).Trisomy 9p may also be diagnosed and/or confirmed after birth (postnatally) by a thorough clinical evaluation, identification of characteristic physical findings, chromosomal analysis, and other specialized tests. Chromosomes can be obtained from a blood sample.
Clinical Testing and Workup
There are different tests that can be performed on sample tissue for chromosomal analysis. Chromosomes obtained from sample tissue are stained so that they can be viewed more easily and are then examined under a microscope where the duplicated segment of chromosome 9p can be detected (high resolution karyotype). To determine the precise breakpoint on 9p, a more sensitive test may be necessary such as fluorescent in situ hybridization (FISH), a diagnostic test in which probes marked by a specific color of fluorescent dye attach to a specific chromosome allowing researchers to better view that specific region of a chromosome; m-array comparative genomic hybridization (CGH) a method in which a normal DNA is mixed to patient’s DNA in order to analyze gains (duplications) or losses (deletions) of chromosomal regions. M-array CGH allows for improved definition of breakpoint(s) in trisomy 9p, but it cannot detect balanced rearrangements (such as balanced translocation that sometimes can be diagnosed in one parent of the affected child).In some cases, diagnostic evaluation may include enzyme tests to detect elevated activity of the galactose-1-phosphate uridyltransferase (GALT) enzyme or the nucleoside triphosphate adenylatekinase (AK3) enzyme, both of which are known to be regulated by genes on the short arm of chromosome 9. In addition, in those diagnosed with trisomy 9p, various specialized tests may be performed to help detect and/or characterize certain abnormalities (e.g., certain skeletal malformations, congenital heart defects, etc.) that may be associated with the syndrome.
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Therapies of Trisomy 9p (Multiple Variants)
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Treatment
The treatment of trisomy 9p is directed toward the specific symptoms and physical findings that are displayed in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons; physicians who diagnose and treat abnormalities of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who specialize in heart abnormalities (cardiologists); neurologists; and/or other healthcare professionals. Genetic counseling is recommended for families with children affected by this condition. Psychosocial support for the entire family may be needed as well.Early intervention services during infancy and toddlerhood (before the age of three) are important in ensuring that affected children reach their potential. Early speech therapy for children who experience severe communication and language problems is extremely important. Special services that may be beneficial during childhood include special education, physical therapy, occupational therapy, speech therapy and/or other medical, and social services. In the US, an Individualized Family Support Plan (IFSP) may be developed to guide the early intervention process for infants and toddlers with disabilities. An Individualized Education Program (IEP) may be developed to assist children in school if special services are required, or a Section 504 plan which can ensure that the child receives access to an equal education through accommodations in their learning environment. Vocational and habilitation services are often necessary during adulthood.Additional treatment for this disorder is symptomatic. For example, for congenital heart defects, treatment with medication, surgical intervention (palliative and/or corrective), and/or other measures may be required. In addition, in some cases, physicians may recommend surgical repair or correction of characteristic craniofacial malformations, skeletal abnormalities, genital defects, hernias, renal anomalies, and/or other malformations associated with the disorder. The specific surgical procedures performed will depend upon the nature and severity of the anatomical abnormalities, their associated symptoms, and other factors. In addition, growth hormone deficiency has been successfully treated with supplemental growth hormone.
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Therapies of Trisomy 9p (Multiple Variants). Treatment
The treatment of trisomy 9p is directed toward the specific symptoms and physical findings that are displayed in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons; physicians who diagnose and treat abnormalities of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who specialize in heart abnormalities (cardiologists); neurologists; and/or other healthcare professionals. Genetic counseling is recommended for families with children affected by this condition. Psychosocial support for the entire family may be needed as well.Early intervention services during infancy and toddlerhood (before the age of three) are important in ensuring that affected children reach their potential. Early speech therapy for children who experience severe communication and language problems is extremely important. Special services that may be beneficial during childhood include special education, physical therapy, occupational therapy, speech therapy and/or other medical, and social services. In the US, an Individualized Family Support Plan (IFSP) may be developed to guide the early intervention process for infants and toddlers with disabilities. An Individualized Education Program (IEP) may be developed to assist children in school if special services are required, or a Section 504 plan which can ensure that the child receives access to an equal education through accommodations in their learning environment. Vocational and habilitation services are often necessary during adulthood.Additional treatment for this disorder is symptomatic. For example, for congenital heart defects, treatment with medication, surgical intervention (palliative and/or corrective), and/or other measures may be required. In addition, in some cases, physicians may recommend surgical repair or correction of characteristic craniofacial malformations, skeletal abnormalities, genital defects, hernias, renal anomalies, and/or other malformations associated with the disorder. The specific surgical procedures performed will depend upon the nature and severity of the anatomical abnormalities, their associated symptoms, and other factors. In addition, growth hormone deficiency has been successfully treated with supplemental growth hormone.
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Overview of Trisomy X
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Trisomy X is a disorder that affects females and is characterized by the presence of an additional X chromosome. Normally, females have two X chromosomes; however, females with trisomy X carry three X chromosomes. The phenotype associated with this chromosomal disorder varies widely, but most commonly includes language-based learning disabilities, developmental dyspraxia, tall stature, low muscle tone (hypotonia), and abnormal bending or curving of the pinkies toward the ring fingers (clinodactyly). Trisomy X occurs randomly as a result from errors during the division of reproductive cells in one of the parents. This disorder occurs in one in 900 to 1,000 live births.
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Overview of Trisomy X. Trisomy X is a disorder that affects females and is characterized by the presence of an additional X chromosome. Normally, females have two X chromosomes; however, females with trisomy X carry three X chromosomes. The phenotype associated with this chromosomal disorder varies widely, but most commonly includes language-based learning disabilities, developmental dyspraxia, tall stature, low muscle tone (hypotonia), and abnormal bending or curving of the pinkies toward the ring fingers (clinodactyly). Trisomy X occurs randomly as a result from errors during the division of reproductive cells in one of the parents. This disorder occurs in one in 900 to 1,000 live births.
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Symptoms of Trisomy X
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The severity of symptoms associated with trisomy X may vary greatly from one person to another, though it is thought that many present mildly or as asymptomatic as about 90% of females with XXX remain undiagnosed throughout life (Nielsen, 1990). It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their specialists and medical team about their specific case, associated symptoms and overall prognosis.While this disorder is not associated with any striking physical features, some individuals with trisomy X may have mild facial abnormalities including vertical skin folds that may cover the eyes’ inner corners (epicanthal folds), widely spaced eyes (hypertelorism), and smaller than normal head circumference. Most also have decreased muscle tone (hypotonia) and the fifth finger may be abnormally bent or curved mildly, which is called clinodactyly. During early childhood, girls with trisomy X usually exhibit increased stature as compared with other girls their age, and by adolescence, most are at or above the 75th percentile for height. In general, these girls are not discernible from neurotypical children in appearance.Trisomy X is often associated with a broad range of neurodevelopmental differences. Infants and children with trisomy X experience delays in attaining developmental milestones, especially the acquisition of motor and speech skills. For example, in infants, walking may be delayed due to the low muscle tone and in older affected girls poor coordination, clumsiness, deficient motor planning skills, and developmental dyspraxia may be exhibited. Speech and language development is also commonly delayed and first words may not occur until 18 months. Expressive ability is almost always more impaired than receptive skills, though both are impacted. Girls with trisomy X have an increased frequency of language-based learning disabilities including reading deficiencies such as dyslexia, reading comprehension deficits and/or reading fluency issues in conjunction with other language-based disabilities. There is a wide range of cognitive abilities in girls with trisomy X, with most having mildly impaired or average non-verbal IQs and below average verbal IQs. However, these deficits are very responsive to treatment, with early intervention often resulting in the most optimal outcome.Though less is known about the psychological symptoms associated with trisomy X, studies have found an increased incidence of anxiety and attention deficit hyperactivity disorder (ADHD). It is believed that their impairments in verbal abilities may exacerbate anxiety in social settings, such as school, and result in low self-esteem, social avoidance, and more behavioral problems. The incidence of ADHD in girls with trisomy X is reported to be about 25-35% with symptoms including inattention, poor executive function, and distractibility rather than hyperactivity (Pennington et al., 1980; Bender et al., 1993). Again, some individuals have minimal to no behavioral or emotional abnormalities while others may need therapeutic services. Early detection is important and in many cases, these girls have few issues later in life when identified early and treated appropriately.For most girls, sexual development and fertility are normal. However, reports indicate that some affected females may have abnormal development of the ovaries (ovarian dysgenesis) and/or the uterus, delayed or early onset of puberty (precocious puberty), and/or fertility problems. There have also been reports of women with trisomy X developing premature ovarian failure (POF), which is the loss of function of the ovaries before the age where menopause is expected to begin due to a decrease in the production of certain hormones.Less often, additional abnormalities have been described in individuals with trisomy X including kidney abnormalities, such as absence of a kidney (unilateral renal agenesis) or malformation (dysplasia) of the kidneys; recurrent urinary tract infections; seizures; constipation; abdominal pain; flatfeet (pes planus); and pectus excavatum, a condition in which the breastbone is mildly depressed into the chest. Heart (cardiac) abnormalities have also been described in some isolated cases.
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Symptoms of Trisomy X. The severity of symptoms associated with trisomy X may vary greatly from one person to another, though it is thought that many present mildly or as asymptomatic as about 90% of females with XXX remain undiagnosed throughout life (Nielsen, 1990). It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their specialists and medical team about their specific case, associated symptoms and overall prognosis.While this disorder is not associated with any striking physical features, some individuals with trisomy X may have mild facial abnormalities including vertical skin folds that may cover the eyes’ inner corners (epicanthal folds), widely spaced eyes (hypertelorism), and smaller than normal head circumference. Most also have decreased muscle tone (hypotonia) and the fifth finger may be abnormally bent or curved mildly, which is called clinodactyly. During early childhood, girls with trisomy X usually exhibit increased stature as compared with other girls their age, and by adolescence, most are at or above the 75th percentile for height. In general, these girls are not discernible from neurotypical children in appearance.Trisomy X is often associated with a broad range of neurodevelopmental differences. Infants and children with trisomy X experience delays in attaining developmental milestones, especially the acquisition of motor and speech skills. For example, in infants, walking may be delayed due to the low muscle tone and in older affected girls poor coordination, clumsiness, deficient motor planning skills, and developmental dyspraxia may be exhibited. Speech and language development is also commonly delayed and first words may not occur until 18 months. Expressive ability is almost always more impaired than receptive skills, though both are impacted. Girls with trisomy X have an increased frequency of language-based learning disabilities including reading deficiencies such as dyslexia, reading comprehension deficits and/or reading fluency issues in conjunction with other language-based disabilities. There is a wide range of cognitive abilities in girls with trisomy X, with most having mildly impaired or average non-verbal IQs and below average verbal IQs. However, these deficits are very responsive to treatment, with early intervention often resulting in the most optimal outcome.Though less is known about the psychological symptoms associated with trisomy X, studies have found an increased incidence of anxiety and attention deficit hyperactivity disorder (ADHD). It is believed that their impairments in verbal abilities may exacerbate anxiety in social settings, such as school, and result in low self-esteem, social avoidance, and more behavioral problems. The incidence of ADHD in girls with trisomy X is reported to be about 25-35% with symptoms including inattention, poor executive function, and distractibility rather than hyperactivity (Pennington et al., 1980; Bender et al., 1993). Again, some individuals have minimal to no behavioral or emotional abnormalities while others may need therapeutic services. Early detection is important and in many cases, these girls have few issues later in life when identified early and treated appropriately.For most girls, sexual development and fertility are normal. However, reports indicate that some affected females may have abnormal development of the ovaries (ovarian dysgenesis) and/or the uterus, delayed or early onset of puberty (precocious puberty), and/or fertility problems. There have also been reports of women with trisomy X developing premature ovarian failure (POF), which is the loss of function of the ovaries before the age where menopause is expected to begin due to a decrease in the production of certain hormones.Less often, additional abnormalities have been described in individuals with trisomy X including kidney abnormalities, such as absence of a kidney (unilateral renal agenesis) or malformation (dysplasia) of the kidneys; recurrent urinary tract infections; seizures; constipation; abdominal pain; flatfeet (pes planus); and pectus excavatum, a condition in which the breastbone is mildly depressed into the chest. Heart (cardiac) abnormalities have also been described in some isolated cases.
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Causes of Trisomy X
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Trisomy X is a chromosomal abnormality characterized by the presence of an extra X chromosome in females. Chromosomes are found in the nucleus of all body cells and carry the genetic characteristics of each individual. There are 23 pairs of human chromosomes with the 23rd pair determining the sex of the individual. Typical males have one X and one Y chromosome (46,XY) while typical females have two X chromosomes resulting in a 46,XX karyotype.However, females with trisomy X have an extra X chromosome resulting in a 47,XXX karyotype. Trisomy X is a genetic disorder, but it is not inherited. The presence of the extra X chromosome results from sporadic, random errors during the normal division of reproductive cells in one of the parents (nondisjunction during meiosis). Studies suggest that the risk of such errors increases with advanced maternal age. In most children, the additional X chromosome comes from the mother.In some affected females, only a certain percentage of their cells may have three X chromosomes, while other cells have a normal chromosomal make-up (46,XX/47,XXX mosaicism). This happens in approximately 20 percent of children when nondisjunction events occur after conception in the developing fetus (postzygotic ondisjunction).These females are thought to have milder symptoms and fewer developmental and learning problems, but further research is needed. Variants have also been described in which cells contain four or five X chromosomes (tetra X syndrome and penta X syndrome). Such variants are typically associated with more severe symptoms and findings. (For further information, please see the “Related Disorders” section of this report below.)Researchers believe that overexpression of genes that escape normal X-inactivation may lead to the neurodevelopmental symptoms associated with 47,XXX. In typical females that have two X chromosomes, one of the X chromosomes is “partially turned off” and some but not all of the genes on that chromosome are inactivated (X-inactivation). Researchers suspect that the presence of a third X chromosome allows some genes that are normally “turned off” to be expressed. However, the link between X-inactivation and symptoms in 47,XXX is not fully understood.
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Causes of Trisomy X. Trisomy X is a chromosomal abnormality characterized by the presence of an extra X chromosome in females. Chromosomes are found in the nucleus of all body cells and carry the genetic characteristics of each individual. There are 23 pairs of human chromosomes with the 23rd pair determining the sex of the individual. Typical males have one X and one Y chromosome (46,XY) while typical females have two X chromosomes resulting in a 46,XX karyotype.However, females with trisomy X have an extra X chromosome resulting in a 47,XXX karyotype. Trisomy X is a genetic disorder, but it is not inherited. The presence of the extra X chromosome results from sporadic, random errors during the normal division of reproductive cells in one of the parents (nondisjunction during meiosis). Studies suggest that the risk of such errors increases with advanced maternal age. In most children, the additional X chromosome comes from the mother.In some affected females, only a certain percentage of their cells may have three X chromosomes, while other cells have a normal chromosomal make-up (46,XX/47,XXX mosaicism). This happens in approximately 20 percent of children when nondisjunction events occur after conception in the developing fetus (postzygotic ondisjunction).These females are thought to have milder symptoms and fewer developmental and learning problems, but further research is needed. Variants have also been described in which cells contain four or five X chromosomes (tetra X syndrome and penta X syndrome). Such variants are typically associated with more severe symptoms and findings. (For further information, please see the “Related Disorders” section of this report below.)Researchers believe that overexpression of genes that escape normal X-inactivation may lead to the neurodevelopmental symptoms associated with 47,XXX. In typical females that have two X chromosomes, one of the X chromosomes is “partially turned off” and some but not all of the genes on that chromosome are inactivated (X-inactivation). Researchers suspect that the presence of a third X chromosome allows some genes that are normally “turned off” to be expressed. However, the link between X-inactivation and symptoms in 47,XXX is not fully understood.
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Affects of Trisomy X
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Trisomy X is a chromosomal disorder that affects only females. Reported estimates of frequency have varied with the most common estimate being one in 1,000 female births. Because many females with the disorder may have few or no symptoms, researchers believe that the disorder is substantially underdiagnosed and that the reported number of affected females reflected in the medical literature is inappropriately low (about 10%). With increased detection, more in depth studies may be conducted and more girls with trisomy X can be appropriately treated.
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Affects of Trisomy X. Trisomy X is a chromosomal disorder that affects only females. Reported estimates of frequency have varied with the most common estimate being one in 1,000 female births. Because many females with the disorder may have few or no symptoms, researchers believe that the disorder is substantially underdiagnosed and that the reported number of affected females reflected in the medical literature is inappropriately low (about 10%). With increased detection, more in depth studies may be conducted and more girls with trisomy X can be appropriately treated.
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Related disorders of Trisomy X
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Symptoms of the following disorders can be similar to those of trisomy X. Researchers currently believe each additional X is associated with a more severe phenotypic outcome. Comparisons may be useful for a differential diagnosis.Tetra X syndrome is a rare chromosomal abnormality in which females have two extra X chromosomes (48,XXXX karyotype). Mild to moderate intellectual disabilities appear to be more common in this group of girls. Affected individuals also commonly have speech difficulties due to verbal and oral motor dysfunction in association with developmental dyspraxia. In some girls, Tetra X syndrome may also be associated with certain facial abnormalities similar to those found in 47,XXX, such as widely set eyes (ocular hypertelorism), upslanting eyelid folds (palpebral fissures), vertical skin folds that may cover the eyes’ inner corners (epicanthal folds), and/or a relatively small jaw (micrognathia). Other associated physical features may sometimes include deviation of the fifth fingers (clinodactyly), abnormal fusion of the forearm bones (radioulnar synostosis), and/or webbing of the neck. Unlike 47,XXX, affected females often have incomplete development of secondary sexual characteristics, such as sparse pubic and underarm hair, small breasts, absence or irregularity of menstrual cycles, and, in some cases, underdevelopment of external genitalia. Tetra X results from errors during the division of a parent’s reproductive cells (nondisjunction during meiosis).Penta X syndrome is a rare chromosomal abnormality in which females have three extra X chromosomes (49,XXXXX karyotype). The condition is typically characterized by certain physical abnormalities, including short stature and malformations of the skull and craniofacial region including small head circumference (microcephaly), a round face, upslanting eyelid folds (palpebral fissures), widely spaced eyes (ocular hypertelorism), droopy upper eyelids (ptosis), vertical skin folds that may cover the eyes’ inner corners (epicanthal folds), malformed ears, a flat nasal bridge, a short neck with a low hairline, thick lips, a small jaw (micrognathia), and dental abnormalities. Other physical findings associated with Penta X syndrome include abnormal fusion of the forearm bones (radioulnar synostosis), narrow shoulders, abnormal deviation (clinodactyly) or permanent flexion (camptodactyly) of one or more fingers, heart and/or kidney defects, deficient development of the ovaries and uterus, and/or delayed puberty. During infancy and childhood, girls with 49,XXXXX may exhibit motor delays, moderate to severe intellectual disability, and speech and communication difficulties. Penta X syndrome results from errors during the division of a parent’s reproductive cells. (For more information on these disorders, choose “Penta X” as your search terms in the Rare Disease Database.)
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Related disorders of Trisomy X. Symptoms of the following disorders can be similar to those of trisomy X. Researchers currently believe each additional X is associated with a more severe phenotypic outcome. Comparisons may be useful for a differential diagnosis.Tetra X syndrome is a rare chromosomal abnormality in which females have two extra X chromosomes (48,XXXX karyotype). Mild to moderate intellectual disabilities appear to be more common in this group of girls. Affected individuals also commonly have speech difficulties due to verbal and oral motor dysfunction in association with developmental dyspraxia. In some girls, Tetra X syndrome may also be associated with certain facial abnormalities similar to those found in 47,XXX, such as widely set eyes (ocular hypertelorism), upslanting eyelid folds (palpebral fissures), vertical skin folds that may cover the eyes’ inner corners (epicanthal folds), and/or a relatively small jaw (micrognathia). Other associated physical features may sometimes include deviation of the fifth fingers (clinodactyly), abnormal fusion of the forearm bones (radioulnar synostosis), and/or webbing of the neck. Unlike 47,XXX, affected females often have incomplete development of secondary sexual characteristics, such as sparse pubic and underarm hair, small breasts, absence or irregularity of menstrual cycles, and, in some cases, underdevelopment of external genitalia. Tetra X results from errors during the division of a parent’s reproductive cells (nondisjunction during meiosis).Penta X syndrome is a rare chromosomal abnormality in which females have three extra X chromosomes (49,XXXXX karyotype). The condition is typically characterized by certain physical abnormalities, including short stature and malformations of the skull and craniofacial region including small head circumference (microcephaly), a round face, upslanting eyelid folds (palpebral fissures), widely spaced eyes (ocular hypertelorism), droopy upper eyelids (ptosis), vertical skin folds that may cover the eyes’ inner corners (epicanthal folds), malformed ears, a flat nasal bridge, a short neck with a low hairline, thick lips, a small jaw (micrognathia), and dental abnormalities. Other physical findings associated with Penta X syndrome include abnormal fusion of the forearm bones (radioulnar synostosis), narrow shoulders, abnormal deviation (clinodactyly) or permanent flexion (camptodactyly) of one or more fingers, heart and/or kidney defects, deficient development of the ovaries and uterus, and/or delayed puberty. During infancy and childhood, girls with 49,XXXXX may exhibit motor delays, moderate to severe intellectual disability, and speech and communication difficulties. Penta X syndrome results from errors during the division of a parent’s reproductive cells. (For more information on these disorders, choose “Penta X” as your search terms in the Rare Disease Database.)
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Diagnosis of Trisomy X
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Trisomy X may be suspected based upon the identification of characteristic neurodevelopmental, behavioral or learning disabilities. A diagnosis may be confirmed by certain specialized tests such as chromosomal analysis performed on blood samples that can reveal the presence of an extra X chromosome in body cells.In addition, trisomy X is increasingly being diagnosed before birth (prenatally) based on non-invasive prenatal testing (NIPT), which reveals if the fetus is at risk for chromosomal disorders. Diagnoses are later confirmed with amniocentesis, in which a sample of fluid that surrounds the developing fetus is removed and analyzed, or chorionic villus sampling (CVS) which involves the removal of tissue samples from a portion of the placenta.
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Diagnosis of Trisomy X. Trisomy X may be suspected based upon the identification of characteristic neurodevelopmental, behavioral or learning disabilities. A diagnosis may be confirmed by certain specialized tests such as chromosomal analysis performed on blood samples that can reveal the presence of an extra X chromosome in body cells.In addition, trisomy X is increasingly being diagnosed before birth (prenatally) based on non-invasive prenatal testing (NIPT), which reveals if the fetus is at risk for chromosomal disorders. Diagnoses are later confirmed with amniocentesis, in which a sample of fluid that surrounds the developing fetus is removed and analyzed, or chorionic villus sampling (CVS) which involves the removal of tissue samples from a portion of the placenta.
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Therapies of Trisomy X
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TreatmentDue to the wide phenotype of this disorder, specific therapeutic strategies depend upon several factors including the age of an affected individual upon diagnosis, the specific symptoms that are present, and the overall severity of the disorder in each case.Genetic counseling is recommended for affected individuals and their families and early intervention services are recommended for infants and children diagnosed with trisomy X. Experts advise a physical assessment by age four months to evaluate muscle tone and strength; language and speech assessment by 12 months of age to evaluate expressive and receptive language development, as well as identify any speech delay; pre-reading assessment during preschool years prior to first grade to look for early signs of reading dysfunction; and behavioral assessment by third grade to address any issues with anxiety and/or ADHD. A neurodevelopmental evaluation is recommended to help assess additional developmental issues, learning disabilities, and social and emotional problems. Infants and children with trisomy X should also receive kidney (renal) and heart (cardiac) evaluations to detect potential abnormalities associated with the disorder.Evidence suggests that affected children are greatly responsive to early intervention services and treatment, so early identification is essential to promote optimal outcome. Such services can include speech therapy, occupational therapy, physical therapy, and developmental therapy and counseling.Adolescent and adult women with 47,XXX who exhibit late periods (menarche), menstrual abnormalities, or fertility issues should be evaluated for primary ovarian failure (POF). Adolescence is challenging for children, and girls with triple X often struggle as they enter middle school years so counseling short term may be necessary to help them during these turbulent years.
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Therapies of Trisomy X. TreatmentDue to the wide phenotype of this disorder, specific therapeutic strategies depend upon several factors including the age of an affected individual upon diagnosis, the specific symptoms that are present, and the overall severity of the disorder in each case.Genetic counseling is recommended for affected individuals and their families and early intervention services are recommended for infants and children diagnosed with trisomy X. Experts advise a physical assessment by age four months to evaluate muscle tone and strength; language and speech assessment by 12 months of age to evaluate expressive and receptive language development, as well as identify any speech delay; pre-reading assessment during preschool years prior to first grade to look for early signs of reading dysfunction; and behavioral assessment by third grade to address any issues with anxiety and/or ADHD. A neurodevelopmental evaluation is recommended to help assess additional developmental issues, learning disabilities, and social and emotional problems. Infants and children with trisomy X should also receive kidney (renal) and heart (cardiac) evaluations to detect potential abnormalities associated with the disorder.Evidence suggests that affected children are greatly responsive to early intervention services and treatment, so early identification is essential to promote optimal outcome. Such services can include speech therapy, occupational therapy, physical therapy, and developmental therapy and counseling.Adolescent and adult women with 47,XXX who exhibit late periods (menarche), menstrual abnormalities, or fertility issues should be evaluated for primary ovarian failure (POF). Adolescence is challenging for children, and girls with triple X often struggle as they enter middle school years so counseling short term may be necessary to help them during these turbulent years.
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Overview of Tropical Sprue
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Tropical Sprue is a rare digestive disease in which the small intestine's ability to absorb nutrients is impaired (malabsorption). Consequently, nutritional deficiencies and abnormalities in the mucous lining of the small intestine may be present. The exact cause of this disorder is not known, however it may be related to environmental and nutritional conditions in the tropical regions where it is most prevalent.
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Overview of Tropical Sprue. Tropical Sprue is a rare digestive disease in which the small intestine's ability to absorb nutrients is impaired (malabsorption). Consequently, nutritional deficiencies and abnormalities in the mucous lining of the small intestine may be present. The exact cause of this disorder is not known, however it may be related to environmental and nutritional conditions in the tropical regions where it is most prevalent.
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Symptoms of Tropical Sprue
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The symptoms of Tropical Sprue may include fatigue and diarrhea with stools that are abundant, pale and foul-smelling. People with this disorder may also experience a profound loss of appetite (anorexia), a sore tongue, night blindness, weight loss, a loss of strength and energy (asthenia) and general weakness.The onset of Tropical Sprue may be sudden. Individuals may have an abnormally high fever, inflammation of the mouth and tongue, experience dry skin, a scaly appearance on the lips and at the angles of the mouth. Sometimes mental depression may occur.For some people with Tropical Sprue, symptoms cease as suddenly as they may have begun (spontaneous remission). Treatment of the disorder in its early stages may result in rapid and complete recovery. The return to normal intestinal structure and function may be slower if treatment is begun later in the course of the disease. In some cases, Tropical Sprue may become chronic with frequent relapses.People with this disorder may develop anemia characterized by the presence of abnormally enlarged blood cells (megaloblastic) in the bone marrow. (For more information on this disorder, choose “Megaloblastic Anemia” as your search term in the Rare Disease Database.)
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Symptoms of Tropical Sprue. The symptoms of Tropical Sprue may include fatigue and diarrhea with stools that are abundant, pale and foul-smelling. People with this disorder may also experience a profound loss of appetite (anorexia), a sore tongue, night blindness, weight loss, a loss of strength and energy (asthenia) and general weakness.The onset of Tropical Sprue may be sudden. Individuals may have an abnormally high fever, inflammation of the mouth and tongue, experience dry skin, a scaly appearance on the lips and at the angles of the mouth. Sometimes mental depression may occur.For some people with Tropical Sprue, symptoms cease as suddenly as they may have begun (spontaneous remission). Treatment of the disorder in its early stages may result in rapid and complete recovery. The return to normal intestinal structure and function may be slower if treatment is begun later in the course of the disease. In some cases, Tropical Sprue may become chronic with frequent relapses.People with this disorder may develop anemia characterized by the presence of abnormally enlarged blood cells (megaloblastic) in the bone marrow. (For more information on this disorder, choose “Megaloblastic Anemia” as your search term in the Rare Disease Database.)
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Causes of Tropical Sprue
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The exact cause of Tropical Sprue is not known. It is an acquired disorder that may be related to environmental and nutritional factors, or Tropical Sprue may be related to an infectious organism (either viral or bacterial), dietary toxin, parasitic infestation, or a nutritional deficiency such as folic acid. Tropical Sprue causes damage to the mucosal lining of the intestine resulting the impaired absorption of food, minerals, and water.
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Causes of Tropical Sprue. The exact cause of Tropical Sprue is not known. It is an acquired disorder that may be related to environmental and nutritional factors, or Tropical Sprue may be related to an infectious organism (either viral or bacterial), dietary toxin, parasitic infestation, or a nutritional deficiency such as folic acid. Tropical Sprue causes damage to the mucosal lining of the intestine resulting the impaired absorption of food, minerals, and water.
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Affects of Tropical Sprue
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Tropical Sprue is a rare disorder in temperate regions. It occurs mainly in the tropical regions of the Caribbean, India, South Africa, and Southeast Asia. Transients, tourists and visitors to these areas can be affected.
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Affects of Tropical Sprue. Tropical Sprue is a rare disorder in temperate regions. It occurs mainly in the tropical regions of the Caribbean, India, South Africa, and Southeast Asia. Transients, tourists and visitors to these areas can be affected.
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Related disorders of Tropical Sprue
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Symptoms of the following disorders can be similar to those of Tropical Sprue. Comparisons may be useful for a differential diagnosis:Malabsorption syndromes refer to a group of digestive disorders which are characterized by the impairment of absorption of nutrients and the excessive loss of nonabsorbed substances in the stool. There are many underlying diseases that are associated with these syndromes. Symptoms vary directly with the severity of the disease. Diarrhea and large volumes of fatty stools are consistent symptoms in people with malabsorption syndromes.Giardiasis is a rare infectious disease of the small intestine caused by the single-celled organism Giardia lamblia. Like Tropical Sprue, this disease is characterized by the impaired absorption of a variety of nutrients by the small intestine. Symptoms may include abdominal cramps, stomach pain, watery diarrhea, excessive gas and fould-smelling stools. Later in the course of the disease, other symptoms such as weight loss and a profound loss of appetite (anorexia) may be encountered. (For more information on this disorder, choose “Giardiasis” as your search term in the Rare Disease Database.)Crohn's disease is an inflammatory bowel disease characterized by severe, chronic inflammation of the intestinal wall or other portion of the gastrointestinal tract. Symptoms that may develop over time include nausea, vomiting, fever, night sweats, a general feeling of weakness and waves of abdominal pain and discomfort. Diarrhea and bleeding from the rectum are often present. Crohn's disease can be difficult to recognize and manage. Diagnosis is often delayed. (For more information on this disorder, choose “Crohn” as your search term in the Rare Disease Database.)Ulcerative colitis is an acute inflammatory bowel disease characterized by diarrhea and blood in the stools because of multiple, irregular ulcerations of the bowel. Initial symptoms may include a general feeling of weakness (malaise) and fatigue. There amy be abdominal discomfort accompanying a change in frequency and consistency of stools. Weight loss and and a decrease in appetite are also met with. Abdominal pain, cramping and urgency (tenesmus) are also often present. (For more information on this disorder, choose “Ulcerative Colitis” as your search term in the Rare Disease Database.)Primary sclerosing cholangitis is a rare collagen disorder involving inflammation and blockage of the bile duct, liver ducts, and gallbladder. Later, yellow skin color (jaundice), fever, chills, and/or itching of the skin may appear. Bacterial infections resulting from ulcerative colitis, Crohn's disease, and/or vasculitis may be associated with the cause of bile duct blockages in this disorder. (For more information on this disorder, choose “Primary Sclerosing Cholangitis as your search term in the Rare Disease Database.)Chronic erosive gastritis is an inflammatory disorder characterized by multiple lesions in the mucosal lining of the stomach. Symptoms of this disorder may include burning or a heavy feeling in the stomach, mild nausea, vomiting, loss of appetite and/or weight loss. In severe cases, bleeding from the stomach may be so extensive that anemia results. (For more information on this disorder, choose “Chronic Erosive Gastritis” as your search term in the Rare Disease Database.)Irritable bowel syndrome, also known as spastic colon, is a common digestive disorder that involves both the small intestine and the large bowel. Patients with irritable bowel syndrome who have “painless diarrhea” may experience an urgent need to defecate upon arising. (For more information on this disorder, choose “Irritable Bowel Syndrome” as your search term in the Rare Disease Database.)
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Related disorders of Tropical Sprue. Symptoms of the following disorders can be similar to those of Tropical Sprue. Comparisons may be useful for a differential diagnosis:Malabsorption syndromes refer to a group of digestive disorders which are characterized by the impairment of absorption of nutrients and the excessive loss of nonabsorbed substances in the stool. There are many underlying diseases that are associated with these syndromes. Symptoms vary directly with the severity of the disease. Diarrhea and large volumes of fatty stools are consistent symptoms in people with malabsorption syndromes.Giardiasis is a rare infectious disease of the small intestine caused by the single-celled organism Giardia lamblia. Like Tropical Sprue, this disease is characterized by the impaired absorption of a variety of nutrients by the small intestine. Symptoms may include abdominal cramps, stomach pain, watery diarrhea, excessive gas and fould-smelling stools. Later in the course of the disease, other symptoms such as weight loss and a profound loss of appetite (anorexia) may be encountered. (For more information on this disorder, choose “Giardiasis” as your search term in the Rare Disease Database.)Crohn's disease is an inflammatory bowel disease characterized by severe, chronic inflammation of the intestinal wall or other portion of the gastrointestinal tract. Symptoms that may develop over time include nausea, vomiting, fever, night sweats, a general feeling of weakness and waves of abdominal pain and discomfort. Diarrhea and bleeding from the rectum are often present. Crohn's disease can be difficult to recognize and manage. Diagnosis is often delayed. (For more information on this disorder, choose “Crohn” as your search term in the Rare Disease Database.)Ulcerative colitis is an acute inflammatory bowel disease characterized by diarrhea and blood in the stools because of multiple, irregular ulcerations of the bowel. Initial symptoms may include a general feeling of weakness (malaise) and fatigue. There amy be abdominal discomfort accompanying a change in frequency and consistency of stools. Weight loss and and a decrease in appetite are also met with. Abdominal pain, cramping and urgency (tenesmus) are also often present. (For more information on this disorder, choose “Ulcerative Colitis” as your search term in the Rare Disease Database.)Primary sclerosing cholangitis is a rare collagen disorder involving inflammation and blockage of the bile duct, liver ducts, and gallbladder. Later, yellow skin color (jaundice), fever, chills, and/or itching of the skin may appear. Bacterial infections resulting from ulcerative colitis, Crohn's disease, and/or vasculitis may be associated with the cause of bile duct blockages in this disorder. (For more information on this disorder, choose “Primary Sclerosing Cholangitis as your search term in the Rare Disease Database.)Chronic erosive gastritis is an inflammatory disorder characterized by multiple lesions in the mucosal lining of the stomach. Symptoms of this disorder may include burning or a heavy feeling in the stomach, mild nausea, vomiting, loss of appetite and/or weight loss. In severe cases, bleeding from the stomach may be so extensive that anemia results. (For more information on this disorder, choose “Chronic Erosive Gastritis” as your search term in the Rare Disease Database.)Irritable bowel syndrome, also known as spastic colon, is a common digestive disorder that involves both the small intestine and the large bowel. Patients with irritable bowel syndrome who have “painless diarrhea” may experience an urgent need to defecate upon arising. (For more information on this disorder, choose “Irritable Bowel Syndrome” as your search term in the Rare Disease Database.)
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Diagnosis of Tropical Sprue
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Diagnosis of Tropical Sprue.
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Therapies of Tropical Sprue
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Treatment for Tropical Sprue includes the use of folic acid, cobalamin, and antibiotics such as tetracycline, oxytetracycline, or ampicillin. The dosage of these medications depends on the severity of the disorder as well as how the patient responds to the therapy. Combined therapy with folic acid and tetracycline seems to rapidly reduce the severity of the symptoms and also heal unhealthy tissue in the small intestine. Other nutrients may be given as needed (i.e., iron, vitamin B12). Diarrhea associated with this disorder may be controlled with anti-diarrhea agents.
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Therapies of Tropical Sprue. Treatment for Tropical Sprue includes the use of folic acid, cobalamin, and antibiotics such as tetracycline, oxytetracycline, or ampicillin. The dosage of these medications depends on the severity of the disorder as well as how the patient responds to the therapy. Combined therapy with folic acid and tetracycline seems to rapidly reduce the severity of the symptoms and also heal unhealthy tissue in the small intestine. Other nutrients may be given as needed (i.e., iron, vitamin B12). Diarrhea associated with this disorder may be controlled with anti-diarrhea agents.
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Overview of Truncus Arteriosus
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Truncus arteriosus is a rare type of heart disease that is present at birth. Affected individuals have one main blood vessel, rather than two, carrying blood away from the heart. Instead of having a separate pulmonary artery to carry blood to the lungs, and an aorta to carry blood to the rest of the body, a baby with truncus arteriosus has just one blood vessel leaving the heart which then branches into other blood vessels. Blood from both pumping chambers (ventricles) of the heart is mixed, resulting in a situation in which some oxygen-rich blood travels needlessly back to the lungs and some oxygen-poor blood travels to the rest of the body. The most common symptoms include a bluish tint to the skin (cyanosis) and rapid breathing (tachypnea). Standard treatment involves corrective open-heart surgery in the newborn period.There are four types of truncus arteriosus:Type I occurs when the left and right pulmonary arteries branch from the pulmonary arterial trunk. Type II occurs when the left and right pulmonary arteries branch from the posterior of the common trunk. Type III occurs when the left and right pulmonary arteries branch separately from the lateral walls of the common trunk. Type IV occurs when a pulmonary artery trunk and pulmonary arteries do not form from the common trunk.
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Overview of Truncus Arteriosus. Truncus arteriosus is a rare type of heart disease that is present at birth. Affected individuals have one main blood vessel, rather than two, carrying blood away from the heart. Instead of having a separate pulmonary artery to carry blood to the lungs, and an aorta to carry blood to the rest of the body, a baby with truncus arteriosus has just one blood vessel leaving the heart which then branches into other blood vessels. Blood from both pumping chambers (ventricles) of the heart is mixed, resulting in a situation in which some oxygen-rich blood travels needlessly back to the lungs and some oxygen-poor blood travels to the rest of the body. The most common symptoms include a bluish tint to the skin (cyanosis) and rapid breathing (tachypnea). Standard treatment involves corrective open-heart surgery in the newborn period.There are four types of truncus arteriosus:Type I occurs when the left and right pulmonary arteries branch from the pulmonary arterial trunk. Type II occurs when the left and right pulmonary arteries branch from the posterior of the common trunk. Type III occurs when the left and right pulmonary arteries branch separately from the lateral walls of the common trunk. Type IV occurs when a pulmonary artery trunk and pulmonary arteries do not form from the common trunk.
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Symptoms of Truncus Arteriosus
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At birth, infants may have symptoms including a bluish tint to the skin (cyanosis), rapid breathing (tachypnea) and poor feeding (sweating with feeds, needing to stop and take breaks and difficulty gaining weight). Most infants have a heart murmur – a sound heard when the heart is listened to with a stethoscope. Some infants may develop an accumulation of fluid in the face, arms and/or legs.Until surgical repair, truncus arteriosus leads to excessive blood flow to the lungs. This can result in congestive heart failure (the lungs are “congested” with fluid resulting in rapid breathing, poor feeding and difficulty gaining weight). Excessive blood flow to the lungs may also lead to abnormal enlargement of the heart (cardiomegaly) and over time, can result in high blood pressure in the lungs (pulmonary hypertension). When the blood pressure in the lungs is high, the amount of work that the heart must perform is increased and blood vessels in the lungs become vulnerable to permanent damage. The presence of high blood pressure in the lungs increases the risk of surgery, so truncus arteriosus is typically repaired within the first month of life. Some infants with truncus arteriosus have an abnormal valve that connects the heart and the main blood vessel leaving the heart (the “truncal valve”). This valve can be too narrow (stenosis) or too leaky (regurgitation). Additionally, some infants with truncus arteriosus can have a narrowing or even complete interruption of the main blood vessel to the body (the aorta). These concurrent conditions can exacerbate the symptoms described above and/or increase the complexity and risk of surgery.If surgery is not performed, the prognosis is very poor, and the life expectancy is shortened. Patients who do not undergo repair may experience recurrent respiratory infections, poor growth and development, high blood pressure in the lungs (pulmonary hypertension) and heart failure.
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Symptoms of Truncus Arteriosus. At birth, infants may have symptoms including a bluish tint to the skin (cyanosis), rapid breathing (tachypnea) and poor feeding (sweating with feeds, needing to stop and take breaks and difficulty gaining weight). Most infants have a heart murmur – a sound heard when the heart is listened to with a stethoscope. Some infants may develop an accumulation of fluid in the face, arms and/or legs.Until surgical repair, truncus arteriosus leads to excessive blood flow to the lungs. This can result in congestive heart failure (the lungs are “congested” with fluid resulting in rapid breathing, poor feeding and difficulty gaining weight). Excessive blood flow to the lungs may also lead to abnormal enlargement of the heart (cardiomegaly) and over time, can result in high blood pressure in the lungs (pulmonary hypertension). When the blood pressure in the lungs is high, the amount of work that the heart must perform is increased and blood vessels in the lungs become vulnerable to permanent damage. The presence of high blood pressure in the lungs increases the risk of surgery, so truncus arteriosus is typically repaired within the first month of life. Some infants with truncus arteriosus have an abnormal valve that connects the heart and the main blood vessel leaving the heart (the “truncal valve”). This valve can be too narrow (stenosis) or too leaky (regurgitation). Additionally, some infants with truncus arteriosus can have a narrowing or even complete interruption of the main blood vessel to the body (the aorta). These concurrent conditions can exacerbate the symptoms described above and/or increase the complexity and risk of surgery.If surgery is not performed, the prognosis is very poor, and the life expectancy is shortened. Patients who do not undergo repair may experience recurrent respiratory infections, poor growth and development, high blood pressure in the lungs (pulmonary hypertension) and heart failure.
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Causes of Truncus Arteriosus
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A single cause of truncus arteriosus has not been identified. Like many congenital heart defects, it has been suggested that the interaction of multiple genetic and environmental factors lead to this disease. The malformation of the heart that characterizes truncus arteriosus occurs during embryonic development. Medical literature suggests that variants of transmembrane protein 260 (TMEM260), a protein coding gene, may be associated with the development of type I truncus arteriosus.
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Causes of Truncus Arteriosus. A single cause of truncus arteriosus has not been identified. Like many congenital heart defects, it has been suggested that the interaction of multiple genetic and environmental factors lead to this disease. The malformation of the heart that characterizes truncus arteriosus occurs during embryonic development. Medical literature suggests that variants of transmembrane protein 260 (TMEM260), a protein coding gene, may be associated with the development of type I truncus arteriosus.
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Affects of Truncus Arteriosus
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Males and females are affected equally by this disease. This disorder occurs in approximately 1 in 15,000 births in the United States. Approximately 35 percent of children with truncus arteriosus also have chromosome 22q11.2 deletion syndrome. Features of the syndrome vary but can include heart defects, immune dysfunction (difficulty fighting infections), low calcium level, developmental delay and facial differences. Physical characteristics may include wide-set eyes (hypertelorism), a downward slant to the eyes, notched and/or low-set ears and/or a small mouth. (For more information on this disorder, choose “chromosome 22q11.2 deletion syndrome” as your search term in the Rare Disease Database.)While no direct cause of truncus arteriosus has been identified, some possible risk factors that have been associated with congenital heart disease include other family members who were born with heart defects and maternal health during pregnancy (e.g., diabetes, viral illnesses, alcohol use and use of certain medications).
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Affects of Truncus Arteriosus. Males and females are affected equally by this disease. This disorder occurs in approximately 1 in 15,000 births in the United States. Approximately 35 percent of children with truncus arteriosus also have chromosome 22q11.2 deletion syndrome. Features of the syndrome vary but can include heart defects, immune dysfunction (difficulty fighting infections), low calcium level, developmental delay and facial differences. Physical characteristics may include wide-set eyes (hypertelorism), a downward slant to the eyes, notched and/or low-set ears and/or a small mouth. (For more information on this disorder, choose “chromosome 22q11.2 deletion syndrome” as your search term in the Rare Disease Database.)While no direct cause of truncus arteriosus has been identified, some possible risk factors that have been associated with congenital heart disease include other family members who were born with heart defects and maternal health during pregnancy (e.g., diabetes, viral illnesses, alcohol use and use of certain medications).
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Related disorders of Truncus Arteriosus
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Similar congenital heart defects that are present in infancy with excessive blood flow to the lungs and congenital heart failure include ventricular septal defects (VSD), atrioventricular septal defects (AVSD) and patent ductus arteriosus (PDA). In patients with VSD, the wall (septum) separating the two ventricles is incompletely formed before birth and a “hole” between the pumping chambers (ventricles) persists. Patients with AVSD have a “hole” in the wall (septum) between the two upper chambers of the heart (atria). Patients with PDA have a persistent opening between the pulmonary artery (which carries blood to the lungs) and aorta (which carries blood to the rest of the body). This duct is a normal fetal connection that functionally closes within 24 hours of birth. Failure of this duct to close results in the excess blood flow to the lungs that characterizes PDA. Other congenital heart defects that present in infancy with cyanosis like truncus arteriosus include tetralogy of Fallot (TOF), transposition of the great arteries (TGA), tricuspid valve abnormalities and total anomalous pulmonary venous return (TAPVR).
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Related disorders of Truncus Arteriosus. Similar congenital heart defects that are present in infancy with excessive blood flow to the lungs and congenital heart failure include ventricular septal defects (VSD), atrioventricular septal defects (AVSD) and patent ductus arteriosus (PDA). In patients with VSD, the wall (septum) separating the two ventricles is incompletely formed before birth and a “hole” between the pumping chambers (ventricles) persists. Patients with AVSD have a “hole” in the wall (septum) between the two upper chambers of the heart (atria). Patients with PDA have a persistent opening between the pulmonary artery (which carries blood to the lungs) and aorta (which carries blood to the rest of the body). This duct is a normal fetal connection that functionally closes within 24 hours of birth. Failure of this duct to close results in the excess blood flow to the lungs that characterizes PDA. Other congenital heart defects that present in infancy with cyanosis like truncus arteriosus include tetralogy of Fallot (TOF), transposition of the great arteries (TGA), tricuspid valve abnormalities and total anomalous pulmonary venous return (TAPVR).
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Diagnosis of Truncus Arteriosus
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Truncus arteriosus can often be detected before the baby is born by prenatal ultrasound evaluation that a mother receives as part of her prenatal care. If it is not detected prenatally, the signs and symptoms described above (rapid breathing, cyanosis, heart murmur etc.) often lead to an evaluation of the baby after birth by a pediatric cardiologist and an echocardiogram (ultrasound of the heart) is performed which confirms the diagnosis. A recording of the heart’s electrical activity (electrocardiogram), a CT scan and/or cardiac catheterization may also be used to further evaluate the heart. Cardiac catheterization is a procedure that measures pressures and oxygen levels within the heart and surrounding blood vessels. Angiography is often performed during cardiac catheterization and involves injection of dye to visualize the flow of blood as it moves through the heart structures.
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Diagnosis of Truncus Arteriosus. Truncus arteriosus can often be detected before the baby is born by prenatal ultrasound evaluation that a mother receives as part of her prenatal care. If it is not detected prenatally, the signs and symptoms described above (rapid breathing, cyanosis, heart murmur etc.) often lead to an evaluation of the baby after birth by a pediatric cardiologist and an echocardiogram (ultrasound of the heart) is performed which confirms the diagnosis. A recording of the heart’s electrical activity (electrocardiogram), a CT scan and/or cardiac catheterization may also be used to further evaluate the heart. Cardiac catheterization is a procedure that measures pressures and oxygen levels within the heart and surrounding blood vessels. Angiography is often performed during cardiac catheterization and involves injection of dye to visualize the flow of blood as it moves through the heart structures.
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Therapies of Truncus Arteriosus
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Open heart surgery is necessary for the infant to thrive and for long-term survival. This corrective surgery will separate the arteries, close the hole in the ventricular septum (VSD) and reattach the pulmonary artery to the ventricle wall via a valve-containing tube (conduit). Without surgery, about 85% of patients will not survive past one year of age. Patients will require regular follow-up evaluation with a cardiologist.
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Therapies of Truncus Arteriosus. Open heart surgery is necessary for the infant to thrive and for long-term survival. This corrective surgery will separate the arteries, close the hole in the ventricular septum (VSD) and reattach the pulmonary artery to the ventricle wall via a valve-containing tube (conduit). Without surgery, about 85% of patients will not survive past one year of age. Patients will require regular follow-up evaluation with a cardiologist.
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Overview of Tuberculosis
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Tuberculosis (TB) is an acute or chronic bacterial infection found most commonly in the lungs. The infection is spread like a cold, mainly through airborne droplets breathed into the air by a person infected with TB. The bacteria causes formation of small tissue masses called tubercles. In the lungs these tubercles produce breathing impairment, coughing and release of sputum. TB may recur after long periods of inactivity (latency) if not treated adequately. Many variations of TB exist and are distinguished by the area of the body affected, degree of severity and affected population. This disease today is considered curable and preventable. It is very rare in the United States but is on an upsurge.
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Overview of Tuberculosis. Tuberculosis (TB) is an acute or chronic bacterial infection found most commonly in the lungs. The infection is spread like a cold, mainly through airborne droplets breathed into the air by a person infected with TB. The bacteria causes formation of small tissue masses called tubercles. In the lungs these tubercles produce breathing impairment, coughing and release of sputum. TB may recur after long periods of inactivity (latency) if not treated adequately. Many variations of TB exist and are distinguished by the area of the body affected, degree of severity and affected population. This disease today is considered curable and preventable. It is very rare in the United States but is on an upsurge.
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Symptoms of Tuberculosis
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Tuberculosis most commonly affects the lungs, producing breathing difficulties. It may also affect the kidneys, bones, lymph nodes, and membranes surrounding the brain. In some cases, it can spread throughout the body. In the initial stages patients may experience fever, loss of appetite, weight loss, weakness, and sometimes a dry cough.In the later stages of lung involvement, blood may appear in the sputum. Bleeding in the lungs may occur if an artery or tubercle (small tissue mass produced by the infection) ruptures. The patient can die of this infection if left untreated.
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Symptoms of Tuberculosis. Tuberculosis most commonly affects the lungs, producing breathing difficulties. It may also affect the kidneys, bones, lymph nodes, and membranes surrounding the brain. In some cases, it can spread throughout the body. In the initial stages patients may experience fever, loss of appetite, weight loss, weakness, and sometimes a dry cough.In the later stages of lung involvement, blood may appear in the sputum. Bleeding in the lungs may occur if an artery or tubercle (small tissue mass produced by the infection) ruptures. The patient can die of this infection if left untreated.
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Causes of Tuberculosis
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Tuberculosis is a bacterial infection usually caused by either Mycobacterium tuberculosis or Mycobacterium bovis. The Mycobacterium tuberculosis is the most common source of infection and is spread by airborne droplets breathed or coughed into the air by a person infected with active TB. In the past the disorder was caused in most cases by Mycobacterium bovis, a bacteria which was passed to humans through dairy products. Today, dairy and cattle are carefully inspected and tested for this type of TB, and infected products are not sold to the public in the United States. However, in less developed countries the TB infection is still passed to humans through dairy products.The entire sequencing of the tuberculosis bacterium genome (genetic blueprint) has been fully documented.
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Causes of Tuberculosis. Tuberculosis is a bacterial infection usually caused by either Mycobacterium tuberculosis or Mycobacterium bovis. The Mycobacterium tuberculosis is the most common source of infection and is spread by airborne droplets breathed or coughed into the air by a person infected with active TB. In the past the disorder was caused in most cases by Mycobacterium bovis, a bacteria which was passed to humans through dairy products. Today, dairy and cattle are carefully inspected and tested for this type of TB, and infected products are not sold to the public in the United States. However, in less developed countries the TB infection is still passed to humans through dairy products.The entire sequencing of the tuberculosis bacterium genome (genetic blueprint) has been fully documented.
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Affects of Tuberculosis
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In 1944, the Public Health Service launched a TB control program when the yearly number of cases in the United States averaged 126,000. In 1985, the number of cases had dropped to 22,201. However, health officials warn that TB is still a serious health problem, due in part to the rise of AIDS cases and the lowered resistance of AIDS patients to the TB infection. There are still approximately 2,000 deaths annually from TB in the United States, which is more than from all other infectious diseases excluding pneumonia and influenza.In 1999, more than 17,000 new cases of TB were diagnosed in the United States. Areas with the highest incidence of AIDS victims such as New York City, California, Florida, and Texas are also the areas with the highest incidence of TB. TB may prove to be the first “opportunistic infection” related to AIDS with potential threat to the general public. An opportunistic infection is one that takes hold because the patient's immune system is weakened. (For more information on these disorders, choose “AIDS” and “Opportunistic Infection” as your search terms in the Rare Disease Database, and also see the AIDS Update area of NORD Services.) Recently, the southeast area of the United States and states bordering Mexico reported the highest Tuberculosis (TB) cases. Additionally, the recent influx of Southeast Asians, who have a high incidence of TB, now constitutes three to five percent of new cases in the U.S.Worldwide, TB is a major health problem with as many as four million new cases and three million deaths each year. The impact of TB is felt most by older and poorer people. Cases usually occur in individuals who were infected years ago, particularly the elderly. Many of these people grew up in the first decades of the century when eighty percent of the population had been infected (though not necessarily afflicted with an active case of TB) by the time they were thirty. The Centers for Disease Control (CDC) in Atlanta, GA currently estimates that ten million people worldwide have been infected by the tubercle bacillus, carrying a small but lifelong risk of developing active TB.There were 1,200 American children diagnosed with TB during 1984, leading to the conclusion that TB is still being spread by people with active infections. Every year, thousands more children are apparently infected, but do not get the active disease, adding to the pool of those at risk of developing active TB in the future.Since 1984 the incidence of TB has been on the rise, especially in the elderly. The elderly are susceptible to TB in two different ways: dormant germs from old infections becoming active again and new exposure at a time of life when immune defense is lower than in youth. In 1991, 25,709 cases were reported, a 9.4 percent increase over the number of cases diagnosed in 1989. Cases in children are also increasing.Other persons with suppressed immune systems, such as AIDS patients and persons taking drugs to suppress the body's immune response to transplants, are also at increased risk from exposure to TB.
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Affects of Tuberculosis. In 1944, the Public Health Service launched a TB control program when the yearly number of cases in the United States averaged 126,000. In 1985, the number of cases had dropped to 22,201. However, health officials warn that TB is still a serious health problem, due in part to the rise of AIDS cases and the lowered resistance of AIDS patients to the TB infection. There are still approximately 2,000 deaths annually from TB in the United States, which is more than from all other infectious diseases excluding pneumonia and influenza.In 1999, more than 17,000 new cases of TB were diagnosed in the United States. Areas with the highest incidence of AIDS victims such as New York City, California, Florida, and Texas are also the areas with the highest incidence of TB. TB may prove to be the first “opportunistic infection” related to AIDS with potential threat to the general public. An opportunistic infection is one that takes hold because the patient's immune system is weakened. (For more information on these disorders, choose “AIDS” and “Opportunistic Infection” as your search terms in the Rare Disease Database, and also see the AIDS Update area of NORD Services.) Recently, the southeast area of the United States and states bordering Mexico reported the highest Tuberculosis (TB) cases. Additionally, the recent influx of Southeast Asians, who have a high incidence of TB, now constitutes three to five percent of new cases in the U.S.Worldwide, TB is a major health problem with as many as four million new cases and three million deaths each year. The impact of TB is felt most by older and poorer people. Cases usually occur in individuals who were infected years ago, particularly the elderly. Many of these people grew up in the first decades of the century when eighty percent of the population had been infected (though not necessarily afflicted with an active case of TB) by the time they were thirty. The Centers for Disease Control (CDC) in Atlanta, GA currently estimates that ten million people worldwide have been infected by the tubercle bacillus, carrying a small but lifelong risk of developing active TB.There were 1,200 American children diagnosed with TB during 1984, leading to the conclusion that TB is still being spread by people with active infections. Every year, thousands more children are apparently infected, but do not get the active disease, adding to the pool of those at risk of developing active TB in the future.Since 1984 the incidence of TB has been on the rise, especially in the elderly. The elderly are susceptible to TB in two different ways: dormant germs from old infections becoming active again and new exposure at a time of life when immune defense is lower than in youth. In 1991, 25,709 cases were reported, a 9.4 percent increase over the number of cases diagnosed in 1989. Cases in children are also increasing.Other persons with suppressed immune systems, such as AIDS patients and persons taking drugs to suppress the body's immune response to transplants, are also at increased risk from exposure to TB.
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Related disorders of Tuberculosis
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AIDS (Acquired Immune Deficiency Syndrome) involves progressive deterioration of the body's ability to ward off infection. Organisms which in a healthy person would either fail to cause disease, cause mild disease, or at least provoke immunity, can completely overwhelm the AIDS patient. Patients with AIDS can contract various life-threatening infections such as pneumocystis carinii pneumonia and Tuberculosis (TB). Additionally, they may develop a rare type of cancer called Kaposi's Sarcoma.Following is a list of the various subtypes of Tuberculosis: 1. Childhood Tuberculosis (TB, primary) involves first-time infection of TB. 2. Cutis Colliquativa Tuberculosis (Gumma, tuberculous) is a childhood type of TB involving lesions on the back and legs. 3. Disseminated Hematogenous Tuberculosis (TB, Miliary) is a serious form of TB with a sudden onset occurring mostly during early childhood. Many areas of the body are involved. 4. Tuberculosis Lichenoides (Lichen Scrofulosorum) occurs in children with a high immunity to TB. It is marked by red skin areas appearing chiefly on the trunk. 5. Lymph node Tuberculosis is an adult form of TB involving the lymph nodes. This disorder is marked by swelling and fever. 6. Papulonecrotic Tuberculosis occurs in adults. This form of TB involves the face, arms, legs, and trunk. Ulceration of the skin occurs causing small scars. This form of TB is likely to recur. 7. Pulmonary Tuberculosis is usually an active flare-up of some type of childhood TB affecting the lungs. 8. Pulmonary Atypical Tuberculosis is a type of TB caused by certain rarely seen Mycobacteria. This type of TB could extend to organs other than the lungs. 9. Tuberculous Arthritis involves the lungs initially then can spread to bones and joints and may be related to various other diseases including prior joint trauma, alcoholism, diabetes mellitus and chronic debilitating states that possibly predispose to activation of disease.10. Tuberculosis of the Spine (Pott Disease) begins gradually and involves pain in the spinal nerve root and weight loss. More serious cases may cause paralysis.11. Tuberculous Meningitis involves the central nervous system and is usually found in children aged one to five years although it may occur at any age. Headache and behavioral changes may be noticed initially. Later symptoms may include convulsive disorders, communicating hydrocephalus (accumulation of fluid in the brain cavity), mental retardation, and other neurological abnormalities.12. Pleural Tuberculosis can occur in at least two forms usually in conjunction with Pulmonary TB. Surgical drainage may be required as well antituberculous treatment.13. Genitourinary Tuberculosis (Tuberculous Pyelonephritis) is characterized by an initial lack of typical TB symptoms. When long established, this disorder may spread from the kidneys to the ureters, bladder, seminal vesicles, and prostate.14. Tuberculous Peritonitis may spread from the lymph nodes, gastrointestinal tract or uterine tube and ovary to surrounding areas. Local tenderness and signs of infection are symptomatic of this type of TB.15. Tuberculous Pericarditis is usually due to spread from infected mediastinal nodes (separating the lungs) and affects the membrane around the heart. Surgery may be necessary in the more serious cases of this type of TB.16. Silicotuberculosis results from exposure to silicon dust.
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Related disorders of Tuberculosis. AIDS (Acquired Immune Deficiency Syndrome) involves progressive deterioration of the body's ability to ward off infection. Organisms which in a healthy person would either fail to cause disease, cause mild disease, or at least provoke immunity, can completely overwhelm the AIDS patient. Patients with AIDS can contract various life-threatening infections such as pneumocystis carinii pneumonia and Tuberculosis (TB). Additionally, they may develop a rare type of cancer called Kaposi's Sarcoma.Following is a list of the various subtypes of Tuberculosis: 1. Childhood Tuberculosis (TB, primary) involves first-time infection of TB. 2. Cutis Colliquativa Tuberculosis (Gumma, tuberculous) is a childhood type of TB involving lesions on the back and legs. 3. Disseminated Hematogenous Tuberculosis (TB, Miliary) is a serious form of TB with a sudden onset occurring mostly during early childhood. Many areas of the body are involved. 4. Tuberculosis Lichenoides (Lichen Scrofulosorum) occurs in children with a high immunity to TB. It is marked by red skin areas appearing chiefly on the trunk. 5. Lymph node Tuberculosis is an adult form of TB involving the lymph nodes. This disorder is marked by swelling and fever. 6. Papulonecrotic Tuberculosis occurs in adults. This form of TB involves the face, arms, legs, and trunk. Ulceration of the skin occurs causing small scars. This form of TB is likely to recur. 7. Pulmonary Tuberculosis is usually an active flare-up of some type of childhood TB affecting the lungs. 8. Pulmonary Atypical Tuberculosis is a type of TB caused by certain rarely seen Mycobacteria. This type of TB could extend to organs other than the lungs. 9. Tuberculous Arthritis involves the lungs initially then can spread to bones and joints and may be related to various other diseases including prior joint trauma, alcoholism, diabetes mellitus and chronic debilitating states that possibly predispose to activation of disease.10. Tuberculosis of the Spine (Pott Disease) begins gradually and involves pain in the spinal nerve root and weight loss. More serious cases may cause paralysis.11. Tuberculous Meningitis involves the central nervous system and is usually found in children aged one to five years although it may occur at any age. Headache and behavioral changes may be noticed initially. Later symptoms may include convulsive disorders, communicating hydrocephalus (accumulation of fluid in the brain cavity), mental retardation, and other neurological abnormalities.12. Pleural Tuberculosis can occur in at least two forms usually in conjunction with Pulmonary TB. Surgical drainage may be required as well antituberculous treatment.13. Genitourinary Tuberculosis (Tuberculous Pyelonephritis) is characterized by an initial lack of typical TB symptoms. When long established, this disorder may spread from the kidneys to the ureters, bladder, seminal vesicles, and prostate.14. Tuberculous Peritonitis may spread from the lymph nodes, gastrointestinal tract or uterine tube and ovary to surrounding areas. Local tenderness and signs of infection are symptomatic of this type of TB.15. Tuberculous Pericarditis is usually due to spread from infected mediastinal nodes (separating the lungs) and affects the membrane around the heart. Surgery may be necessary in the more serious cases of this type of TB.16. Silicotuberculosis results from exposure to silicon dust.
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Diagnosis of Tuberculosis
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Diagnosis of Tuberculosis.
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Therapies of Tuberculosis
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The continued testing of dairy herds as preventive therapy remains essential to the control of tuberculosis. Since some individuals with tuberculosis do not develop respiratory symptoms (latent tuberculosis), they often go undiagnosed and can potentially spread the disease. A tuberculin skin test, required for school age children in the United States, is also extremely useful in identifying unsuspected cases of TB. Researchers have developed blood tests that can identify latent cases of tuberculosis. These blood tests can be used alone or in combination with the tuberculin skin test.Vaccination with BCG (a weakened strain of Mycobacterium tuberculosis) is useful in many parts of the world where the incidence of TB is high. However, this vaccine is used rarely in the United States. Antibiotic therapy with careful monitoring by a physician is necessary for cases of active tuberculosis. Hospitalizing or isolating a patient under treatment, as was done in the past, is usually no longer necessary to prevent the spread of TB. Hospitalization may be useful now in some cases for treating disabling symptoms or complications. Ten to fourteen days of antibiotic treatment is usually necessary before patients become noninfectious.Four drugs commonly used to treat tuberculosis are isoniazid, streptomycin, rifampin, and/or ethambutol. These drugs are used separately or in various combinations. Recently, researchers have identified drug-resistant strains of tuberculosis in various countries around the world.Surgical treatment of some skin manifestations of TB may be of limited usefulness. Corticosteroid therapy (in conjunction with antibiotics) may be advantageous in some recurrent or very persistent cases, or in some cases that overlap with other diseases.The Food and Drug Administration (FDA) has given marketing approval for the use of the orphan drug Aminosalicylic Acid (Paser Granules) for the treatment of tuberculosis infections. The drug is produced by:Jacobus Pharmaceutical Company37 Cleveland LanePrinceton, NJ 08540The drug rifapentine has been approved by the FDA for the treatment of pulmonary tuberculosis. Rifapentine is manufactured by Marion Merrell Dow, Inc.Researchers are studying the effectiveness of several drugs known as fluoroquinolones (e.g., levoflaxin, gatifloxacin, moxifloxacin) for the treatment of individuals with pulmonary tuberculosis. More research is necessary to determine the long-term safety and effectiveness of these potential treatments for pulmonary tuberculosis.
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Therapies of Tuberculosis. The continued testing of dairy herds as preventive therapy remains essential to the control of tuberculosis. Since some individuals with tuberculosis do not develop respiratory symptoms (latent tuberculosis), they often go undiagnosed and can potentially spread the disease. A tuberculin skin test, required for school age children in the United States, is also extremely useful in identifying unsuspected cases of TB. Researchers have developed blood tests that can identify latent cases of tuberculosis. These blood tests can be used alone or in combination with the tuberculin skin test.Vaccination with BCG (a weakened strain of Mycobacterium tuberculosis) is useful in many parts of the world where the incidence of TB is high. However, this vaccine is used rarely in the United States. Antibiotic therapy with careful monitoring by a physician is necessary for cases of active tuberculosis. Hospitalizing or isolating a patient under treatment, as was done in the past, is usually no longer necessary to prevent the spread of TB. Hospitalization may be useful now in some cases for treating disabling symptoms or complications. Ten to fourteen days of antibiotic treatment is usually necessary before patients become noninfectious.Four drugs commonly used to treat tuberculosis are isoniazid, streptomycin, rifampin, and/or ethambutol. These drugs are used separately or in various combinations. Recently, researchers have identified drug-resistant strains of tuberculosis in various countries around the world.Surgical treatment of some skin manifestations of TB may be of limited usefulness. Corticosteroid therapy (in conjunction with antibiotics) may be advantageous in some recurrent or very persistent cases, or in some cases that overlap with other diseases.The Food and Drug Administration (FDA) has given marketing approval for the use of the orphan drug Aminosalicylic Acid (Paser Granules) for the treatment of tuberculosis infections. The drug is produced by:Jacobus Pharmaceutical Company37 Cleveland LanePrinceton, NJ 08540The drug rifapentine has been approved by the FDA for the treatment of pulmonary tuberculosis. Rifapentine is manufactured by Marion Merrell Dow, Inc.Researchers are studying the effectiveness of several drugs known as fluoroquinolones (e.g., levoflaxin, gatifloxacin, moxifloxacin) for the treatment of individuals with pulmonary tuberculosis. More research is necessary to determine the long-term safety and effectiveness of these potential treatments for pulmonary tuberculosis.
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Overview of Tuberous Sclerosis
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Tuberous sclerosis is a rare genetic multisystem disorder that is typically apparent shortly after birth. The disorder can cause a wide range of potential signs and symptoms and is associated with the formation of benign (non-cancerous) tumors in various organ systems of the body. The skin, brain, eyes, heart, kidneys and lungs are frequently affected. These tumors are often referred to as hamartomas. Hamartoma is a general term for a tumor or tumor-like growth that is made up of cells normally found in the area of the body where the hamartoma forms. Hamartomas are not malignant; they do not typically metastasize and spread to other areas of the body. However, these abnormal growths can grow larger and can damage the affected organ system. The number, size, and specific location of these abnormal growths in individuals with tuberous sclerosis can vary widely and consequently the severity of the disorder can vary widely as well. Tuberous sclerosis results from alterations (mutations) in a gene or genes that may occur spontaneously (sporadically) for unknown reasons or be inherited as an autosomal dominant trait. Most cases represent new (sporadic or de novo) gene mutations, with no family history of the disease. Mutations within at least two different genes are known to cause tuberous sclerosis, the TSC1 gene or the TSC2 gene.
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Overview of Tuberous Sclerosis. Tuberous sclerosis is a rare genetic multisystem disorder that is typically apparent shortly after birth. The disorder can cause a wide range of potential signs and symptoms and is associated with the formation of benign (non-cancerous) tumors in various organ systems of the body. The skin, brain, eyes, heart, kidneys and lungs are frequently affected. These tumors are often referred to as hamartomas. Hamartoma is a general term for a tumor or tumor-like growth that is made up of cells normally found in the area of the body where the hamartoma forms. Hamartomas are not malignant; they do not typically metastasize and spread to other areas of the body. However, these abnormal growths can grow larger and can damage the affected organ system. The number, size, and specific location of these abnormal growths in individuals with tuberous sclerosis can vary widely and consequently the severity of the disorder can vary widely as well. Tuberous sclerosis results from alterations (mutations) in a gene or genes that may occur spontaneously (sporadically) for unknown reasons or be inherited as an autosomal dominant trait. Most cases represent new (sporadic or de novo) gene mutations, with no family history of the disease. Mutations within at least two different genes are known to cause tuberous sclerosis, the TSC1 gene or the TSC2 gene.
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Symptoms of Tuberous Sclerosis
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Tuberous sclerosis is a highly variable disorder. The signs, symptoms, and severity of the disorder can vary dramatically from one person to another, even among members of the same family. This is due, in part, to the specific organ systems that are involved. Any organ system of the body can be affected. Tuberous sclerosis can cause mild disease in which individuals go undiagnosed into adulthood or it can cause significant complications that can impact quality of life or the disorder can cause potentially severe, life-threatening complications.Because of the highly variable nature of the disorder, it is important to note that affected individuals may not have all of the symptoms discussed below and that the disorder’s expression and progression will be unique in every individual person. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.Nearly all individuals with tuberous sclerosis develop abnormalities of the skin. Many infants have white patches or spots (hypomelanotic macules) on their skin at birth or early during infancy. These abnormal patches of skin can vary in size and shape and sometimes may be quite small and difficult to notice on infants with fair skin. They occur most often on the arms, legs and trunk of the body. The macules may be distinctly white or may appear lighter in color in relation to the surrounding skin.Small bumps or red spots known as angiofibromas may appear between the ages of 3 and 5 years, primarily on the face and often in a butterfly pattern. The small bumps generally become more numerous and larger as children grow older (until they reach adolescence). Some individuals will develop an irregularly-shaped, thickened, flesh-colored skin rash called a shagreen patch. This rash or plaque of abnormal skin usually develops on the lower back and is sometimes described as having the texture or feel of an orange peel, e.g. rough and dimpled.Raised, thickened areas of skin called fibrous plaques may develop on the forehead and, less often, the scalp or cheeks. When on the scalp, these lesions may occur with the loss of nearby hair or be surrounded by thick, white hair. Adolescents and adults may develop small benign tumors around or under the nail beds of the fingers or toes (ungual fibroma).The central nervous system is frequently involved in individuals with tuberous sclerosis. Central nervous system tumors can include subependymal nodules (SENs), cortical dysplasias, and subependymal giant cell astrocytomas or SEGAs. SEGAs occur in approximately 5%-15% of affected individuals and can cause pressure and obstruction within the brain. More than 80% of individuals with tuberous sclerosis develop seizures during childhood. Many initially manifest infantile spasms during infancy, which are characterized by a sudden jerk with flexion at the waist and raising of the arms. Alternatively, other seizure types can occur such as focal seizures involving part of the body or altered awareness, in which there is abnormal electrical activity in one specific area of the brain or generalized seizures where whole body convulsions or drop attacks develop that are associated with abnormal electrical activity throughout the brain. Most individuals will develop seizures at some point during life and most seizure types have been associated with tuberous sclerosis.Affected individuals may have normal development and cognitive function but a majority experience delays in reaching developmental milestones (developmental delays) and have some degree of intellectual disability. Individuals can potentially develop a range of neuropsychiatric disorders including autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), sleep disturbances or disorders, learning and cognitive impairments, or behavioral issues including disruptive and emotional behaviors or problems. The term TSC-associated neuropsychiatric disorders (TANDs) may be used to describe the interrelated, collective behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial abnormalities potentially associated with the disorder.Brain tumors, especially SEGAs, can also cause hydrocephalus by blocking the flow of cerebrospinal fluid (CSF) within the brain. Hydrocephalus is characterized by the accumulation of excess amounts of CSF in and around the brain. The accumulation of CSF within the skull puts abnormal pressure on the brain and can cause a variety of symptoms including headaches, nausea, vomiting, irritability, and behavioral changes.Another form of tumor associated with tuberous sclerosis is a benign angiomyolipoma. These tumors are made up of fat, blood vessels and smooth muscle cells, usually affect the kidneys, and may not cause any symptoms (asymptomatic). In some instances, they may cause flank pain or kidney (renal) dysfunction. Angiomyolipomas are prone to rupturing and bleeding (hemorrhaging), which can potentially become life-threatening (approximately 20% of the time). Around 70% of affected children may develop a benign angiomyolipoma, usually in later childhood or adolescence. In rare instances, angiomyolipomas or cysts may be found outside of the kidneys such as in the liver. Usually, these growths do not cause any symptoms.Some women with tuberous sclerosis develop lymphangioleiomyomatosis (LAM), a condition in which the spread and uncontrolled growth (proliferation) of specialized cells (smooth muscle cells) form progressive cystic cavities within the lungs resulting in shortness of breath, coughing, and/or difficulty breathing (dyspnea), especially following periods of exercise or exertion. LAM mostly occurs in women of childbearing age and is extremely rare in men.Some individuals may develop multifocal micronodular pneumocyte hyperplasia (MMPH), a condition in which multiple nodules form throughout the lungs because of the abnormal proliferation of certain lung cells called pneumocytes. MMPH usually is not associated with any symptoms, but there have been at least two reports in the medical literature of breathing difficulties and eventually respiratory failure associated with MMPH.In addition to difficulty breathing, the lung complications associated with tuberous sclerosis can cause a collapsed lung (pneumothorax) and chylothorax, a condition in which there is an accumulation of chyle in the space between the membranes (pleura) that line the lungs and chest cavity. Chyle is a milky fluid that consists of lymph and emulsified fats. Chylothorax can cause difficulty breathing, rapid breathing (tachypnea), chest pain, or respiratory compromise.A benign tumor known as a rhabdomyoma can develop in the heart of infants and young children. The tumor initially forms before birth (antenatally) in the developing fetus. These tumors usually do not cause symptoms and may regress on their own and disappear over time. In some instances, they can interfere or obstruct the flow of blood from the heart (outflow tract obstruction) and/or cause irregular heartbeats (arrhythmias).Another common finding is the formation of small growths or tumors on the retina, the light-sensitive membrane that coats the inside of the eyes (multiple retinal hamartomas). These tumors rarely cause problems and seldom affect vision.Some signs and symptoms associated with tuberous sclerosis occur less often than those described above. These findings are referred to as minor features of the disorder. Such symptoms include patches or areas of lightened color or a lack of color affecting the retina due to pigment loss (retinal achromatic patch). Some individuals may develop pitting or tiny holes in the enamel of teeth (dental enamel pitting) or the formation of fibrous growths within the mouth (intraoral fibromas), particularly in the gums. In some instances, individuals may develop “confetti” skin lesions during childhood, early adolescence, or adulthood. These lesions are tiny (1-3 millimeters) spots that are lighter in color (hypopigmented) than the surrounding skin. They may be scattered across certain areas of the skin.Renal cysts, sometimes referred to as epithelial cysts, occur in approximately 20-30% of individuals and usually do not cause symptoms. These small, fluid-filled cysts can, in some instances, result in increased blood pressure. If the kidneys are filled with cysts, kidney dysfunction and kidney failure can eventually develop. Individuals with tuberous sclerosis may have a greater risk of developing certain cancers of the kidney than the general population, although their overall occurrence is still very uncommon. Less than 3% of individuals may eventually develop renal cell carcinoma. In extremely rare instances (less than 1%), an oncocytoma or a malignant angiomyolipoma may occur.Some affected individuals will develop neuroendocrine tumors (NETs). Neuroendocrine tumors arise from hormone-producing cells of the neuroendocrine system. These cells are a cross or combination of endocrine cells and nerve cells. They are found throughout the body and perform many functions such as regulating air and blood flow through the lungs.
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Symptoms of Tuberous Sclerosis. Tuberous sclerosis is a highly variable disorder. The signs, symptoms, and severity of the disorder can vary dramatically from one person to another, even among members of the same family. This is due, in part, to the specific organ systems that are involved. Any organ system of the body can be affected. Tuberous sclerosis can cause mild disease in which individuals go undiagnosed into adulthood or it can cause significant complications that can impact quality of life or the disorder can cause potentially severe, life-threatening complications.Because of the highly variable nature of the disorder, it is important to note that affected individuals may not have all of the symptoms discussed below and that the disorder’s expression and progression will be unique in every individual person. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.Nearly all individuals with tuberous sclerosis develop abnormalities of the skin. Many infants have white patches or spots (hypomelanotic macules) on their skin at birth or early during infancy. These abnormal patches of skin can vary in size and shape and sometimes may be quite small and difficult to notice on infants with fair skin. They occur most often on the arms, legs and trunk of the body. The macules may be distinctly white or may appear lighter in color in relation to the surrounding skin.Small bumps or red spots known as angiofibromas may appear between the ages of 3 and 5 years, primarily on the face and often in a butterfly pattern. The small bumps generally become more numerous and larger as children grow older (until they reach adolescence). Some individuals will develop an irregularly-shaped, thickened, flesh-colored skin rash called a shagreen patch. This rash or plaque of abnormal skin usually develops on the lower back and is sometimes described as having the texture or feel of an orange peel, e.g. rough and dimpled.Raised, thickened areas of skin called fibrous plaques may develop on the forehead and, less often, the scalp or cheeks. When on the scalp, these lesions may occur with the loss of nearby hair or be surrounded by thick, white hair. Adolescents and adults may develop small benign tumors around or under the nail beds of the fingers or toes (ungual fibroma).The central nervous system is frequently involved in individuals with tuberous sclerosis. Central nervous system tumors can include subependymal nodules (SENs), cortical dysplasias, and subependymal giant cell astrocytomas or SEGAs. SEGAs occur in approximately 5%-15% of affected individuals and can cause pressure and obstruction within the brain. More than 80% of individuals with tuberous sclerosis develop seizures during childhood. Many initially manifest infantile spasms during infancy, which are characterized by a sudden jerk with flexion at the waist and raising of the arms. Alternatively, other seizure types can occur such as focal seizures involving part of the body or altered awareness, in which there is abnormal electrical activity in one specific area of the brain or generalized seizures where whole body convulsions or drop attacks develop that are associated with abnormal electrical activity throughout the brain. Most individuals will develop seizures at some point during life and most seizure types have been associated with tuberous sclerosis.Affected individuals may have normal development and cognitive function but a majority experience delays in reaching developmental milestones (developmental delays) and have some degree of intellectual disability. Individuals can potentially develop a range of neuropsychiatric disorders including autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), sleep disturbances or disorders, learning and cognitive impairments, or behavioral issues including disruptive and emotional behaviors or problems. The term TSC-associated neuropsychiatric disorders (TANDs) may be used to describe the interrelated, collective behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial abnormalities potentially associated with the disorder.Brain tumors, especially SEGAs, can also cause hydrocephalus by blocking the flow of cerebrospinal fluid (CSF) within the brain. Hydrocephalus is characterized by the accumulation of excess amounts of CSF in and around the brain. The accumulation of CSF within the skull puts abnormal pressure on the brain and can cause a variety of symptoms including headaches, nausea, vomiting, irritability, and behavioral changes.Another form of tumor associated with tuberous sclerosis is a benign angiomyolipoma. These tumors are made up of fat, blood vessels and smooth muscle cells, usually affect the kidneys, and may not cause any symptoms (asymptomatic). In some instances, they may cause flank pain or kidney (renal) dysfunction. Angiomyolipomas are prone to rupturing and bleeding (hemorrhaging), which can potentially become life-threatening (approximately 20% of the time). Around 70% of affected children may develop a benign angiomyolipoma, usually in later childhood or adolescence. In rare instances, angiomyolipomas or cysts may be found outside of the kidneys such as in the liver. Usually, these growths do not cause any symptoms.Some women with tuberous sclerosis develop lymphangioleiomyomatosis (LAM), a condition in which the spread and uncontrolled growth (proliferation) of specialized cells (smooth muscle cells) form progressive cystic cavities within the lungs resulting in shortness of breath, coughing, and/or difficulty breathing (dyspnea), especially following periods of exercise or exertion. LAM mostly occurs in women of childbearing age and is extremely rare in men.Some individuals may develop multifocal micronodular pneumocyte hyperplasia (MMPH), a condition in which multiple nodules form throughout the lungs because of the abnormal proliferation of certain lung cells called pneumocytes. MMPH usually is not associated with any symptoms, but there have been at least two reports in the medical literature of breathing difficulties and eventually respiratory failure associated with MMPH.In addition to difficulty breathing, the lung complications associated with tuberous sclerosis can cause a collapsed lung (pneumothorax) and chylothorax, a condition in which there is an accumulation of chyle in the space between the membranes (pleura) that line the lungs and chest cavity. Chyle is a milky fluid that consists of lymph and emulsified fats. Chylothorax can cause difficulty breathing, rapid breathing (tachypnea), chest pain, or respiratory compromise.A benign tumor known as a rhabdomyoma can develop in the heart of infants and young children. The tumor initially forms before birth (antenatally) in the developing fetus. These tumors usually do not cause symptoms and may regress on their own and disappear over time. In some instances, they can interfere or obstruct the flow of blood from the heart (outflow tract obstruction) and/or cause irregular heartbeats (arrhythmias).Another common finding is the formation of small growths or tumors on the retina, the light-sensitive membrane that coats the inside of the eyes (multiple retinal hamartomas). These tumors rarely cause problems and seldom affect vision.Some signs and symptoms associated with tuberous sclerosis occur less often than those described above. These findings are referred to as minor features of the disorder. Such symptoms include patches or areas of lightened color or a lack of color affecting the retina due to pigment loss (retinal achromatic patch). Some individuals may develop pitting or tiny holes in the enamel of teeth (dental enamel pitting) or the formation of fibrous growths within the mouth (intraoral fibromas), particularly in the gums. In some instances, individuals may develop “confetti” skin lesions during childhood, early adolescence, or adulthood. These lesions are tiny (1-3 millimeters) spots that are lighter in color (hypopigmented) than the surrounding skin. They may be scattered across certain areas of the skin.Renal cysts, sometimes referred to as epithelial cysts, occur in approximately 20-30% of individuals and usually do not cause symptoms. These small, fluid-filled cysts can, in some instances, result in increased blood pressure. If the kidneys are filled with cysts, kidney dysfunction and kidney failure can eventually develop. Individuals with tuberous sclerosis may have a greater risk of developing certain cancers of the kidney than the general population, although their overall occurrence is still very uncommon. Less than 3% of individuals may eventually develop renal cell carcinoma. In extremely rare instances (less than 1%), an oncocytoma or a malignant angiomyolipoma may occur.Some affected individuals will develop neuroendocrine tumors (NETs). Neuroendocrine tumors arise from hormone-producing cells of the neuroendocrine system. These cells are a cross or combination of endocrine cells and nerve cells. They are found throughout the body and perform many functions such as regulating air and blood flow through the lungs.
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Causes of Tuberous Sclerosis
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Tuberous sclerosis is caused by an alteration (mutation) in one of two different genes, the TSC1 gene or the TSC2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. Generally, alterations in the TSC2 gene result in a more severe disease expression.In many instances, an alteration causing tuberous sclerosis occurs as a new (sporadic or de novo) mutation, which means that the gene alteration has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is not inherited from or “carried” by a healthy parent. However, such alterations can also be passed on through dominant inheritance (where a trait is transmitted from either an affected mother or father to their child).Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular 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 an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.The TSC1 gene is located on the long arm (q) of chromosome 9 (9q34); the TSC2 is located on the short arm (p) of chromosome 16 (16p13.3). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered.The TSC1 gene regulates (encodes for) production of a protein known as hamartin that is thought to function as a tumor suppressor. The TSC2 gene encodes for a different tumor suppressor protein known as tuberin. A tumor suppressor gene is a gene that slows down cell division, repairs damage to the DNA of cells, and/or tells cell when to die, a normal process called apoptosis. Hamartin and tuberin are believed to inhibit the activity of a chemical pathway in the body called the mammalian target of rapamycin or mTOR pathway. Such a chemical pathway involves a number of complex interactions and is critical for normal human development; the mTOR pathway regulates the creation (synthesis) of proteins that are involved in many cellular functions including cell growth, proliferation, and survival. Alterations in the TSC1 and TSC2 genes ultimately lead to the uncontrolled activity or “hyperactivation” of the mTOR pathway and, consequently, to the development of the tumors that characterize tuberous sclerosis.
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Causes of Tuberous Sclerosis. Tuberous sclerosis is caused by an alteration (mutation) in one of two different genes, the TSC1 gene or the TSC2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. Generally, alterations in the TSC2 gene result in a more severe disease expression.In many instances, an alteration causing tuberous sclerosis occurs as a new (sporadic or de novo) mutation, which means that the gene alteration has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is not inherited from or “carried” by a healthy parent. However, such alterations can also be passed on through dominant inheritance (where a trait is transmitted from either an affected mother or father to their child).Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular 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 an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.The TSC1 gene is located on the long arm (q) of chromosome 9 (9q34); the TSC2 is located on the short arm (p) of chromosome 16 (16p13.3). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered.The TSC1 gene regulates (encodes for) production of a protein known as hamartin that is thought to function as a tumor suppressor. The TSC2 gene encodes for a different tumor suppressor protein known as tuberin. A tumor suppressor gene is a gene that slows down cell division, repairs damage to the DNA of cells, and/or tells cell when to die, a normal process called apoptosis. Hamartin and tuberin are believed to inhibit the activity of a chemical pathway in the body called the mammalian target of rapamycin or mTOR pathway. Such a chemical pathway involves a number of complex interactions and is critical for normal human development; the mTOR pathway regulates the creation (synthesis) of proteins that are involved in many cellular functions including cell growth, proliferation, and survival. Alterations in the TSC1 and TSC2 genes ultimately lead to the uncontrolled activity or “hyperactivation” of the mTOR pathway and, consequently, to the development of the tumors that characterize tuberous sclerosis.
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Tuberous Sclerosis
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Affects of Tuberous Sclerosis
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Tuberous sclerosis is a rare genetic disorder that affects 1 in 6,000 newborns in the United States. Approximately 40,000 to 80,000 people in the United States have tuberous sclerosis. The prevalence in Europe is estimated to be approximately 1 in 25,000 to 1 in 11,300. As many as 2 million people worldwide are believed to have the disorder. Males and females are affected in equal numbers and the disorder occurs in all races and ethnic groups.
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Affects of Tuberous Sclerosis. Tuberous sclerosis is a rare genetic disorder that affects 1 in 6,000 newborns in the United States. Approximately 40,000 to 80,000 people in the United States have tuberous sclerosis. The prevalence in Europe is estimated to be approximately 1 in 25,000 to 1 in 11,300. As many as 2 million people worldwide are believed to have the disorder. Males and females are affected in equal numbers and the disorder occurs in all races and ethnic groups.
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Related disorders of Tuberous Sclerosis
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Symptoms of the following disorders can be similar to those of tuberous sclerosis. Comparisons may be useful for a differential diagnosis:The various symptoms of tuberous sclerosis are nonspecific and many can occur as isolated findings or as part of another syndrome or disorder. Examples of such disorders include hypomelanosis of Ito, Sturge-Weber syndrome, epidermal nevus syndromes, Birt-Hogg-Dube syndrome, multiple endocrine neoplasia, and various seizures disorders. Isolated brain tumors and cardiac myxoma as well as other tumors may need to be differentiated from tuberous sclerosis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Some individuals with tuberous sclerosis syndrome will also have symptoms of autosomal dominant polycystic kidney disease (ADPKD), a rare kidney disorder. This is due to a loss (deletion) of genetic material from chromosome 16 that contains both the TSC2 gene and the PKD1 gene that causes ADPKD. This is referred to as a contiguous gene syndrome.
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Related disorders of Tuberous Sclerosis. Symptoms of the following disorders can be similar to those of tuberous sclerosis. Comparisons may be useful for a differential diagnosis:The various symptoms of tuberous sclerosis are nonspecific and many can occur as isolated findings or as part of another syndrome or disorder. Examples of such disorders include hypomelanosis of Ito, Sturge-Weber syndrome, epidermal nevus syndromes, Birt-Hogg-Dube syndrome, multiple endocrine neoplasia, and various seizures disorders. Isolated brain tumors and cardiac myxoma as well as other tumors may need to be differentiated from tuberous sclerosis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Some individuals with tuberous sclerosis syndrome will also have symptoms of autosomal dominant polycystic kidney disease (ADPKD), a rare kidney disorder. This is due to a loss (deletion) of genetic material from chromosome 16 that contains both the TSC2 gene and the PKD1 gene that causes ADPKD. This is referred to as a contiguous gene syndrome.
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Diagnosis of Tuberous Sclerosis
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A diagnosis of tuberous sclerosis is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests. For example, the presence of hypopigmented macules on the skin occurring along with seizures or autism are diagnostic clues for tuberous sclerosis. Clinical diagnostic criteria have been established and updated for tuberous sclerosis (Northrup et al. 2018).Generally, a diagnosis is considered definitive in individuals with two or more major features or one major feature and two or more minor features of the disorder. A possible diagnosis is suspected when one major feature or two or more minor features are present.In some instances, a cardiac rhabdomyoma can be detected before birth (prenatally).Clinical Testing and WorkupMolecular genetic testing can confirm a diagnosis of tuberous sclerosis. Molecular genetic testing can detect alterations in one of the two genes known to cause the disorder, and is available as a diagnostic service at specialized laboratories.A variety of tests can be used to help obtain a diagnosis of tuberous sclerosis or to assess or establish the extent of the disorder in an individual. Such tests include computerized tomography (CT) scanning and magnetic resonance imaging (MRI) to evaluate the brain for the presence of tumors or other brain involvement. An MRI can also be used to evaluate the kidneys or liver for the presence of tumors. A high resolution CT scan can be used to evaluate the lungs. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues.An echocardiogram and an electrocardiogram (EKG) can be used to evaluate the heart for the presence of a rhabdomyoma. During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac function and motion. An electrocardiogram records the heart’s electrical impulses and may reveal abnormal electrical patterns.
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Diagnosis of Tuberous Sclerosis. A diagnosis of tuberous sclerosis is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests. For example, the presence of hypopigmented macules on the skin occurring along with seizures or autism are diagnostic clues for tuberous sclerosis. Clinical diagnostic criteria have been established and updated for tuberous sclerosis (Northrup et al. 2018).Generally, a diagnosis is considered definitive in individuals with two or more major features or one major feature and two or more minor features of the disorder. A possible diagnosis is suspected when one major feature or two or more minor features are present.In some instances, a cardiac rhabdomyoma can be detected before birth (prenatally).Clinical Testing and WorkupMolecular genetic testing can confirm a diagnosis of tuberous sclerosis. Molecular genetic testing can detect alterations in one of the two genes known to cause the disorder, and is available as a diagnostic service at specialized laboratories.A variety of tests can be used to help obtain a diagnosis of tuberous sclerosis or to assess or establish the extent of the disorder in an individual. Such tests include computerized tomography (CT) scanning and magnetic resonance imaging (MRI) to evaluate the brain for the presence of tumors or other brain involvement. An MRI can also be used to evaluate the kidneys or liver for the presence of tumors. A high resolution CT scan can be used to evaluate the lungs. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues.An echocardiogram and an electrocardiogram (EKG) can be used to evaluate the heart for the presence of a rhabdomyoma. During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac function and motion. An electrocardiogram records the heart’s electrical impulses and may reveal abnormal electrical patterns.
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Tuberous Sclerosis
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