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nord_0_0 | Overview of 47, XXY (Klinefelter Syndrome) | SummaryKlinefelter Syndrome (47, XXY) is a chromosomal variation in males in which one extra X chromosome is present, resulting in a 47,XXY karyotype. The extra X chromosome typically affects physical, neurodevelopmental, behavioral, and neurocognitive functioning. Common physical features may include tall stature, reduced muscle tone, small testes (hypogonadism), delayed pubertal development and lack of secondary male sex characteristics such as decreased facial and body hair. Increased breast growth (gynecomastia) may occur later in puberty without appropriate biological care. With proper treatment, the incidence of gynecomastia typically occurs in less than 10% of boys with 47,XXY (KS).There is great variability to the neurodevelopmental profile or phenotype in boys with 47,XXY (KS). Common cognitive and behavioral features may include speech and language delays, ADHD and emotional and social functioning challenges. The features of 47, XXY (KS) are typically associated with decreased testosterone level and elevated gonadotropin levels. Early hormonal treatment (EHT) with three monthly injections of 25 mg. of testosterone enanthate, typically given between 4-12 months of age, may optimize brain development and neurodevelopmental outcomes. Testosterone should be administered based upon an evaluation with a pediatrician and pediatric endocrinologist familiar with 47,XXY (KS). | Overview of 47, XXY (Klinefelter Syndrome). SummaryKlinefelter Syndrome (47, XXY) is a chromosomal variation in males in which one extra X chromosome is present, resulting in a 47,XXY karyotype. The extra X chromosome typically affects physical, neurodevelopmental, behavioral, and neurocognitive functioning. Common physical features may include tall stature, reduced muscle tone, small testes (hypogonadism), delayed pubertal development and lack of secondary male sex characteristics such as decreased facial and body hair. Increased breast growth (gynecomastia) may occur later in puberty without appropriate biological care. With proper treatment, the incidence of gynecomastia typically occurs in less than 10% of boys with 47,XXY (KS).There is great variability to the neurodevelopmental profile or phenotype in boys with 47,XXY (KS). Common cognitive and behavioral features may include speech and language delays, ADHD and emotional and social functioning challenges. The features of 47, XXY (KS) are typically associated with decreased testosterone level and elevated gonadotropin levels. Early hormonal treatment (EHT) with three monthly injections of 25 mg. of testosterone enanthate, typically given between 4-12 months of age, may optimize brain development and neurodevelopmental outcomes. Testosterone should be administered based upon an evaluation with a pediatrician and pediatric endocrinologist familiar with 47,XXY (KS). | 0 | 47, XXY (Klinefelter Syndrome) |
nord_0_1 | Symptoms of 47, XXY (Klinefelter Syndrome) | At birth, most neonates with 47, XXY (KS) have no significant dysmorphic or unusual features. Most individuals with 47, XXY (KS) are identified though prenatal diagnosis or when the child does not progress through puberty completely or adequately. Infants and young children with 47, XXY (KS) are sometimes initially identified because of an abnormality in the location of the urinary opening in the penis (hypospadias), small penis or testes, or developmental delay (e.g. speech delay). Older children and teenagers are sometimes diagnosed with 47, XXY (KS) if secondary sexual characteristics do not develop completely, puberty is delayed, testes are small, or breast development occurs. Many males with 47, XXY (KS) are not identified until they have low fertility problems as adults. Men with 47, XXY (KS) may have a relatively increased risk to develop breast cancer but not until after 60 years of age. Most males with 47, XXY (KS) have normal intelligence but there is an increased risk of language based learning disorders, dyslexia and mild social and executive functioning challenges. Often, boys and men with 47, XXY (KS) will present with verbal communication delays due to language-based learning disorders and subtle motor planning deficits. Research has shown, however, that nonverbal capacities in males with 47, XXY (KS), such as perceptual reasoning and receptive language skills, may be intact or even advanced. Thus, PIQ (nonverbal IQ) is often higher than VIQ (verbal IQ) on neurodevelopmental testing. Socially, males with 47, XXY (KS) may have difficulty perceiving social cues and regulating their emotions in stressful situations.Men with 47, XXY (KS) may have an increased risk for endocrine conditions such as diabetes mellitus, hypothyroidism and hypoparathyroidism and autoimmune diseases such as systemic lupus erythematosus, Sjogren syndrome and rheumatoid arthritis. Many of these conditions can be treated with medications and lifestyle changes. | Symptoms of 47, XXY (Klinefelter Syndrome). At birth, most neonates with 47, XXY (KS) have no significant dysmorphic or unusual features. Most individuals with 47, XXY (KS) are identified though prenatal diagnosis or when the child does not progress through puberty completely or adequately. Infants and young children with 47, XXY (KS) are sometimes initially identified because of an abnormality in the location of the urinary opening in the penis (hypospadias), small penis or testes, or developmental delay (e.g. speech delay). Older children and teenagers are sometimes diagnosed with 47, XXY (KS) if secondary sexual characteristics do not develop completely, puberty is delayed, testes are small, or breast development occurs. Many males with 47, XXY (KS) are not identified until they have low fertility problems as adults. Men with 47, XXY (KS) may have a relatively increased risk to develop breast cancer but not until after 60 years of age. Most males with 47, XXY (KS) have normal intelligence but there is an increased risk of language based learning disorders, dyslexia and mild social and executive functioning challenges. Often, boys and men with 47, XXY (KS) will present with verbal communication delays due to language-based learning disorders and subtle motor planning deficits. Research has shown, however, that nonverbal capacities in males with 47, XXY (KS), such as perceptual reasoning and receptive language skills, may be intact or even advanced. Thus, PIQ (nonverbal IQ) is often higher than VIQ (verbal IQ) on neurodevelopmental testing. Socially, males with 47, XXY (KS) may have difficulty perceiving social cues and regulating their emotions in stressful situations.Men with 47, XXY (KS) may have an increased risk for endocrine conditions such as diabetes mellitus, hypothyroidism and hypoparathyroidism and autoimmune diseases such as systemic lupus erythematosus, Sjogren syndrome and rheumatoid arthritis. Many of these conditions can be treated with medications and lifestyle changes. | 0 | 47, XXY (Klinefelter Syndrome) |
nord_0_2 | Causes of 47, XXY (Klinefelter Syndrome) | 47, XXY (KS) is not inherited. Males with 47, XXY (KS) have one extra X chromosome because of a nondisjunction error that randomly occurs during the division of the sex chromosomes in the egg or sperm. Some males with 47, XXY (KS) are mosaic, meaning that some cells have an extra X chromosome and other cells do not. Mosaic 47, XXY (KS) occurs because of an error in the division of the sex chromosomes in the zygote after fertilization. The extra X chromosome typically results in primary testicular failure leading to androgen deficiency. | Causes of 47, XXY (Klinefelter Syndrome). 47, XXY (KS) is not inherited. Males with 47, XXY (KS) have one extra X chromosome because of a nondisjunction error that randomly occurs during the division of the sex chromosomes in the egg or sperm. Some males with 47, XXY (KS) are mosaic, meaning that some cells have an extra X chromosome and other cells do not. Mosaic 47, XXY (KS) occurs because of an error in the division of the sex chromosomes in the zygote after fertilization. The extra X chromosome typically results in primary testicular failure leading to androgen deficiency. | 0 | 47, XXY (Klinefelter Syndrome) |
nord_0_3 | Affects of 47, XXY (Klinefelter Syndrome) | 47, XXY (KS) is the most common human sex chromosome disorder and occurs in approximately 1 in 500-1,000 males. It is estimated that 3,000 affected boys are born each year in the United States. | Affects of 47, XXY (Klinefelter Syndrome). 47, XXY (KS) is the most common human sex chromosome disorder and occurs in approximately 1 in 500-1,000 males. It is estimated that 3,000 affected boys are born each year in the United States. | 0 | 47, XXY (Klinefelter Syndrome) |
nord_0_4 | Related disorders of 47, XXY (Klinefelter Syndrome) | Kallmann syndrome is a rare inherited disorder that mostly, but not exclusively, affects men. The major characteristics of Kallmann syndrome, in both men and women, are the failure to experience puberty and the complete or partial loss of the sense of smell. Failure to go through puberty reflects a hormonal imbalance that is caused by a failure of a part of the brain known as the hypothalamus. Patients with Kallmann syndrome show evidence of small genitalia, sterile gonads that cannot produce the sex cells (hypogonadism), and a loss of the sense of smell (anosmia). The impaired production of hormones as well as sperm and egg cells causes delayed puberty, growth and infertility. (For more information on this disorder, choose “Kallmann syndrome” as your search term in the Rare Disease Database.) | Related disorders of 47, XXY (Klinefelter Syndrome). Kallmann syndrome is a rare inherited disorder that mostly, but not exclusively, affects men. The major characteristics of Kallmann syndrome, in both men and women, are the failure to experience puberty and the complete or partial loss of the sense of smell. Failure to go through puberty reflects a hormonal imbalance that is caused by a failure of a part of the brain known as the hypothalamus. Patients with Kallmann syndrome show evidence of small genitalia, sterile gonads that cannot produce the sex cells (hypogonadism), and a loss of the sense of smell (anosmia). The impaired production of hormones as well as sperm and egg cells causes delayed puberty, growth and infertility. (For more information on this disorder, choose “Kallmann syndrome” as your search term in the Rare Disease Database.) | 0 | 47, XXY (Klinefelter Syndrome) |
nord_0_5 | Diagnosis of 47, XXY (Klinefelter Syndrome) | Males with 47, XXY (KS) are most commonly identified before birth (e.g. through prenatal screenings for chromosomal disorders), at puberty or later in life because of low fertility. 47, XXY (KS) is diagnosed by a chromosome karyotype analysis on a blood sample or by a chromosomal microarray (CMA) test. CMA consists of an oral cheek (buccal) swab and is an easy and painless way to detect abnormalities of chromosome numbers and provide a definitive diagnosis. 47, XXY (KS) can also be diagnosed prenatally on chorionic villous or amniotic fluid cells. | Diagnosis of 47, XXY (Klinefelter Syndrome). Males with 47, XXY (KS) are most commonly identified before birth (e.g. through prenatal screenings for chromosomal disorders), at puberty or later in life because of low fertility. 47, XXY (KS) is diagnosed by a chromosome karyotype analysis on a blood sample or by a chromosomal microarray (CMA) test. CMA consists of an oral cheek (buccal) swab and is an easy and painless way to detect abnormalities of chromosome numbers and provide a definitive diagnosis. 47, XXY (KS) can also be diagnosed prenatally on chorionic villous or amniotic fluid cells. | 0 | 47, XXY (Klinefelter Syndrome) |
nord_0_6 | Therapies of 47, XXY (Klinefelter Syndrome) | Treatment
One of the hallmarks of Klinefelter syndrome is hypergonadotropic hypogonadism, a condition that results in testosterone deficiency. Treatment involves the targeted administration of male hormones (androgens), such as testosterone enanthate, cypionate, or androgel. Early hormonal treatment (EHT), three monthly injections of 25 mg of testosterone enanthate, is typically administered between 4-12 months of age. These hormones are given to promote the development of secondary male sexual characteristics (virilization) and alleviate feminization effects that have occurred due to insufficient testosterone levels. Hormone replacement therapy is effective when initiated during early infancy or around pubertal development or even later in life. Some men with 47, XXY (KS) who have gynecomastia may elect to have surgical breast reduction for cosmetic purposes. This procedure often may be avoided if proper and timely dosage of testosterone as well as estrogen inhibitor is administered to an individual, although it varies with each individual.As infants, these boys need to be monitored for positional torticollis which can be treated with pediatric physical therapy. Speech and language therapy, physical therapy and occupational therapy are often helpful for boys with 47, XXY (KS). These interventions are shown to significantly improve academic, physical, cognitive, and social outcomes in boys with 47, XXY (KS). A comprehensive psychoeducational evaluation is recommended to determine what resources may be helpful in the classroom. Social skills training classes can also be beneficial.Men with 47, XXY (KS) have low fertility, and with novel assistive and reproductive techniques, more men with 47, XXY (KS) have the opportunity to reproduce a child. Men with mosaic 47, XXY (KS) have higher likelihood of fewer complications with reproduction. Surgical extraction of sperm from the testes and intracytoplasmic sperm injection (ICSI) directly into an ovum is a medical technology available to assist men with 47, XXY (KS) father children. | Therapies of 47, XXY (Klinefelter Syndrome). Treatment
One of the hallmarks of Klinefelter syndrome is hypergonadotropic hypogonadism, a condition that results in testosterone deficiency. Treatment involves the targeted administration of male hormones (androgens), such as testosterone enanthate, cypionate, or androgel. Early hormonal treatment (EHT), three monthly injections of 25 mg of testosterone enanthate, is typically administered between 4-12 months of age. These hormones are given to promote the development of secondary male sexual characteristics (virilization) and alleviate feminization effects that have occurred due to insufficient testosterone levels. Hormone replacement therapy is effective when initiated during early infancy or around pubertal development or even later in life. Some men with 47, XXY (KS) who have gynecomastia may elect to have surgical breast reduction for cosmetic purposes. This procedure often may be avoided if proper and timely dosage of testosterone as well as estrogen inhibitor is administered to an individual, although it varies with each individual.As infants, these boys need to be monitored for positional torticollis which can be treated with pediatric physical therapy. Speech and language therapy, physical therapy and occupational therapy are often helpful for boys with 47, XXY (KS). These interventions are shown to significantly improve academic, physical, cognitive, and social outcomes in boys with 47, XXY (KS). A comprehensive psychoeducational evaluation is recommended to determine what resources may be helpful in the classroom. Social skills training classes can also be beneficial.Men with 47, XXY (KS) have low fertility, and with novel assistive and reproductive techniques, more men with 47, XXY (KS) have the opportunity to reproduce a child. Men with mosaic 47, XXY (KS) have higher likelihood of fewer complications with reproduction. Surgical extraction of sperm from the testes and intracytoplasmic sperm injection (ICSI) directly into an ovum is a medical technology available to assist men with 47, XXY (KS) father children. | 0 | 47, XXY (Klinefelter Syndrome) |
nord_1_0 | Overview of 48, XXYY Syndrome | 48, XXYY is a genetic disorder that occurs in males and is characterized by additional sex chromosomes compared to the typical male karyotype of 46, XY. 48, XXYY syndrome has previously been described as a variant of Klinefelter syndrome because affected males have similar physical characteristics (tall stature and small, dysfunctional testes), however the medical and neurodevelopmental features are more complex than typically seen in 47, XXY/Klinefelter syndrome. | Overview of 48, XXYY Syndrome. 48, XXYY is a genetic disorder that occurs in males and is characterized by additional sex chromosomes compared to the typical male karyotype of 46, XY. 48, XXYY syndrome has previously been described as a variant of Klinefelter syndrome because affected males have similar physical characteristics (tall stature and small, dysfunctional testes), however the medical and neurodevelopmental features are more complex than typically seen in 47, XXY/Klinefelter syndrome. | 1 | 48, XXYY Syndrome |
nord_1_1 | Symptoms of 48, XXYY Syndrome | In infancy and early childhood, delayed milestones in speech and motor skills are common, as are medical features including low muscle tone (hypotonia), feeding disorders, delayed appearance of teeth, crossed eyes (strabismus) and a twisted neck (torticollis) with flattening on one side of the head. Other physical features can include a skin fold of the upper eyelid covering the inner corner of the eye (epicanthal fold), an abnormally large distance between the eyes (hypertelorism) and an abnormally bend or curved 5th finger (clinodactyly). There are also increased risks for congenital heart defects, kidney malformations and skeletal abnormalities including pes planus, club foot, radioulnar synostosis, cubitus varus (with prominent elbows), scoliosis and kyphosis.Other medical conditions that are more frequent in 48, XXYY syndrome include epilepsy (~15%), tremor (~60% of adults), asthma/allergies (~60%), significant dental problems (~90%), gastrointestinal problems (feeding intolerance, reflux, constipation, eosinophilic esophagitis), joint laxity, sleep apnea, thrombosis (~18%) and type 2 diabetes (~20% in adulthood). Tall stature is another common physical feature that can be more noticeable in adolescence.Small testes (microorchidism) and resulting testicular dysfunction leads to hypergonadotropic hypogonadism (low testosterone levels) that is nearly universal which starts in adolescence and persists throughout the lifetime. Low testosterone levels can be associated with incomplete pubertal development (decreased development of facial and body hair), decreased muscle bulk and strength, fatigue, low endurance and mental health effects such as depression. Testicular dysfunction is also associated with impaired fertility. Undescended testes (cryptorchidism), inguinal hernias, micropenis, and enlargement of breast tissue (gynecomastia) can also be associated, however gynecomastia can be prevented or minimized with appropriate testosterone management starting in adolescence.48, XXYY syndrome presents with more significant cognitive impairments and behavior challenges compared to 47, XXY. Developmental delays are often present in the first 3 years of life in the areas of speech and motor development. Overall cognitive abilities tend to be in the borderline range (IQ of 70 – 80) with approximately 1/3 of males with 48, XXYY with full scale IQ in the intellectual disability range (<70). Cognitive profiles often show significantly lower verbal reasoning skills compared to nonverbal and visual-spatial skills (which are often areas of strength). Language disorders and learning disabilities (especially with reading) are very common. Adaptive functioning (life skills) also commonly show deficits in communication, social skills, self-care and self-direction. Motor coordination deficits are also common.Behavioral characteristics can include executive function impairments, difficulties with attention, impulsivity and hyperactivity. Attention-deficit/hyperactivity disorder (ADHD) is often diagnosed. Mood instability, short frustration tolerance, anxiety, compulsive behaviors and emotional immaturity are also characteristic of 48, XXYY. Additional features can include nail biting, sugar cravings and intense interests. There is increased risk for social difficulties, including difficulties in social skills, reciprocal social interactions and insight into social relationships. As a result, there is an increased risk for an autism spectrum disorder (ASD) diagnosis, and approximately half of males with 48, XXYY met DSM-5 criteria for ASD in a research study. Common strengths include artistic skills, computer skills and navigation skills. | Symptoms of 48, XXYY Syndrome. In infancy and early childhood, delayed milestones in speech and motor skills are common, as are medical features including low muscle tone (hypotonia), feeding disorders, delayed appearance of teeth, crossed eyes (strabismus) and a twisted neck (torticollis) with flattening on one side of the head. Other physical features can include a skin fold of the upper eyelid covering the inner corner of the eye (epicanthal fold), an abnormally large distance between the eyes (hypertelorism) and an abnormally bend or curved 5th finger (clinodactyly). There are also increased risks for congenital heart defects, kidney malformations and skeletal abnormalities including pes planus, club foot, radioulnar synostosis, cubitus varus (with prominent elbows), scoliosis and kyphosis.Other medical conditions that are more frequent in 48, XXYY syndrome include epilepsy (~15%), tremor (~60% of adults), asthma/allergies (~60%), significant dental problems (~90%), gastrointestinal problems (feeding intolerance, reflux, constipation, eosinophilic esophagitis), joint laxity, sleep apnea, thrombosis (~18%) and type 2 diabetes (~20% in adulthood). Tall stature is another common physical feature that can be more noticeable in adolescence.Small testes (microorchidism) and resulting testicular dysfunction leads to hypergonadotropic hypogonadism (low testosterone levels) that is nearly universal which starts in adolescence and persists throughout the lifetime. Low testosterone levels can be associated with incomplete pubertal development (decreased development of facial and body hair), decreased muscle bulk and strength, fatigue, low endurance and mental health effects such as depression. Testicular dysfunction is also associated with impaired fertility. Undescended testes (cryptorchidism), inguinal hernias, micropenis, and enlargement of breast tissue (gynecomastia) can also be associated, however gynecomastia can be prevented or minimized with appropriate testosterone management starting in adolescence.48, XXYY syndrome presents with more significant cognitive impairments and behavior challenges compared to 47, XXY. Developmental delays are often present in the first 3 years of life in the areas of speech and motor development. Overall cognitive abilities tend to be in the borderline range (IQ of 70 – 80) with approximately 1/3 of males with 48, XXYY with full scale IQ in the intellectual disability range (<70). Cognitive profiles often show significantly lower verbal reasoning skills compared to nonverbal and visual-spatial skills (which are often areas of strength). Language disorders and learning disabilities (especially with reading) are very common. Adaptive functioning (life skills) also commonly show deficits in communication, social skills, self-care and self-direction. Motor coordination deficits are also common.Behavioral characteristics can include executive function impairments, difficulties with attention, impulsivity and hyperactivity. Attention-deficit/hyperactivity disorder (ADHD) is often diagnosed. Mood instability, short frustration tolerance, anxiety, compulsive behaviors and emotional immaturity are also characteristic of 48, XXYY. Additional features can include nail biting, sugar cravings and intense interests. There is increased risk for social difficulties, including difficulties in social skills, reciprocal social interactions and insight into social relationships. As a result, there is an increased risk for an autism spectrum disorder (ASD) diagnosis, and approximately half of males with 48, XXYY met DSM-5 criteria for ASD in a research study. Common strengths include artistic skills, computer skills and navigation skills. | 1 | 48, XXYY Syndrome |
nord_1_2 | Causes of 48, XXYY Syndrome | 48, XXYY syndrome is not inherited, Males with 48, XXYY have an extra X and Y chromosome because of a nondisjunction error that randomly occurs during the division of the sex chromosomes in the egg or sperm cells. There are no commonly known factors predisposing to the specific occurrence of these nondisjunction events resulting in 48, XXYY. | Causes of 48, XXYY Syndrome. 48, XXYY syndrome is not inherited, Males with 48, XXYY have an extra X and Y chromosome because of a nondisjunction error that randomly occurs during the division of the sex chromosomes in the egg or sperm cells. There are no commonly known factors predisposing to the specific occurrence of these nondisjunction events resulting in 48, XXYY. | 1 | 48, XXYY Syndrome |
nord_1_3 | Affects of 48, XXYY Syndrome | There is an estimated incidence of 48, XXYY in 1/18,000 to 1/50,000 male births. | Affects of 48, XXYY Syndrome. There is an estimated incidence of 48, XXYY in 1/18,000 to 1/50,000 male births. | 1 | 48, XXYY Syndrome |
nord_1_4 | Related disorders of 48, XXYY Syndrome | The hypergonadotropic hypogonadism present in 48, XXYY can be seen in other male sex chromosome aneuploidies including Klinefelter (47, XXY) syndrome, 48, XXXY syndrome and 49, XXXXY syndrome as well as 45, X/46, XY mosaicism and 46, XX sex reversal. Other genetic conditions that may have overlap with some of the behavioral and cognitive/neurodevelopmental features seen in 48, XXYY syndrome include Fragile X syndrome, Jacob syndrome, Prader Willi syndrome, Soto syndrome, Börjeson-Forssman-Lehman syndrome, Weaver syndrome and Cohen syndrome. Due to tall stature and joint laxity, some males with 48, XXYY are also identified during genetic evaluation for Marfan syndrome or other connective tissue disorders. Also, many of the neurodevelopmental disorders often diagnosed in males with XXYY syndrome are commonly found in 46, XY males as well, including intellectual disability, autism spectrum disorder, learning disabilities, language disorders and ADHD. | Related disorders of 48, XXYY Syndrome. The hypergonadotropic hypogonadism present in 48, XXYY can be seen in other male sex chromosome aneuploidies including Klinefelter (47, XXY) syndrome, 48, XXXY syndrome and 49, XXXXY syndrome as well as 45, X/46, XY mosaicism and 46, XX sex reversal. Other genetic conditions that may have overlap with some of the behavioral and cognitive/neurodevelopmental features seen in 48, XXYY syndrome include Fragile X syndrome, Jacob syndrome, Prader Willi syndrome, Soto syndrome, Börjeson-Forssman-Lehman syndrome, Weaver syndrome and Cohen syndrome. Due to tall stature and joint laxity, some males with 48, XXYY are also identified during genetic evaluation for Marfan syndrome or other connective tissue disorders. Also, many of the neurodevelopmental disorders often diagnosed in males with XXYY syndrome are commonly found in 46, XY males as well, including intellectual disability, autism spectrum disorder, learning disabilities, language disorders and ADHD. | 1 | 48, XXYY Syndrome |
nord_1_5 | Diagnosis of 48, XXYY Syndrome | 48, XXYY is usually identified by a standard karyotype or chromosomal microarray (CMA) performed on peripheral blood, amniotic fluid or buccal swab. Fluorescence In Situ Hybridization (FISH) is another approach to investigate the presence of extra copies of chromosomes X and Y on a larger sample of cells. Prenatal diagnosis is possible, but 48, XXYY is usually diagnosed during childhood during evaluation of physical and/or developmental concerns that warrant genetic testing. A 2008 study looking at 95 males with 48, XXYY syndrome reported the mean age of diagnosis to be 7.7 years of age. | Diagnosis of 48, XXYY Syndrome. 48, XXYY is usually identified by a standard karyotype or chromosomal microarray (CMA) performed on peripheral blood, amniotic fluid or buccal swab. Fluorescence In Situ Hybridization (FISH) is another approach to investigate the presence of extra copies of chromosomes X and Y on a larger sample of cells. Prenatal diagnosis is possible, but 48, XXYY is usually diagnosed during childhood during evaluation of physical and/or developmental concerns that warrant genetic testing. A 2008 study looking at 95 males with 48, XXYY syndrome reported the mean age of diagnosis to be 7.7 years of age. | 1 | 48, XXYY Syndrome |
nord_1_6 | Therapies of 48, XXYY Syndrome | Treatment Comprehensive interdisciplinary care is important to evaluate and manage developmental, medical, and psychological conditions that may be associated with 48, XXYY syndrome. At diagnosis, a thorough physical exam, renal ultrasound and echocardiography should be performed to evaluate for congenital defects. Vision and hearing screening and routine dental care are important throughout the lifespan. Physical examination should focus on common physical features and medical findings described above. Starting around age 10, pubertal examinations and serum hormone profiles should be monitored by endocrinology and testosterone supplementation should be considered when evidence of hypogonadism is present. Routine screening for hyperlipidemia, diabetes and thyroid disease is recommended starting in adolescence. Eosinophilic esophagitis should be considered in males with XXYY who have feeding problems, dysphagia (pain with swallowing), reflux, choking or other feeding problems, especially in patients with food allergies. Symptoms suggestive of any other associated medical conditions should be promptly evaluated and treated as appropriate.The neurodevelopmental and behavioral phenotype in 48, XXYY warrants a comprehensive interdisciplinary evaluation to include psychological functioning (cognitive, learning, executive, social, emotional, and behavioral functioning), speech/language skills, motor skills and self-care skills. For infants and young children, close developmental screening is important to identify delays and the need for early intervention therapies. Further, speech-language therapy to target developmentally appropriate goals around oral-motor planning deficits, apraxia of speech, expressive and receptive language skills and pragmatic language may be necessary through early adulthood. Occupational and/or physical therapies to target decreased motor skills, dyspraxia, coordination, sensory sensitivities and overall self-care are also often warranted.Documentation of psychological diagnoses (such as learning or intellectual disability, ADHD, anxiety and/or autism spectrum disorder) is important for qualification and access to community-based services. Interventions are recommended when psychological diagnoses are present, and treatments for emotional and behavioral disorders should be evidence-based, individualized, and chosen with consideration of language deficits, learning disabilities and other associated diagnoses. Social skills therapy can also address difficulties with social understanding, relationships and communication. Services that are tailored to the developmental disability or ASD population and delivered by providers who specialize in developmental disabilities and/or ASD are often a good fit for 48, XXYY. School-based supports including services outlined by an individualized education plan (IEP) are most often a part of the treatment plan, and evidence-based interventions for learning disabilities do not differ from those used with the general population. Through adolescence and early adulthood, adaptive skills, transition services and community-based supports are important areas of focus.In addition to endocrinology, consultation with other medical specialists including developmental pediatrics, psychiatry and/or neurology may also help to develop treatment plans and provide medication management. Psychopharmacologic medications, in conjunction with behavioral therapy, may be warranted for behavioral and emotional symptoms and are commonly part of the treatment plan. Positive response to standard medication treatments for ADHD, anxiety and externalizing behaviors has been seen in males with 48, XXYY. There are specialized clinics primarily in the US that have experience supporting individuals with 48, XXYY. For a list of clinics, please go to the AXYS website: https://genetic.org/im-adult-looking-answers/clinics/acrc-clinics-list/ | Therapies of 48, XXYY Syndrome. Treatment Comprehensive interdisciplinary care is important to evaluate and manage developmental, medical, and psychological conditions that may be associated with 48, XXYY syndrome. At diagnosis, a thorough physical exam, renal ultrasound and echocardiography should be performed to evaluate for congenital defects. Vision and hearing screening and routine dental care are important throughout the lifespan. Physical examination should focus on common physical features and medical findings described above. Starting around age 10, pubertal examinations and serum hormone profiles should be monitored by endocrinology and testosterone supplementation should be considered when evidence of hypogonadism is present. Routine screening for hyperlipidemia, diabetes and thyroid disease is recommended starting in adolescence. Eosinophilic esophagitis should be considered in males with XXYY who have feeding problems, dysphagia (pain with swallowing), reflux, choking or other feeding problems, especially in patients with food allergies. Symptoms suggestive of any other associated medical conditions should be promptly evaluated and treated as appropriate.The neurodevelopmental and behavioral phenotype in 48, XXYY warrants a comprehensive interdisciplinary evaluation to include psychological functioning (cognitive, learning, executive, social, emotional, and behavioral functioning), speech/language skills, motor skills and self-care skills. For infants and young children, close developmental screening is important to identify delays and the need for early intervention therapies. Further, speech-language therapy to target developmentally appropriate goals around oral-motor planning deficits, apraxia of speech, expressive and receptive language skills and pragmatic language may be necessary through early adulthood. Occupational and/or physical therapies to target decreased motor skills, dyspraxia, coordination, sensory sensitivities and overall self-care are also often warranted.Documentation of psychological diagnoses (such as learning or intellectual disability, ADHD, anxiety and/or autism spectrum disorder) is important for qualification and access to community-based services. Interventions are recommended when psychological diagnoses are present, and treatments for emotional and behavioral disorders should be evidence-based, individualized, and chosen with consideration of language deficits, learning disabilities and other associated diagnoses. Social skills therapy can also address difficulties with social understanding, relationships and communication. Services that are tailored to the developmental disability or ASD population and delivered by providers who specialize in developmental disabilities and/or ASD are often a good fit for 48, XXYY. School-based supports including services outlined by an individualized education plan (IEP) are most often a part of the treatment plan, and evidence-based interventions for learning disabilities do not differ from those used with the general population. Through adolescence and early adulthood, adaptive skills, transition services and community-based supports are important areas of focus.In addition to endocrinology, consultation with other medical specialists including developmental pediatrics, psychiatry and/or neurology may also help to develop treatment plans and provide medication management. Psychopharmacologic medications, in conjunction with behavioral therapy, may be warranted for behavioral and emotional symptoms and are commonly part of the treatment plan. Positive response to standard medication treatments for ADHD, anxiety and externalizing behaviors has been seen in males with 48, XXYY. There are specialized clinics primarily in the US that have experience supporting individuals with 48, XXYY. For a list of clinics, please go to the AXYS website: https://genetic.org/im-adult-looking-answers/clinics/acrc-clinics-list/ | 1 | 48, XXYY Syndrome |
nord_2_0 | Overview of Aarskog Syndrome | Aarskog syndrome is a rare genetic condition characterized by short stature and multiple facial, limb and genital abnormalities. Additionally, some types of cognitive disorders may occasionally be present. Up to now, the FGD1 gene on the X chromosome is the only gene known to be associated with Aarskog syndrome. | Overview of Aarskog Syndrome. Aarskog syndrome is a rare genetic condition characterized by short stature and multiple facial, limb and genital abnormalities. Additionally, some types of cognitive disorders may occasionally be present. Up to now, the FGD1 gene on the X chromosome is the only gene known to be associated with Aarskog syndrome. | 2 | Aarskog Syndrome |
nord_2_1 | Symptoms of Aarskog Syndrome | Aarskog syndrome primarily affects males. Affected boys exhibit a characteristic set of facial, skeletal, and genital abnormalities. Clinical signs may vary from person to person (clinical heterogeneity), even within families. Males with Aarskog syndrome often have a rounded face with a broad forehead. Additional characteristic facial features include widely spaced eyes (ocular hypertelorism), drooping (ptosis) of the eyelids, downwardly slanting eyelid folds (palpebral fissures), a small nose with nostrils that are flared forward (anteverted nares), an underdeveloped upper jawbone (maxilliary hypoplasia), and a widow’s peak. Affected individuals may also have an abnormally long groove in the upper lip (philtrum) and a broad nasal bridge.These children may also have a variety of abnormalities affecting the ears and teeth. Ear abnormalities include low-set ears and thickened, “fleshy” earlobes. Dental abnormalities include missing teeth at birth, delayed eruption of teeth, and underdevelopment of the hard outer covering of teeth (enamel hypoplasia).Aarskog syndrome is basically a skeletal dysplasia and affected males develop characteristic malformations of the skeletal system including disproportionate short stature; broad, short hands and feet; short, stubby fingers (brachydactyly) with permanent fixation of the fifth fingers in a bent position (clinodactyly); abnormally extendible finger joints; and wide flat feet with bulbous toes. In addition, affected individuals may have a sunken chest (pectus excavatum), protrusion of portions of the large intestine through an abnormal opening in the muscular lining of the abdominal cavity (inguinal hernia), and a prominent navel (umbilicus). Individuals with Aarskog syndrome may have spinal abnormalities such as incomplete closure of the bones of the spinal column (spina bifida occulta), fusion of the upper bones of the spinal column (cervical vertebrae), and underdevelopment of the “peg-like” projection of the second cervical vertebra (odontoid hypoplasia).Signs that help to make a diagnosis in males with Aarskog syndrome are the genital abnormalities, including a characteristic abnormal fold of skin extending around the base of the penis (“shawl” scrotum) and/or failure of one or both of the testes to descend into the scrotum (cryptorchidism). In addition, the urinary opening (meatus) may be located on the underside of the penis (hypospadias) and the scrotum may appear clefted or divided (bifid scrotum).Intellectual disability has been described in some affected boys but it is not a consistent feature of the disorder. Affected individuals may present with a range of mild learning difficulty and/or behavioral disorders: affected children may exhibit developmental delay during infancy, hyperactivity, attention deficit, impulsivity and opposition. Due to this possible spectrum of characteristics, the condition is also referred to as an ADHD syndromic disorder (MRXS16). Failure to gain weight and grow at the expected rate (failure to thrive) and development of chronic respiratory infections have also been described.An additional spectrum of signs and/or symptoms may occur less frequently, including congenital heart defects; abnormal side-to-side curvature of the spine (scoliosis); additional pairs of ribs; incomplete closure of the roof of the mouth (cleft palate) and/or a vertical groove in the upper lip (cleft lip); mild webbing of the fingers; and a short neck with or without webbing. Additional eye abnormalities may be present including crossed eyes (strabismus), farsightedness (hyperopia), and paralysis of certain eye muscles (ophthalmoplegia). Some patients have been reported to have a tendency to be overweight. | Symptoms of Aarskog Syndrome. Aarskog syndrome primarily affects males. Affected boys exhibit a characteristic set of facial, skeletal, and genital abnormalities. Clinical signs may vary from person to person (clinical heterogeneity), even within families. Males with Aarskog syndrome often have a rounded face with a broad forehead. Additional characteristic facial features include widely spaced eyes (ocular hypertelorism), drooping (ptosis) of the eyelids, downwardly slanting eyelid folds (palpebral fissures), a small nose with nostrils that are flared forward (anteverted nares), an underdeveloped upper jawbone (maxilliary hypoplasia), and a widow’s peak. Affected individuals may also have an abnormally long groove in the upper lip (philtrum) and a broad nasal bridge.These children may also have a variety of abnormalities affecting the ears and teeth. Ear abnormalities include low-set ears and thickened, “fleshy” earlobes. Dental abnormalities include missing teeth at birth, delayed eruption of teeth, and underdevelopment of the hard outer covering of teeth (enamel hypoplasia).Aarskog syndrome is basically a skeletal dysplasia and affected males develop characteristic malformations of the skeletal system including disproportionate short stature; broad, short hands and feet; short, stubby fingers (brachydactyly) with permanent fixation of the fifth fingers in a bent position (clinodactyly); abnormally extendible finger joints; and wide flat feet with bulbous toes. In addition, affected individuals may have a sunken chest (pectus excavatum), protrusion of portions of the large intestine through an abnormal opening in the muscular lining of the abdominal cavity (inguinal hernia), and a prominent navel (umbilicus). Individuals with Aarskog syndrome may have spinal abnormalities such as incomplete closure of the bones of the spinal column (spina bifida occulta), fusion of the upper bones of the spinal column (cervical vertebrae), and underdevelopment of the “peg-like” projection of the second cervical vertebra (odontoid hypoplasia).Signs that help to make a diagnosis in males with Aarskog syndrome are the genital abnormalities, including a characteristic abnormal fold of skin extending around the base of the penis (“shawl” scrotum) and/or failure of one or both of the testes to descend into the scrotum (cryptorchidism). In addition, the urinary opening (meatus) may be located on the underside of the penis (hypospadias) and the scrotum may appear clefted or divided (bifid scrotum).Intellectual disability has been described in some affected boys but it is not a consistent feature of the disorder. Affected individuals may present with a range of mild learning difficulty and/or behavioral disorders: affected children may exhibit developmental delay during infancy, hyperactivity, attention deficit, impulsivity and opposition. Due to this possible spectrum of characteristics, the condition is also referred to as an ADHD syndromic disorder (MRXS16). Failure to gain weight and grow at the expected rate (failure to thrive) and development of chronic respiratory infections have also been described.An additional spectrum of signs and/or symptoms may occur less frequently, including congenital heart defects; abnormal side-to-side curvature of the spine (scoliosis); additional pairs of ribs; incomplete closure of the roof of the mouth (cleft palate) and/or a vertical groove in the upper lip (cleft lip); mild webbing of the fingers; and a short neck with or without webbing. Additional eye abnormalities may be present including crossed eyes (strabismus), farsightedness (hyperopia), and paralysis of certain eye muscles (ophthalmoplegia). Some patients have been reported to have a tendency to be overweight. | 2 | Aarskog Syndrome |
nord_2_2 | Causes of Aarskog Syndrome | Although Aarskog syndrome is a clinically and genetically heterogeneous condition, the best characterized form of the disorder is inherited as an X-linked trait and caused by changes (mutations) in the FGD1 gene. Aarskog syndrome primarily affects males. However, females who carry a single copy of a FGD1 gene mutation (heterozygotes) may exhibit some of the symptoms associated with the disorder. FGD1 gene mutations have been identified in approximately 22% of affected males; therefore, it is likely that other genes not yet identified may also be associated with this condition.X-linked recessive genetic disorders are conditions caused by mutations in a gene located on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” to correct a dosage imbalance and almost all of the genes on that chromosome are silenced (inactivated) through a process defined as X-chromosome inactivation. Females who have a disease causing mutation on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “silenced”. Males have one only X chromosome and, if they inherit the X chromosome that contains a disease gene, they will develop the disease. In turn, males with a X-linked disorder will pass the disease gene to all of their daughters, who will be carriers of the trait (obligate carriers). Males cannot pass X-linked traits to their sons because they always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter (like themselves), a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. | Causes of Aarskog Syndrome. Although Aarskog syndrome is a clinically and genetically heterogeneous condition, the best characterized form of the disorder is inherited as an X-linked trait and caused by changes (mutations) in the FGD1 gene. Aarskog syndrome primarily affects males. However, females who carry a single copy of a FGD1 gene mutation (heterozygotes) may exhibit some of the symptoms associated with the disorder. FGD1 gene mutations have been identified in approximately 22% of affected males; therefore, it is likely that other genes not yet identified may also be associated with this condition.X-linked recessive genetic disorders are conditions caused by mutations in a gene located on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” to correct a dosage imbalance and almost all of the genes on that chromosome are silenced (inactivated) through a process defined as X-chromosome inactivation. Females who have a disease causing mutation on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “silenced”. Males have one only X chromosome and, if they inherit the X chromosome that contains a disease gene, they will develop the disease. In turn, males with a X-linked disorder will pass the disease gene to all of their daughters, who will be carriers of the trait (obligate carriers). Males cannot pass X-linked traits to their sons because they always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter (like themselves), a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. | 2 | Aarskog Syndrome |
nord_2_3 | Affects of Aarskog Syndrome | Approximately 60 reports of Aarskog syndrome confirmed by identification of a FGD1 gene mutation have been published worldwide. However, it is possible that some mildly affected children may be unrecognized, making it difficult to determine the true frequency of this condition in the general population. An estimated population prevalence of Aarskog syndrome is equal to or slightly lower than to 1/25,000. | Affects of Aarskog Syndrome. Approximately 60 reports of Aarskog syndrome confirmed by identification of a FGD1 gene mutation have been published worldwide. However, it is possible that some mildly affected children may be unrecognized, making it difficult to determine the true frequency of this condition in the general population. An estimated population prevalence of Aarskog syndrome is equal to or slightly lower than to 1/25,000. | 2 | Aarskog Syndrome |
nord_2_4 | Related disorders of Aarskog Syndrome | Symptoms of the following disorders can be similar to those of Aarskog syndrome. Comparisons may be useful for a differential diagnosis:Noonan syndrome is a relatively common genetic disorder characterized by short stature, dysmorphic facial features and congenital heart disease. The disorder is characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low posterior hairline; a typical chest deformity and short stature. Characteristic abnormalities of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); skin folds that may cover the eyes’ inner corners (epicanthal folds); drooping of the upper eyelids (ptosis); a small jaw (micrognathia); a depressed nasal root; a short nose with broad base; and low-set, posteriorly rotated ears (pinnae). Distinctive skeletal malformations are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart (cardiac) defects, such as obstruction of proper blood flow from the lower right chamber of the heart to the lungs (pulmonary valvular stenosis). Additional abnormalities may include malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, learning difficulties or mild intellectual disability, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males, and/or other symptoms and findings. Noonan syndrome is may be caused by mutations in a number of genes, including PTPN11, KRAS, SOS1, RAF1, NRAS, RIT1 and SOS2 (For more information on this disorder, choose “Noonan” as your search term in the Rare Disease Database.)Robinow syndrome is a rare genetic disorder that can be inherited in either a dominant or recessive pattern and is characterized by mild to moderate short stature due to growth delays after birth (postnatal growth retardation); distinctive abnormalities of the head and facial (craniofacial) area; additional skeletal malformations; and/or genital abnormalities. The facial features of infants with Robinow syndrome resemble those of an eight-week-old fetus; within the medical literature, this condition is often referred to as “fetal face.” Characteristic craniofacial features may include an abnormally large head (macrocephaly) with a bulging forehead (frontal bossing); widely spaced eyes (ocular hypertelorism) that are abnormally prominent; a small, upturned nose with nostrils that are flared forward (anteverted); and/or a sunken (depressed) nasal bridge. Skeletal malformations may include forearm bones (radius and ulna) that are unusually short (forearm brachymelia), abnormally short fingers and toes, permanent fixation of the fifth fingers in a bent position (clinodactyly), unusually small hands with broad thumbs, malformation of the ribs, abnormal side-to-side curvature of the spine (scoliosis), and/or underdevelopment of one side of the bones in the middle (thoracic) portion of the spinal column (hemivertebrae). Genital abnormalities associated with Robinow syndrome may include an abnormally small penis (micropenis) and failure of the testes to descend into the scrotum (cryptorchidism) in affected males and underdevelopment (hypoplasia) of the clitoris and the outer, elongated folds of skin on either side of the vaginal opening (labia majora) in affected females. The range and severity of symptoms vary from person to person. The Robinow syndrome may be caused by mutations in different genes, such as WNT5A, ROR2, DVL3 and DVL1 (For more information on this disorder, choose “Robinow” as your search term in the Rare Disease Database.)Noonan syndrome with multiple lentigines (NSML) is a rare genetic disorder characterized by abnormalities of the skin, the structure and function of the heart, the inner ear, the head and facial (craniofacial) area, and/or the genitals. In individuals with the disorder, the range and severity of symptoms and physical characteristics may vary from person to person. LEOPARD is an acronym for the characteristic abnormalities associated with the disorder: L stands for (L)entigines (multiple black or dark brown spots on the skin); (E)lectrocardiographic conduction defects (abnormalities of the electrical activity and the coordination of proper contractions of the heart); (0)cular hypertelorism (widely-spaced eyes); (P)ulmonary stenosis (obstruction of the normal outflow of blood from the right ventricle of the heart); (A)bnormalities of the genitals; (R)etarded growth resulting in short stature; and (D)eafness or hearing loss due to malfunction of the inner ear (sensorineural deafness). Some affected individuals may also exhibit mild intellectual disability, speech difficulties, and/or, in some cases, additional physical abnormalities. NSML is an autosomal dominant genetic disorder. NSML and Noonan syndrome are both caused by mutations in the PTPN11 and RAF1 genes. (For more information on this disorder, choose “LEOPARD” as your search term in the Rare Disease Database.) | Related disorders of Aarskog Syndrome. Symptoms of the following disorders can be similar to those of Aarskog syndrome. Comparisons may be useful for a differential diagnosis:Noonan syndrome is a relatively common genetic disorder characterized by short stature, dysmorphic facial features and congenital heart disease. The disorder is characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low posterior hairline; a typical chest deformity and short stature. Characteristic abnormalities of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); skin folds that may cover the eyes’ inner corners (epicanthal folds); drooping of the upper eyelids (ptosis); a small jaw (micrognathia); a depressed nasal root; a short nose with broad base; and low-set, posteriorly rotated ears (pinnae). Distinctive skeletal malformations are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart (cardiac) defects, such as obstruction of proper blood flow from the lower right chamber of the heart to the lungs (pulmonary valvular stenosis). Additional abnormalities may include malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, learning difficulties or mild intellectual disability, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males, and/or other symptoms and findings. Noonan syndrome is may be caused by mutations in a number of genes, including PTPN11, KRAS, SOS1, RAF1, NRAS, RIT1 and SOS2 (For more information on this disorder, choose “Noonan” as your search term in the Rare Disease Database.)Robinow syndrome is a rare genetic disorder that can be inherited in either a dominant or recessive pattern and is characterized by mild to moderate short stature due to growth delays after birth (postnatal growth retardation); distinctive abnormalities of the head and facial (craniofacial) area; additional skeletal malformations; and/or genital abnormalities. The facial features of infants with Robinow syndrome resemble those of an eight-week-old fetus; within the medical literature, this condition is often referred to as “fetal face.” Characteristic craniofacial features may include an abnormally large head (macrocephaly) with a bulging forehead (frontal bossing); widely spaced eyes (ocular hypertelorism) that are abnormally prominent; a small, upturned nose with nostrils that are flared forward (anteverted); and/or a sunken (depressed) nasal bridge. Skeletal malformations may include forearm bones (radius and ulna) that are unusually short (forearm brachymelia), abnormally short fingers and toes, permanent fixation of the fifth fingers in a bent position (clinodactyly), unusually small hands with broad thumbs, malformation of the ribs, abnormal side-to-side curvature of the spine (scoliosis), and/or underdevelopment of one side of the bones in the middle (thoracic) portion of the spinal column (hemivertebrae). Genital abnormalities associated with Robinow syndrome may include an abnormally small penis (micropenis) and failure of the testes to descend into the scrotum (cryptorchidism) in affected males and underdevelopment (hypoplasia) of the clitoris and the outer, elongated folds of skin on either side of the vaginal opening (labia majora) in affected females. The range and severity of symptoms vary from person to person. The Robinow syndrome may be caused by mutations in different genes, such as WNT5A, ROR2, DVL3 and DVL1 (For more information on this disorder, choose “Robinow” as your search term in the Rare Disease Database.)Noonan syndrome with multiple lentigines (NSML) is a rare genetic disorder characterized by abnormalities of the skin, the structure and function of the heart, the inner ear, the head and facial (craniofacial) area, and/or the genitals. In individuals with the disorder, the range and severity of symptoms and physical characteristics may vary from person to person. LEOPARD is an acronym for the characteristic abnormalities associated with the disorder: L stands for (L)entigines (multiple black or dark brown spots on the skin); (E)lectrocardiographic conduction defects (abnormalities of the electrical activity and the coordination of proper contractions of the heart); (0)cular hypertelorism (widely-spaced eyes); (P)ulmonary stenosis (obstruction of the normal outflow of blood from the right ventricle of the heart); (A)bnormalities of the genitals; (R)etarded growth resulting in short stature; and (D)eafness or hearing loss due to malfunction of the inner ear (sensorineural deafness). Some affected individuals may also exhibit mild intellectual disability, speech difficulties, and/or, in some cases, additional physical abnormalities. NSML is an autosomal dominant genetic disorder. NSML and Noonan syndrome are both caused by mutations in the PTPN11 and RAF1 genes. (For more information on this disorder, choose “LEOPARD” as your search term in the Rare Disease Database.) | 2 | Aarskog Syndrome |
nord_2_5 | Diagnosis of Aarskog Syndrome | A diagnosis of Aarskog syndrome may be considered based upon a thorough clinical evaluation, a detailed patient and family history, and the identification of characteristic findings. Molecular genetic testing for FGD1 gene mutations is available to confirm the diagnosis. If a FGD1 gene mutation is not identified, molecular genetic testing for genes associated with similar conditions may be suggested, such as the ROR2 and WNT5A genes associated with Robinow syndrome.
The transition from the classic sequencing of single genes to protocols of next generation sequencing (NGS), recommends at least the use of panels that include, in addition to FGD1, the genes that cause overlapping conditions such as ROR2, WNT5A, PIK3R1, SRCAP, KMT2D, KDM6A, SHOX, CUL7. | Diagnosis of Aarskog Syndrome. A diagnosis of Aarskog syndrome may be considered based upon a thorough clinical evaluation, a detailed patient and family history, and the identification of characteristic findings. Molecular genetic testing for FGD1 gene mutations is available to confirm the diagnosis. If a FGD1 gene mutation is not identified, molecular genetic testing for genes associated with similar conditions may be suggested, such as the ROR2 and WNT5A genes associated with Robinow syndrome.
The transition from the classic sequencing of single genes to protocols of next generation sequencing (NGS), recommends at least the use of panels that include, in addition to FGD1, the genes that cause overlapping conditions such as ROR2, WNT5A, PIK3R1, SRCAP, KMT2D, KDM6A, SHOX, CUL7. | 2 | Aarskog Syndrome |
nord_2_6 | Therapies of Aarskog Syndrome | Treatment
The treatment of Aarskog syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, dental specialists, speech pathologists, specialists who asses and treat hearing problems (audiologists), eye specialists, and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.Surgery may be necessary to treat specific congenital or structural malformations sometimes associated with Aarskog syndrome (hypospadias, inguinal or umbilical hernias, cryptorchidism, unusually severe craniofacial features). Individuals with Aarskog syndrome should receive complete eye and dental evaluations. Growth hormone treatment has been reported to improve height in some children, but confirmation is needed to determine appropriate management and expectations for response. For the possibly neurodevelopmental symptoms, a neuropsychiatric evaluation and input may be indicated. Other treatment is symptomatic and supportive.Genetic counseling is recommended for affected individuals and their families to clarify the genetic and clinical characteristics, the inheritance, and the recurrence risks of the condition in their families. | Therapies of Aarskog Syndrome. Treatment
The treatment of Aarskog syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, dental specialists, speech pathologists, specialists who asses and treat hearing problems (audiologists), eye specialists, and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.Surgery may be necessary to treat specific congenital or structural malformations sometimes associated with Aarskog syndrome (hypospadias, inguinal or umbilical hernias, cryptorchidism, unusually severe craniofacial features). Individuals with Aarskog syndrome should receive complete eye and dental evaluations. Growth hormone treatment has been reported to improve height in some children, but confirmation is needed to determine appropriate management and expectations for response. For the possibly neurodevelopmental symptoms, a neuropsychiatric evaluation and input may be indicated. Other treatment is symptomatic and supportive.Genetic counseling is recommended for affected individuals and their families to clarify the genetic and clinical characteristics, the inheritance, and the recurrence risks of the condition in their families. | 2 | Aarskog Syndrome |
nord_3_0 | Overview of Abetalipoproteinemia | SummaryAbetalipoproteinemia is a rare inherited disorder affecting fat absorption by the intestine and mobilization by the liver. Inability to absorb fat results in deficiencies of lipids and various essential vitamins. Affected individuals experience progressive neurological deterioration, muscle weakness, difficulty walking and blood abnormalities including a condition in which the red blood cells are malformed (acanthocytosis) resulting in low levels of circulating red blood cells (anemia). Affected individuals may also develop degeneration of the retina of the eyes potentially resulting in loss of vision, a condition known as retinitis pigmentosa. Abetalipoproteinemia is inherited in an autosomal recessive pattern and is caused by changes (mutations or variants) in the microsomal triglyceride transfer protein (MTTP) gene.IntroductionAbetalipoproteinemia was first reported in the medical literature by doctors Bassen and Kornzweig in 1950 and is also known as Bassen-Kornzweig syndrome. The disorder is sometimes classified as a neuroacanthocytosis syndrome, which refers to a group of disorders characterized by spiky or burr-shaped red blood cells (acanthocytosis) and neurological disorders, especially movement disorders. | Overview of Abetalipoproteinemia. SummaryAbetalipoproteinemia is a rare inherited disorder affecting fat absorption by the intestine and mobilization by the liver. Inability to absorb fat results in deficiencies of lipids and various essential vitamins. Affected individuals experience progressive neurological deterioration, muscle weakness, difficulty walking and blood abnormalities including a condition in which the red blood cells are malformed (acanthocytosis) resulting in low levels of circulating red blood cells (anemia). Affected individuals may also develop degeneration of the retina of the eyes potentially resulting in loss of vision, a condition known as retinitis pigmentosa. Abetalipoproteinemia is inherited in an autosomal recessive pattern and is caused by changes (mutations or variants) in the microsomal triglyceride transfer protein (MTTP) gene.IntroductionAbetalipoproteinemia was first reported in the medical literature by doctors Bassen and Kornzweig in 1950 and is also known as Bassen-Kornzweig syndrome. The disorder is sometimes classified as a neuroacanthocytosis syndrome, which refers to a group of disorders characterized by spiky or burr-shaped red blood cells (acanthocytosis) and neurological disorders, especially movement disorders. | 3 | Abetalipoproteinemia |
nord_3_1 | Symptoms of Abetalipoproteinemia | Individuals with abetalipoproteinemia may experience a wide variety of symptoms affecting various parts of the body including the gastrointestinal tract, neurological system, eyes and blood.Affected infants often present with symptoms relating to gastrointestinal disease, which occur secondary to poor fat absorption. Such symptoms include pale, bulky foul-smelling stools (steatorrhea), diarrhea, vomiting and swelling (distension) of the abdomen. Affected infants often fail to gain weight and grow at the expected rate (failure to thrive). These symptoms result from poor absorption of fat from the diet. In addition to poor fat absorption, fat-soluble vitamins such as vitamins A, E, and K are also poorly absorbed potentially resulting in fat-soluble vitamin deficiency. Further, patients do not have any apoB-containing lipoproteins in their plasma, and consequently they have very low levels of triglycerides, cholesterol, phospholipids and ceramides. Thus, lipids and fat-soluble vitamins are inadequately transported throughout the blood stream. Some patients may also have reduced non-apoB-containing lipoproteins (high density lipoproteins) or apoA1 levels in their plasma.Between the ages of 2 and 20 years, a variety of neurological complications occur that resemble spinocerebellar degeneration, a general term for a group of disorders characterized by progressive impairment of the ability to coordinate voluntary movements due to degeneration of certain structures in the brain (cerebellar ataxia). Ataxia results in a lack of coordination and, eventually, difficulty in controlling the range of voluntary movement (dysmetria). Additional neurological symptoms include loss of deep tendon reflexes such as at the kneecap, difficulty speaking (dysarthria), tremors, motor tics and muscle weakness. Intelligence is usually normal, but developmental delays or intellectual disability has been reported.In some people, the damage or malfunction of the peripheral nervous system (peripheral neuropathy) may occur. The peripheral nervous system contains all the nerves outside of the central nervous system. The associated symptoms can vary greatly from one person to another but can include weakness of the muscles of the arms and legs or abnormal sensations such as tingling (paresthesias), burning or numbness.Some individuals with abetalipoproteinemia may develop skeletal abnormalities including backward curvature (lordosis) or backward and sideways curvature of the spine (kyphoscoliosis), a highly arched foot (pes cavus) or clubfoot. These skeletal abnormalities may result from muscle imbalances during crucial stages of bone development. Eventually, affected individuals may be unable to stand or to walk unaided due to progressive neurological and skeletal abnormalities.Some affected individuals may develop a rare eye condition called retinitis pigmentosa in which progressive degeneration of the nerve-rich membrane lining the eyes (retina) results in tunnel vision (loss of peripheral vision), loss of color vision and night blindness. Affected individuals may eventually develop loss of visual acuity. Retinitis pigmentosa occurs most often around the age of 10 years and may be due to vitamin A and/or E deficiency. If left untreated, visual acuity may deteriorate to virtual blindness by the fourth decade of life.Less often, additional symptoms that affect the eyes have been reported including rapid, involuntary eye movements (nystagmus), irregular concentric and some fine radial streaks (algioid streaks), droopy upper eyelid (ptosis), crossed eyes (strabismus), unequal size of the pupils (anisocoria) and weakness or paralysis of muscles that control eye movements (ophthalmoplegia).Individuals with abetalipoproteinemia may also have blood abnormalities including a condition called acanthocytosis in which deformed (i.e., burr-shaped) red blood cells (acanthocytes) are present in the body. Acanthocytosis may result in low levels of circulating red blood cells (anemia). Anemia may result in tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, palpitations, headaches and pale skin color. Additional blood abnormalities may be due to vitamin K deficiency. Blood clotting factor levels may be reduced resulting in bleeding tendencies such as severe gastrointestinal bleeding.Patients may have fatty liver, which can cause liver damage. In rare cases, fibrosis or scarring of the liver (cirrhosis) has also been reported. | Symptoms of Abetalipoproteinemia. Individuals with abetalipoproteinemia may experience a wide variety of symptoms affecting various parts of the body including the gastrointestinal tract, neurological system, eyes and blood.Affected infants often present with symptoms relating to gastrointestinal disease, which occur secondary to poor fat absorption. Such symptoms include pale, bulky foul-smelling stools (steatorrhea), diarrhea, vomiting and swelling (distension) of the abdomen. Affected infants often fail to gain weight and grow at the expected rate (failure to thrive). These symptoms result from poor absorption of fat from the diet. In addition to poor fat absorption, fat-soluble vitamins such as vitamins A, E, and K are also poorly absorbed potentially resulting in fat-soluble vitamin deficiency. Further, patients do not have any apoB-containing lipoproteins in their plasma, and consequently they have very low levels of triglycerides, cholesterol, phospholipids and ceramides. Thus, lipids and fat-soluble vitamins are inadequately transported throughout the blood stream. Some patients may also have reduced non-apoB-containing lipoproteins (high density lipoproteins) or apoA1 levels in their plasma.Between the ages of 2 and 20 years, a variety of neurological complications occur that resemble spinocerebellar degeneration, a general term for a group of disorders characterized by progressive impairment of the ability to coordinate voluntary movements due to degeneration of certain structures in the brain (cerebellar ataxia). Ataxia results in a lack of coordination and, eventually, difficulty in controlling the range of voluntary movement (dysmetria). Additional neurological symptoms include loss of deep tendon reflexes such as at the kneecap, difficulty speaking (dysarthria), tremors, motor tics and muscle weakness. Intelligence is usually normal, but developmental delays or intellectual disability has been reported.In some people, the damage or malfunction of the peripheral nervous system (peripheral neuropathy) may occur. The peripheral nervous system contains all the nerves outside of the central nervous system. The associated symptoms can vary greatly from one person to another but can include weakness of the muscles of the arms and legs or abnormal sensations such as tingling (paresthesias), burning or numbness.Some individuals with abetalipoproteinemia may develop skeletal abnormalities including backward curvature (lordosis) or backward and sideways curvature of the spine (kyphoscoliosis), a highly arched foot (pes cavus) or clubfoot. These skeletal abnormalities may result from muscle imbalances during crucial stages of bone development. Eventually, affected individuals may be unable to stand or to walk unaided due to progressive neurological and skeletal abnormalities.Some affected individuals may develop a rare eye condition called retinitis pigmentosa in which progressive degeneration of the nerve-rich membrane lining the eyes (retina) results in tunnel vision (loss of peripheral vision), loss of color vision and night blindness. Affected individuals may eventually develop loss of visual acuity. Retinitis pigmentosa occurs most often around the age of 10 years and may be due to vitamin A and/or E deficiency. If left untreated, visual acuity may deteriorate to virtual blindness by the fourth decade of life.Less often, additional symptoms that affect the eyes have been reported including rapid, involuntary eye movements (nystagmus), irregular concentric and some fine radial streaks (algioid streaks), droopy upper eyelid (ptosis), crossed eyes (strabismus), unequal size of the pupils (anisocoria) and weakness or paralysis of muscles that control eye movements (ophthalmoplegia).Individuals with abetalipoproteinemia may also have blood abnormalities including a condition called acanthocytosis in which deformed (i.e., burr-shaped) red blood cells (acanthocytes) are present in the body. Acanthocytosis may result in low levels of circulating red blood cells (anemia). Anemia may result in tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, palpitations, headaches and pale skin color. Additional blood abnormalities may be due to vitamin K deficiency. Blood clotting factor levels may be reduced resulting in bleeding tendencies such as severe gastrointestinal bleeding.Patients may have fatty liver, which can cause liver damage. In rare cases, fibrosis or scarring of the liver (cirrhosis) has also been reported. | 3 | Abetalipoproteinemia |
nord_3_2 | Causes of Abetalipoproteinemia | Abetalipoproteinemia is caused by changes (mutations or variants) in the MTTP gene and is inherited as an autosomal recessive genetic condition. Genetic diseases are determined by two alleles, one received from the father and one from the mother. An allele refers to one of two or more alternate forms of a particular gene.Recessive genetic disorders occur when an individual inherits two abnormal alleles for the same trait from each parent. If an individual receives one normal allele and one allele for the disease, the person will be a carrier for the disease, but usually will not show symptoms. When both parents are carriers, then the risk of an affected child is 25%. 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%.All individuals carry some abnormal genes. Parents who are close relatives have a higher chance than unrelated parents of both carrying the same altered gene. Some individuals with abetalipoproteinemia have had parents who were blood relatives (consanguineous). This increases the risk of having children with a recessive genetic disorder.The MTTP gene contains instructions for producing (encoding) a protein known as microsomal triglyceride transfer protein (MTTP or MTP). This protein is required for the proper assembly and secretion of apoB-containing lipoproteins in the liver and intestines. Variants in the MTTP gene lead to low levels of functional MTP, which in turn, hinders the liver and intestines from making and secreting apoB-containing lipoproteins. This, in turn, results in the inability to properly absorb and transport fats and fat-soluble vitamins throughout the body. Therefore, a deficiency in MTP results in the absence of lipoproteins such as very low-density lipoproteins (VLDLs), low density lipoproteins (LDLs) and chylomicrons in the blood. Lipoproteins are macromolecular complexes consisting of lipids and proteins. These lipid and protein complexes act as transporters that carry fats and fat-soluble vitamins (e.g., vitamin E) throughout the body. The symptoms of abetalipoproteinemia are caused by the lack of these apoB-containing lipoproteins in the plasma and fat-soluble vitamin deficiency.Recent research has determined that MTP is also involved in the maturation of a family of proteins known as CD1, which are involved in lipid antigen-presentation to immune cells. MTP has also been shown to modulate fat hydrolysis in adipose tissue by inhibiting adipose triglyceride lipase. More research is necessary to determine the complete functions of the MTP protein and the exact underlying mechanisms that cause disease in abetalipoproteinemia.Additionally, several studies have shown that MTP is expressed in the heart and is involved in exporting lipids out of the heart. Low levels of MTP may lead to fat accumulation in the heart and affect heart function. | Causes of Abetalipoproteinemia. Abetalipoproteinemia is caused by changes (mutations or variants) in the MTTP gene and is inherited as an autosomal recessive genetic condition. Genetic diseases are determined by two alleles, one received from the father and one from the mother. An allele refers to one of two or more alternate forms of a particular gene.Recessive genetic disorders occur when an individual inherits two abnormal alleles for the same trait from each parent. If an individual receives one normal allele and one allele for the disease, the person will be a carrier for the disease, but usually will not show symptoms. When both parents are carriers, then the risk of an affected child is 25%. 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%.All individuals carry some abnormal genes. Parents who are close relatives have a higher chance than unrelated parents of both carrying the same altered gene. Some individuals with abetalipoproteinemia have had parents who were blood relatives (consanguineous). This increases the risk of having children with a recessive genetic disorder.The MTTP gene contains instructions for producing (encoding) a protein known as microsomal triglyceride transfer protein (MTTP or MTP). This protein is required for the proper assembly and secretion of apoB-containing lipoproteins in the liver and intestines. Variants in the MTTP gene lead to low levels of functional MTP, which in turn, hinders the liver and intestines from making and secreting apoB-containing lipoproteins. This, in turn, results in the inability to properly absorb and transport fats and fat-soluble vitamins throughout the body. Therefore, a deficiency in MTP results in the absence of lipoproteins such as very low-density lipoproteins (VLDLs), low density lipoproteins (LDLs) and chylomicrons in the blood. Lipoproteins are macromolecular complexes consisting of lipids and proteins. These lipid and protein complexes act as transporters that carry fats and fat-soluble vitamins (e.g., vitamin E) throughout the body. The symptoms of abetalipoproteinemia are caused by the lack of these apoB-containing lipoproteins in the plasma and fat-soluble vitamin deficiency.Recent research has determined that MTP is also involved in the maturation of a family of proteins known as CD1, which are involved in lipid antigen-presentation to immune cells. MTP has also been shown to modulate fat hydrolysis in adipose tissue by inhibiting adipose triglyceride lipase. More research is necessary to determine the complete functions of the MTP protein and the exact underlying mechanisms that cause disease in abetalipoproteinemia.Additionally, several studies have shown that MTP is expressed in the heart and is involved in exporting lipids out of the heart. Low levels of MTP may lead to fat accumulation in the heart and affect heart function. | 3 | Abetalipoproteinemia |
nord_3_3 | Affects of Abetalipoproteinemia | The exact prevalence and incidence of abetalipoproteinemia is unknown, but it is estimated to affect less than 1 in 1,000,000 people in the general population. Abetalipoproteinemia affects both males and females. There are no known racial or ethnic preferences for the disorder. Abetalipoproteinemia is more prevalent in populations with a high incidence of consanguineous marriages. Symptoms usually become apparent during infancy. | Affects of Abetalipoproteinemia. The exact prevalence and incidence of abetalipoproteinemia is unknown, but it is estimated to affect less than 1 in 1,000,000 people in the general population. Abetalipoproteinemia affects both males and females. There are no known racial or ethnic preferences for the disorder. Abetalipoproteinemia is more prevalent in populations with a high incidence of consanguineous marriages. Symptoms usually become apparent during infancy. | 3 | Abetalipoproteinemia |
nord_3_4 | Related disorders of Abetalipoproteinemia | Symptoms of the following disorders can be similar to those of abetalipoproteinemia. Comparisons may be useful for a differential diagnosis.Familial hypobetalipoproteinemia due to secretion defect 2 (FHBL-SD2) is a rare genetic disorder that is highly variable in its expression and is due to variants in the APOB gene. Severe cases are nearly indistinguishable from individuals with abetalipoproteinemia. Symptoms can include steatorrhea, ataxia, retinitis pigmentosa and neuropathy. Acanthocytosis occurs in some patients as well. Treatment of individuals with FHBL is similar to treatment for individuals with abetalipoproteinemia. FHBL-SD2 is inherited in an autosomal dominant pattern. Contrary to abetalipoproteinemia, the presence of only one altered allele is sufficient to display symptoms of the disease.Celiac disease is a digestive disorder characterized by intolerance to dietary gluten, which is a protein found in wheat, rye, and barley. Consumption of gluten leads to abnormal changes of the mucous membrane (mucosa) of the small intestine, impairing its ability to properly absorb fats and additional nutrients during digestion (intestinal malabsorption). Symptom onset may occur during childhood or adulthood. In affected children, such symptoms may include diarrhea, vomiting, weight loss or lack of weight gain, painful abdominal bloating, irritability and/or other abnormalities. Affected adults may have diarrhea or constipation; abdominal cramping and bloating; abnormally bulky, pale, frothy stools that contain increased levels of fat (steatorrhea); weight loss; anemia; muscle cramping; bone pain; exhaustion (lassitude); and/or other symptoms and indications. Although the exact cause of celiac disease is unknown, genetic, immunologic, and environmental factors are thought to play some role. Friedreich’s ataxia (FRDA) is a genetic, progressive, neurodegerative movement disorder, with a mean age of onset between 10 and 15 years. Initial symptoms may include unsteady posture, frequent falling and progressive difficulty walking due to impaired ability to coordinate voluntary movements (ataxia). Affected individuals may also develop slurred speech (dysarthria), characteristic foot deformities; and irregular lateral or sideways curvature of the spine (scoliosis). FRDA is often associated with cardiomyopathy, a disease of cardiac muscle that may lead to heart failure, which could present as shortness of breath upon exertion and chest pain. Some individuals may also experience irregularities in heart rhythm (cardiac arrhythmias). Some individuals may develop diabetes mellitus. The symptoms and clinical findings associated with FRDA result primarily from degenerative changes in the sensory nerve fibers at the point where they enter the spinal cord in structures known as dorsal root ganglia. This results in secondary degeneration of nerve fibers in the spinal cord which leads to a deficiency of sensory signals to the cerebellum, the part of the brain that helps to coordinate voluntary movements. FRDA is caused by variants in the FXN gene and follows autosomal recessive inheritance. (For more information on this disorder, choose “Friedreich’s Ataxia” as your search term in the Rare Disease Database.)Ataxia with vitamin E deficiency (AVED) is a rare inherited neurodegenerative disorder characterized by impaired ability to coordinate voluntary movements (ataxia) and disease of the peripheral nervous system (peripheral neuropathy). AVED is a progressive disorder that can affect many different systems of the body (multisystem disorder). Specific symptoms vary from person to person. In addition to neurological symptoms, affected individuals may experience eye abnormalities, disorders affecting the heart muscles (cardiomyopathy) and abnormal curvature of the spine (scoliosis). AVED is extremely similar to a more common disorder known as Friedreich’s ataxia. AVED is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “Ataxia with Vitamin E Deficiency” as your search term in the Rare Disease Database.) | Related disorders of Abetalipoproteinemia. Symptoms of the following disorders can be similar to those of abetalipoproteinemia. Comparisons may be useful for a differential diagnosis.Familial hypobetalipoproteinemia due to secretion defect 2 (FHBL-SD2) is a rare genetic disorder that is highly variable in its expression and is due to variants in the APOB gene. Severe cases are nearly indistinguishable from individuals with abetalipoproteinemia. Symptoms can include steatorrhea, ataxia, retinitis pigmentosa and neuropathy. Acanthocytosis occurs in some patients as well. Treatment of individuals with FHBL is similar to treatment for individuals with abetalipoproteinemia. FHBL-SD2 is inherited in an autosomal dominant pattern. Contrary to abetalipoproteinemia, the presence of only one altered allele is sufficient to display symptoms of the disease.Celiac disease is a digestive disorder characterized by intolerance to dietary gluten, which is a protein found in wheat, rye, and barley. Consumption of gluten leads to abnormal changes of the mucous membrane (mucosa) of the small intestine, impairing its ability to properly absorb fats and additional nutrients during digestion (intestinal malabsorption). Symptom onset may occur during childhood or adulthood. In affected children, such symptoms may include diarrhea, vomiting, weight loss or lack of weight gain, painful abdominal bloating, irritability and/or other abnormalities. Affected adults may have diarrhea or constipation; abdominal cramping and bloating; abnormally bulky, pale, frothy stools that contain increased levels of fat (steatorrhea); weight loss; anemia; muscle cramping; bone pain; exhaustion (lassitude); and/or other symptoms and indications. Although the exact cause of celiac disease is unknown, genetic, immunologic, and environmental factors are thought to play some role. Friedreich’s ataxia (FRDA) is a genetic, progressive, neurodegerative movement disorder, with a mean age of onset between 10 and 15 years. Initial symptoms may include unsteady posture, frequent falling and progressive difficulty walking due to impaired ability to coordinate voluntary movements (ataxia). Affected individuals may also develop slurred speech (dysarthria), characteristic foot deformities; and irregular lateral or sideways curvature of the spine (scoliosis). FRDA is often associated with cardiomyopathy, a disease of cardiac muscle that may lead to heart failure, which could present as shortness of breath upon exertion and chest pain. Some individuals may also experience irregularities in heart rhythm (cardiac arrhythmias). Some individuals may develop diabetes mellitus. The symptoms and clinical findings associated with FRDA result primarily from degenerative changes in the sensory nerve fibers at the point where they enter the spinal cord in structures known as dorsal root ganglia. This results in secondary degeneration of nerve fibers in the spinal cord which leads to a deficiency of sensory signals to the cerebellum, the part of the brain that helps to coordinate voluntary movements. FRDA is caused by variants in the FXN gene and follows autosomal recessive inheritance. (For more information on this disorder, choose “Friedreich’s Ataxia” as your search term in the Rare Disease Database.)Ataxia with vitamin E deficiency (AVED) is a rare inherited neurodegenerative disorder characterized by impaired ability to coordinate voluntary movements (ataxia) and disease of the peripheral nervous system (peripheral neuropathy). AVED is a progressive disorder that can affect many different systems of the body (multisystem disorder). Specific symptoms vary from person to person. In addition to neurological symptoms, affected individuals may experience eye abnormalities, disorders affecting the heart muscles (cardiomyopathy) and abnormal curvature of the spine (scoliosis). AVED is extremely similar to a more common disorder known as Friedreich’s ataxia. AVED is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “Ataxia with Vitamin E Deficiency” as your search term in the Rare Disease Database.) | 3 | Abetalipoproteinemia |
nord_3_5 | Diagnosis of Abetalipoproteinemia | A diagnosis of abetalipoproteinemia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including tests to measure lipids (triglyceride and cholesterol) and apoB-containing lipoproteins in the plasma, determine the form and structure (morphology) of red blood cells and an eye (ophthalmological) exam.Blood tests will detect low levels of both lipids, such as cholesterol and triglycerides, and lipid-soluble vitamins such as A, E, and K. ApoB-containing lipoproteins, such as chylomicrons or very low-density lipoproteins, are not detectable in the plasma.The identification of malformed red blood cells (acanthocytosis) may also be detected by blood tests.A complete neurological assessment, an eye examination, an endoscopy and a liver (hepatic) ultrasound may be performed to evaluate the presence of potentially associated symptoms.Molecular genetic testing to detect pathogenic variants in the MTTP gene is available to confirm the diagnosis. | Diagnosis of Abetalipoproteinemia. A diagnosis of abetalipoproteinemia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including tests to measure lipids (triglyceride and cholesterol) and apoB-containing lipoproteins in the plasma, determine the form and structure (morphology) of red blood cells and an eye (ophthalmological) exam.Blood tests will detect low levels of both lipids, such as cholesterol and triglycerides, and lipid-soluble vitamins such as A, E, and K. ApoB-containing lipoproteins, such as chylomicrons or very low-density lipoproteins, are not detectable in the plasma.The identification of malformed red blood cells (acanthocytosis) may also be detected by blood tests.A complete neurological assessment, an eye examination, an endoscopy and a liver (hepatic) ultrasound may be performed to evaluate the presence of potentially associated symptoms.Molecular genetic testing to detect pathogenic variants in the MTTP gene is available to confirm the diagnosis. | 3 | Abetalipoproteinemia |
nord_3_6 | Therapies of Abetalipoproteinemia | Treatment
The treatment of abetalipoproteinemia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Neurologists, liver specialists (hepatologists), eye specialists (ophthalmologists), specialists in the study of fats (lipidologists), gastroenterologists, nutritionists and other healthcare professionals may need to plan an affected child’s treatment systematically, comprehensively and collaboratively. Patients should be closely monitored every 6-12 months. Neurological and eye exams should be performed routinely to measure any ophthalmological or neurological deteriorations. Further, amino transaminases in the blood should be measured every year to determine if there is liver damage. Hepatic ultrasound can be performed to detect the presence of fatty liver. Echocardiography should be performed every three years to ensure the heart is working properly.Most affected individuals respond to dietary therapy consisting of a diet low in long-chain saturated fatty acids. The reduction of the intake of dietary fats generally relieves gastrointestinal symptoms. Patients should receive frequent dietary counseling. Diets in infants may be supplemented with medium chain fatty acids, which can be transported in the blood without apoB-containing lipoproteins, to promote normal growth and development.The oral administration of high doses of fat-soluble vitamins (e.g., A, E, K) helps to prevent or improve many of the symptoms associated with abetalipoproteinemia. For example, treatment with vitamin E (i.e., tocopherol therapy) and vitamin A supplementation may prevent the neurological and retinal complications associated with abetalipoproteinemia. Vitamin D supplementation may help alleviate some of the symptoms associated with bone growth. Blood levels of fat-soluble vitamins should be measured at each follow up because the blood levels do not always correlate with the amount of vitamins ingested. Doses should be adjusted based on the results of blood panels, neurological exams, and ophthalmological exams. It should be noted that vitamin E levels are not reliably measurable in these patients even after high dose supplementations. Despite this, vitamin E therapy should continue in these patients. The prognosis of patients is highly variable. Early detection, treatment and fat-soluble vitamin supplementation can help curtail some of the neurological and ophthalmological deficiencies. Patients should be carefully monitored if receiving fat soluble drug treatments (i.e., for diseases unrelated to abetalipoproteinemia) as their pharmacokinetics, absorption and transport may also be affected. Additional treatment is symptomatic and supportive.Genetic counseling is recommended for families of children with abetalipoproteinemia. | Therapies of Abetalipoproteinemia. Treatment
The treatment of abetalipoproteinemia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Neurologists, liver specialists (hepatologists), eye specialists (ophthalmologists), specialists in the study of fats (lipidologists), gastroenterologists, nutritionists and other healthcare professionals may need to plan an affected child’s treatment systematically, comprehensively and collaboratively. Patients should be closely monitored every 6-12 months. Neurological and eye exams should be performed routinely to measure any ophthalmological or neurological deteriorations. Further, amino transaminases in the blood should be measured every year to determine if there is liver damage. Hepatic ultrasound can be performed to detect the presence of fatty liver. Echocardiography should be performed every three years to ensure the heart is working properly.Most affected individuals respond to dietary therapy consisting of a diet low in long-chain saturated fatty acids. The reduction of the intake of dietary fats generally relieves gastrointestinal symptoms. Patients should receive frequent dietary counseling. Diets in infants may be supplemented with medium chain fatty acids, which can be transported in the blood without apoB-containing lipoproteins, to promote normal growth and development.The oral administration of high doses of fat-soluble vitamins (e.g., A, E, K) helps to prevent or improve many of the symptoms associated with abetalipoproteinemia. For example, treatment with vitamin E (i.e., tocopherol therapy) and vitamin A supplementation may prevent the neurological and retinal complications associated with abetalipoproteinemia. Vitamin D supplementation may help alleviate some of the symptoms associated with bone growth. Blood levels of fat-soluble vitamins should be measured at each follow up because the blood levels do not always correlate with the amount of vitamins ingested. Doses should be adjusted based on the results of blood panels, neurological exams, and ophthalmological exams. It should be noted that vitamin E levels are not reliably measurable in these patients even after high dose supplementations. Despite this, vitamin E therapy should continue in these patients. The prognosis of patients is highly variable. Early detection, treatment and fat-soluble vitamin supplementation can help curtail some of the neurological and ophthalmological deficiencies. Patients should be carefully monitored if receiving fat soluble drug treatments (i.e., for diseases unrelated to abetalipoproteinemia) as their pharmacokinetics, absorption and transport may also be affected. Additional treatment is symptomatic and supportive.Genetic counseling is recommended for families of children with abetalipoproteinemia. | 3 | Abetalipoproteinemia |
nord_4_0 | Overview of Ablepharon-Macrostomia Syndrome | SummaryAblepharon-macrostomia syndrome (AMS) is a rare genetic disorder characterized by absent or underdeveloped eyelids (ablepharon or microblepharon) and a wide mouth (macrostomia). Characteristics mainly involve the face and skin and rarely involve the internal organs (viscera). Common signs and symptoms in addition to eye and mouth findings include low-set ears with attached earlobes, distortion or fusion of the digits (syndactyly or camptodactyly), bulging cheeks, absent or very small nipples, wrinkled and redundant skin, absent or sparse hair and genital malformations. Other, less frequently reported findings include umbilical abnormalities, growth delay and intellectual disability. AMS has been grouped within the category of diseases called ectodermal dysplasias (genetic disorders that involve defects in the skin, hair, nails, sweat glands, and/or teeth) but because many characteristics involve tissues that are not derived from the ectoderm, it would be better to define AMS as a genuine malformation syndrome. AMS is caused by changes (mutations) in the TWIST2 gene. The pattern of inheritance is autosomal dominant, and most cases arise as spontaneous mutations, so occur sporadically.Mutations in TWIST2 also cause the Barber Say syndrome and Setleis syndrome, which have very similar features. Indeed, it has been suggested the three disorders in fact form a continuum (De Maria 2016).IntroductionABS was originally described in 1977 (McCarthy and West 1977) in two unrelated boys. Advances have been made in the surgical techniques that improve visual function and cosmetic appearance. | Overview of Ablepharon-Macrostomia Syndrome. SummaryAblepharon-macrostomia syndrome (AMS) is a rare genetic disorder characterized by absent or underdeveloped eyelids (ablepharon or microblepharon) and a wide mouth (macrostomia). Characteristics mainly involve the face and skin and rarely involve the internal organs (viscera). Common signs and symptoms in addition to eye and mouth findings include low-set ears with attached earlobes, distortion or fusion of the digits (syndactyly or camptodactyly), bulging cheeks, absent or very small nipples, wrinkled and redundant skin, absent or sparse hair and genital malformations. Other, less frequently reported findings include umbilical abnormalities, growth delay and intellectual disability. AMS has been grouped within the category of diseases called ectodermal dysplasias (genetic disorders that involve defects in the skin, hair, nails, sweat glands, and/or teeth) but because many characteristics involve tissues that are not derived from the ectoderm, it would be better to define AMS as a genuine malformation syndrome. AMS is caused by changes (mutations) in the TWIST2 gene. The pattern of inheritance is autosomal dominant, and most cases arise as spontaneous mutations, so occur sporadically.Mutations in TWIST2 also cause the Barber Say syndrome and Setleis syndrome, which have very similar features. Indeed, it has been suggested the three disorders in fact form a continuum (De Maria 2016).IntroductionABS was originally described in 1977 (McCarthy and West 1977) in two unrelated boys. Advances have been made in the surgical techniques that improve visual function and cosmetic appearance. | 4 | Ablepharon-Macrostomia Syndrome |
nord_4_1 | Symptoms of Ablepharon-Macrostomia Syndrome | AMS is apparent at birth from features of the head and facial (craniofacial) region. The absence of, or underdevelopment of eyelids and a wide mouth are cardinal features. The abnormalities around the eyes, poor eyelid development and absent eyebrows and eyelashes cause the upper and lower lids to turn outwards (ectropion), exposing the inner mucous membranes and prohibiting complete closure of the eyes (lagophthalmos). This results in dry eyes and corneal clouding, which, if left untreated, can lead to light sensitivity (photophobia) and vision loss. Other potential eye issues include inability to produce tears (alacrimia); repeated involuntary eye movements (nystagmus); an unequal, inward deviation of the eyes (strabismus); and/or complete or partial separation of the retina, the nerve-rich membrane lining the inner layer of the back of the eye, from membranes (choroids) in the outer layer (detached retina).Infants affected with AMS may have additional, characteristic craniofacial features. Prominent features include a wide nasal bridge, long groove between the nose and lips (philtrum), flared nostrils and thick-flared edges of nostrils (alae nasi). The cheeks superolateral to the corners of mouth may bulge; a sign called “cheek pads”. In addition, in some patients, the zygomatic arches of the skull may be absent. Zygomotic arches are the two bony arches spanning from the lower portion of the orbits of the eyes, across the prominence of the cheekbones to the bones forming part of the lower skull. A small chin, low set ears with attached earlobes and impaired hearing can also be present.The absence of the soft, downy hair at birth that typically covers most of the body (lanugo), sparse scalp hair, redundant and wrinkled skin, small or absent nipples and underdeveloped genitalia can be found. Unusually formed genitalia can include undescended testis (cryptochordism), urethral opening on the underside of the penis (hypospadias), and a small penis in males or small labia minora in females. Sometimes there is an abdominal hernia, so protrusion of portions of the large intestine through an abnormal opening in the abdominal wall which is covered by skin. At the extremities, it is common to find syndactyly and camptodactyly; the skin over the hands may be abnormally loose, the fingers may be permanently flexed due to tight skin over the finger joints. While physical growth is generally undisturbed, cognitive development may be delayed. It is possible that many of these signs and symptoms do not capture the entirety of the syndrome, as there are relatively few cases and presentations vary in severity from person to person. | Symptoms of Ablepharon-Macrostomia Syndrome. AMS is apparent at birth from features of the head and facial (craniofacial) region. The absence of, or underdevelopment of eyelids and a wide mouth are cardinal features. The abnormalities around the eyes, poor eyelid development and absent eyebrows and eyelashes cause the upper and lower lids to turn outwards (ectropion), exposing the inner mucous membranes and prohibiting complete closure of the eyes (lagophthalmos). This results in dry eyes and corneal clouding, which, if left untreated, can lead to light sensitivity (photophobia) and vision loss. Other potential eye issues include inability to produce tears (alacrimia); repeated involuntary eye movements (nystagmus); an unequal, inward deviation of the eyes (strabismus); and/or complete or partial separation of the retina, the nerve-rich membrane lining the inner layer of the back of the eye, from membranes (choroids) in the outer layer (detached retina).Infants affected with AMS may have additional, characteristic craniofacial features. Prominent features include a wide nasal bridge, long groove between the nose and lips (philtrum), flared nostrils and thick-flared edges of nostrils (alae nasi). The cheeks superolateral to the corners of mouth may bulge; a sign called “cheek pads”. In addition, in some patients, the zygomatic arches of the skull may be absent. Zygomotic arches are the two bony arches spanning from the lower portion of the orbits of the eyes, across the prominence of the cheekbones to the bones forming part of the lower skull. A small chin, low set ears with attached earlobes and impaired hearing can also be present.The absence of the soft, downy hair at birth that typically covers most of the body (lanugo), sparse scalp hair, redundant and wrinkled skin, small or absent nipples and underdeveloped genitalia can be found. Unusually formed genitalia can include undescended testis (cryptochordism), urethral opening on the underside of the penis (hypospadias), and a small penis in males or small labia minora in females. Sometimes there is an abdominal hernia, so protrusion of portions of the large intestine through an abnormal opening in the abdominal wall which is covered by skin. At the extremities, it is common to find syndactyly and camptodactyly; the skin over the hands may be abnormally loose, the fingers may be permanently flexed due to tight skin over the finger joints. While physical growth is generally undisturbed, cognitive development may be delayed. It is possible that many of these signs and symptoms do not capture the entirety of the syndrome, as there are relatively few cases and presentations vary in severity from person to person. | 4 | Ablepharon-Macrostomia Syndrome |
nord_4_2 | Causes of Ablepharon-Macrostomia Syndrome | AMS is caused by changes (mutations) in the gene called TWIST2. The mutation has often occurred spontaneously in the affected individual (so not inherited from one of the parents) but inheritance from one of the parents in an autosomal dominant pattern has been reported. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. | Causes of Ablepharon-Macrostomia Syndrome. AMS is caused by changes (mutations) in the gene called TWIST2. The mutation has often occurred spontaneously in the affected individual (so not inherited from one of the parents) but inheritance from one of the parents in an autosomal dominant pattern has been reported. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. | 4 | Ablepharon-Macrostomia Syndrome |
nord_4_3 | Affects of Ablepharon-Macrostomia Syndrome | Between 1977 and 2020, there have been 16 documented cases of AMS in the literature and a worldwide prevalence of less than <1/1,000,000. No apparent sex or ethnic disparity exists, and males and females present with similar signs and symptoms.
| Affects of Ablepharon-Macrostomia Syndrome. Between 1977 and 2020, there have been 16 documented cases of AMS in the literature and a worldwide prevalence of less than <1/1,000,000. No apparent sex or ethnic disparity exists, and males and females present with similar signs and symptoms.
| 4 | Ablepharon-Macrostomia Syndrome |
nord_4_4 | Related disorders of Ablepharon-Macrostomia Syndrome | Barber-Say syndrome (BSS) and Setleis syndrome (also known as focal facial dermal dysplasia 3) fall within the spectrum of disorders resulting from TWIST2 mutations. Key features that differentiate BSS from AMS are presence of excessive hair (hypertrichosis), less marked eye findings, narrow ear canals and relatively normal hands and genitalia. Setleis syndrome presents with some overlap to AMS and BSS but is typically milder and can be differentiated by the finding of inward folding eyelids (entropion), bitemporal narrowing and absence of cheek pads. | Related disorders of Ablepharon-Macrostomia Syndrome. Barber-Say syndrome (BSS) and Setleis syndrome (also known as focal facial dermal dysplasia 3) fall within the spectrum of disorders resulting from TWIST2 mutations. Key features that differentiate BSS from AMS are presence of excessive hair (hypertrichosis), less marked eye findings, narrow ear canals and relatively normal hands and genitalia. Setleis syndrome presents with some overlap to AMS and BSS but is typically milder and can be differentiated by the finding of inward folding eyelids (entropion), bitemporal narrowing and absence of cheek pads. | 4 | Ablepharon-Macrostomia Syndrome |
nord_4_5 | Diagnosis of Ablepharon-Macrostomia Syndrome | A diagnosis of AMS may be suspected at birth based upon a thorough clinical evaluation, a detailed patient and family history and identification of characteristic physical findings; typically, a reliable diagnosis is possible on clinical grounds only. Differentiation from BSS and Setleis syndrome may sometimes be difficult. The clinical diagnosis can be confirmed by molecular genetic testing for mutations in TWIST2.Clinical Testing and Work-Up
Computerized tomography (CT) scanning may be helpful in demonstrating absence of the zygomatic arch, improper union of portions of the upper and lower jawbones (maxillary and mandibular prominences), although this rarely will have consequences for management. Thorough examination and specialized testing may be conducted by eye specialists (ophthalmologists) to appropriately characterize eyelid characteristics, detect any additional or associated eye abnormalities and ensure appropriate preventive steps or treatment. | Diagnosis of Ablepharon-Macrostomia Syndrome. A diagnosis of AMS may be suspected at birth based upon a thorough clinical evaluation, a detailed patient and family history and identification of characteristic physical findings; typically, a reliable diagnosis is possible on clinical grounds only. Differentiation from BSS and Setleis syndrome may sometimes be difficult. The clinical diagnosis can be confirmed by molecular genetic testing for mutations in TWIST2.Clinical Testing and Work-Up
Computerized tomography (CT) scanning may be helpful in demonstrating absence of the zygomatic arch, improper union of portions of the upper and lower jawbones (maxillary and mandibular prominences), although this rarely will have consequences for management. Thorough examination and specialized testing may be conducted by eye specialists (ophthalmologists) to appropriately characterize eyelid characteristics, detect any additional or associated eye abnormalities and ensure appropriate preventive steps or treatment. | 4 | Ablepharon-Macrostomia Syndrome |
nord_4_6 | Therapies of Ablepharon-Macrostomia Syndrome | Treatment
The currently accepted treatment is corrective and reconstructive surgery aimed at preserving vision and reducing visual complications such as corneal clouding (opacification) during the neonatal period. Providing supportive therapy such as lubricant eye drops early on may improve symptoms of eye dryness. Additional surgery at a later age can be aimed at improving function and appearance. Severe ectropion and underdevelopment of eyelids is managed with the transfer of skin flaps to the lid region, thus improving the ability to close the eyes. A possible complication of this procedure is the inability to completely close the eyes (lagophthalmos). Corrective surgery can also be pursued for the fingers, skin, or ears, but there is minimal evidence to support this. These surgical procedures include local flaps, face-lift procedures, forehead lifting, Botox injections, fat grafting, orthognathic surgery and nasal reconstruction with rib cartilage grafts (De Maria 2016). These procedures may be riskier in younger individuals because craniofacial growth may be impaired. Psychosocial support for children with AMS is also important as they grow and face the societal pressures related to physical appearance. Receiving care from a well-informed team of healthcare providers may be beneficial, as they are able to offer care for both the medical and psychosocial aspects of the condition. Testimonies from individuals with AMS report positive experiences from corrective surgery and emphasize the importance of building self-esteem and having continued support from family members. Despite the challenges that are posed by this condition, patients report that they are aware it is mainly external and does not affect their intellectual and physical abilities or their capacity to pursue their ambitions (De Maria 2017).Genetic counseling is recommended for affected individuals and their families to understand the genetics and natural history of AMS, and to provide psychosocial support. | Therapies of Ablepharon-Macrostomia Syndrome. Treatment
The currently accepted treatment is corrective and reconstructive surgery aimed at preserving vision and reducing visual complications such as corneal clouding (opacification) during the neonatal period. Providing supportive therapy such as lubricant eye drops early on may improve symptoms of eye dryness. Additional surgery at a later age can be aimed at improving function and appearance. Severe ectropion and underdevelopment of eyelids is managed with the transfer of skin flaps to the lid region, thus improving the ability to close the eyes. A possible complication of this procedure is the inability to completely close the eyes (lagophthalmos). Corrective surgery can also be pursued for the fingers, skin, or ears, but there is minimal evidence to support this. These surgical procedures include local flaps, face-lift procedures, forehead lifting, Botox injections, fat grafting, orthognathic surgery and nasal reconstruction with rib cartilage grafts (De Maria 2016). These procedures may be riskier in younger individuals because craniofacial growth may be impaired. Psychosocial support for children with AMS is also important as they grow and face the societal pressures related to physical appearance. Receiving care from a well-informed team of healthcare providers may be beneficial, as they are able to offer care for both the medical and psychosocial aspects of the condition. Testimonies from individuals with AMS report positive experiences from corrective surgery and emphasize the importance of building self-esteem and having continued support from family members. Despite the challenges that are posed by this condition, patients report that they are aware it is mainly external and does not affect their intellectual and physical abilities or their capacity to pursue their ambitions (De Maria 2017).Genetic counseling is recommended for affected individuals and their families to understand the genetics and natural history of AMS, and to provide psychosocial support. | 4 | Ablepharon-Macrostomia Syndrome |
nord_5_0 | Overview of Acanthocheilonemiasis | Acanthocheilonemiasis is a rare tropical infectious disease caused by a parasite known as Acanthocheilonema perstans, which belongs to a group of parasitic diseases known as filarial diseases (nematode). This parasite is found, for the most part, in Africa. Symptoms of infection may include red, itchy skin (pruritis), abdominal and chest pain, muscular pain (myalgia), and areas of localized swelling (edema). In addition, the liver and spleen may become abnormally enlarged (hepatosplenomegaly). Laboratory testing may also reveal abnormally elevated levels of certain specialized white blood cells (eosinophilia). The parasite is transmitted through the bite of small flies (A. coliroides). | Overview of Acanthocheilonemiasis. Acanthocheilonemiasis is a rare tropical infectious disease caused by a parasite known as Acanthocheilonema perstans, which belongs to a group of parasitic diseases known as filarial diseases (nematode). This parasite is found, for the most part, in Africa. Symptoms of infection may include red, itchy skin (pruritis), abdominal and chest pain, muscular pain (myalgia), and areas of localized swelling (edema). In addition, the liver and spleen may become abnormally enlarged (hepatosplenomegaly). Laboratory testing may also reveal abnormally elevated levels of certain specialized white blood cells (eosinophilia). The parasite is transmitted through the bite of small flies (A. coliroides). | 5 | Acanthocheilonemiasis |
nord_5_1 | Symptoms of Acanthocheilonemiasis | Initially people with Acanthocheilonemiasis may have no symptoms. Symptoms occur more frequently in people who visit the areas where this parasite is common (endemic), than in people who are native to that area. One common laboratory finding, in people who have recently returned from infected areas, is abnormally high levels of specialized white blood cells (eosinophilia). Generally there are no symptoms associated with the laboratory finding.When symptoms appear they may include itchy skin (pruritis), abdominal pain, chest pain, muscle pains (myalgias), and/or areas of swelling under the skin (subcutaneous). Examination by a physician may reveal an abnormally enlarged liver and spleen (hepatosplenomegaly), and abnormally high levels of granular white blood cells (eosinophilia). The adult worm (nematode) may lodge in the tissues of the abdomen and chest causing inflammation and immune reactions. This may result in inflammation of the lining of the lungs (pleuritis) and/or the membranes that surround the heart (pericarditis).The early or prelarval form (microfilariae) of Acanthocheilonema perstans can be isolated from the blood from patients with Acanthocheilonemiasis. Generally this disease is diagnosed by the examination under a microscope of a thick blood smear taken from the patient. | Symptoms of Acanthocheilonemiasis. Initially people with Acanthocheilonemiasis may have no symptoms. Symptoms occur more frequently in people who visit the areas where this parasite is common (endemic), than in people who are native to that area. One common laboratory finding, in people who have recently returned from infected areas, is abnormally high levels of specialized white blood cells (eosinophilia). Generally there are no symptoms associated with the laboratory finding.When symptoms appear they may include itchy skin (pruritis), abdominal pain, chest pain, muscle pains (myalgias), and/or areas of swelling under the skin (subcutaneous). Examination by a physician may reveal an abnormally enlarged liver and spleen (hepatosplenomegaly), and abnormally high levels of granular white blood cells (eosinophilia). The adult worm (nematode) may lodge in the tissues of the abdomen and chest causing inflammation and immune reactions. This may result in inflammation of the lining of the lungs (pleuritis) and/or the membranes that surround the heart (pericarditis).The early or prelarval form (microfilariae) of Acanthocheilonema perstans can be isolated from the blood from patients with Acanthocheilonemiasis. Generally this disease is diagnosed by the examination under a microscope of a thick blood smear taken from the patient. | 5 | Acanthocheilonemiasis |
nord_5_2 | Causes of Acanthocheilonemiasis | Acanthocheilonemiasis is a rare infectious disease caused by long “thread-like” worms, Acanthocheilonema perstans, also known as Dipetalonema perstans. The disease is transmitted by a small black insect (midge), called A. Culicoides. | Causes of Acanthocheilonemiasis. Acanthocheilonemiasis is a rare infectious disease caused by long “thread-like” worms, Acanthocheilonema perstans, also known as Dipetalonema perstans. The disease is transmitted by a small black insect (midge), called A. Culicoides. | 5 | Acanthocheilonemiasis |
nord_5_3 | Affects of Acanthocheilonemiasis | Acanthocheilonema perstans, the parasite that causes Acanthocheilonemiasis is common in central Africa and in some areas of South America. This disorder affects males and females in equal numbers. | Affects of Acanthocheilonemiasis. Acanthocheilonema perstans, the parasite that causes Acanthocheilonemiasis is common in central Africa and in some areas of South America. This disorder affects males and females in equal numbers. | 5 | Acanthocheilonemiasis |
nord_5_4 | Related disorders of Acanthocheilonemiasis | Symptoms of the following disorders can be similar to those of Acanthocheilonemiasis. Comparisons may be useful for a differential diagnosis:Filariasis is a group of rare infectious diseases caused by parasitic worms. These disorders are characterized by abnormal changes with the lymph glands (lymphadenopathy) and chronic obstruction of the flow of lymphatic fluid. This may result in the extreme swelling of the legs and/or genitalia (elephantiasis). This parasite enters the body by a mosquito bite. (For more information on this disorder, choose “Filariasis” as your search term in the Rare Disease Database.)Other tropical diseases can cause similar symptoms to Acanthocheilonemiais. For more information choose “Tropical” as your search term in the Rare Disease Database. | Related disorders of Acanthocheilonemiasis. Symptoms of the following disorders can be similar to those of Acanthocheilonemiasis. Comparisons may be useful for a differential diagnosis:Filariasis is a group of rare infectious diseases caused by parasitic worms. These disorders are characterized by abnormal changes with the lymph glands (lymphadenopathy) and chronic obstruction of the flow of lymphatic fluid. This may result in the extreme swelling of the legs and/or genitalia (elephantiasis). This parasite enters the body by a mosquito bite. (For more information on this disorder, choose “Filariasis” as your search term in the Rare Disease Database.)Other tropical diseases can cause similar symptoms to Acanthocheilonemiais. For more information choose “Tropical” as your search term in the Rare Disease Database. | 5 | Acanthocheilonemiasis |
nord_5_5 | Diagnosis of Acanthocheilonemiasis | Diagnosis of Acanthocheilonemiasis. | 5 | Acanthocheilonemiasis |
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nord_5_6 | Therapies of Acanthocheilonemiasis | Acanthocheilonemiasis is treated by means of the administration of antifilarial drugs, some of which are newer than others. Ivermectin or diethyl-carbamazine (DEC) are frequently prescribed. Occasionally, surgery may be required to remove large adult worms. Mild cases of acanthocheilonemiasis do not require treatment. | Therapies of Acanthocheilonemiasis. Acanthocheilonemiasis is treated by means of the administration of antifilarial drugs, some of which are newer than others. Ivermectin or diethyl-carbamazine (DEC) are frequently prescribed. Occasionally, surgery may be required to remove large adult worms. Mild cases of acanthocheilonemiasis do not require treatment. | 5 | Acanthocheilonemiasis |
nord_6_0 | Overview of Aceruloplasminemia | Aceruloplasminemia is a rare genetic disorder characterized by the abnormal accumulation of iron in the brain and various internal organs. Affected individuals develop neurological symptoms including cognitive impairment and movement disorders. Degeneration of the retina and diabetes may also occur. Symptoms usually become apparent during adulthood between 20 and 60 years of age. Aceruloplasminemia is caused by mutations of the ceruloplasmin (CP) gene. This mutation is inherited in an autosomal recessive pattern.Aceruloplasminemia is classified as a neurodegenerative disorder with brain iron accumulation (NBIA). NBIA are a group of rare inherited disorders characterized by iron accumulation in the brain. Aceruloplasminemia is also classified as an iron overload disorder. | Overview of Aceruloplasminemia. Aceruloplasminemia is a rare genetic disorder characterized by the abnormal accumulation of iron in the brain and various internal organs. Affected individuals develop neurological symptoms including cognitive impairment and movement disorders. Degeneration of the retina and diabetes may also occur. Symptoms usually become apparent during adulthood between 20 and 60 years of age. Aceruloplasminemia is caused by mutations of the ceruloplasmin (CP) gene. This mutation is inherited in an autosomal recessive pattern.Aceruloplasminemia is classified as a neurodegenerative disorder with brain iron accumulation (NBIA). NBIA are a group of rare inherited disorders characterized by iron accumulation in the brain. Aceruloplasminemia is also classified as an iron overload disorder. | 6 | Aceruloplasminemia |
nord_6_1 | Symptoms of Aceruloplasminemia | The symptoms and severity of aceruloplasminemia vary from one person to another even among members of the same family. The age of onset varies as well, ranging from anywhere between the 20s and 60s. The three main findings associated with aceruloplasminemia are retinal degeneration, neurological symptoms and diabetes mellitus.Some individuals with aceruloplasminemia develop mild anemia (low levels of circulating red blood cells), which can cause fatigue, weakness, shortness of breath and pale skin. Anemia often occurs before the development of other symptoms commonly associated with aceruloplasminemia.Many affected individuals develop progressive degeneration of the retinas. The retinas are the thin layers of nerve cells that line the inner surface of the eyes. The retinas sense light and convert it to nerve signals, which are then relayed to the brain through the optic nerve. The damage to the retinal tissue can result from iron deposition or be related to the diabetes that develops as part of aceruloplasminemia.A variety of neurological symptoms occur in individuals with aceruloplasminemia because of the accumulation of iron in the brain. Specific symptoms may vary, but often include movement disorders, an inability to coordinate voluntary movements (ataxia), slurred speech or difficulty speaking (dysarthria), behavioral changes and cognitive impairment.Movement disorders associated with aceruloplasminemia include tremors, chorea (rapid, involuntary, jerky movements) and dystonia, which refers to a group of muscle disorders generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). An example of dystonia is blepharospasm, a condition characterized by involuntary muscle spasms and contractions of the muscles around the eyes.Some affected individuals develop symptoms may resemble those found in Parkinson’s disease, which is sometimes referred to as Parkinsonism. These symptoms include tremors, abnormal slowness of movement and an inability to remain in a stable or balanced position. Some individuals with aceruloplasminemia develop cognitive impairment, which can progress to dementia. Behavioral or emotional changes (e.g., depression) may also occur.Iron accumulation in individuals with aceruloplasminemia may also occur in the pancreas. The pancreas is a small organ located behind the stomach that secretes enzymes that travel to the intestines and aid in digestion. The pancreas also secretes other hormones such as insulin, which helps break down sugar. Damage to the pancreas may ultimately lead to diabetes mellitus. Diabetes is a common disorder in which the body does not produce enough or is unable to properly use insulin. Therefore, the body is not able to properly convert nutrients into the energy necessary for daily activities. The most obvious symptoms are unusually excessive thirst and urination. | Symptoms of Aceruloplasminemia. The symptoms and severity of aceruloplasminemia vary from one person to another even among members of the same family. The age of onset varies as well, ranging from anywhere between the 20s and 60s. The three main findings associated with aceruloplasminemia are retinal degeneration, neurological symptoms and diabetes mellitus.Some individuals with aceruloplasminemia develop mild anemia (low levels of circulating red blood cells), which can cause fatigue, weakness, shortness of breath and pale skin. Anemia often occurs before the development of other symptoms commonly associated with aceruloplasminemia.Many affected individuals develop progressive degeneration of the retinas. The retinas are the thin layers of nerve cells that line the inner surface of the eyes. The retinas sense light and convert it to nerve signals, which are then relayed to the brain through the optic nerve. The damage to the retinal tissue can result from iron deposition or be related to the diabetes that develops as part of aceruloplasminemia.A variety of neurological symptoms occur in individuals with aceruloplasminemia because of the accumulation of iron in the brain. Specific symptoms may vary, but often include movement disorders, an inability to coordinate voluntary movements (ataxia), slurred speech or difficulty speaking (dysarthria), behavioral changes and cognitive impairment.Movement disorders associated with aceruloplasminemia include tremors, chorea (rapid, involuntary, jerky movements) and dystonia, which refers to a group of muscle disorders generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). An example of dystonia is blepharospasm, a condition characterized by involuntary muscle spasms and contractions of the muscles around the eyes.Some affected individuals develop symptoms may resemble those found in Parkinson’s disease, which is sometimes referred to as Parkinsonism. These symptoms include tremors, abnormal slowness of movement and an inability to remain in a stable or balanced position. Some individuals with aceruloplasminemia develop cognitive impairment, which can progress to dementia. Behavioral or emotional changes (e.g., depression) may also occur.Iron accumulation in individuals with aceruloplasminemia may also occur in the pancreas. The pancreas is a small organ located behind the stomach that secretes enzymes that travel to the intestines and aid in digestion. The pancreas also secretes other hormones such as insulin, which helps break down sugar. Damage to the pancreas may ultimately lead to diabetes mellitus. Diabetes is a common disorder in which the body does not produce enough or is unable to properly use insulin. Therefore, the body is not able to properly convert nutrients into the energy necessary for daily activities. The most obvious symptoms are unusually excessive thirst and urination. | 6 | Aceruloplasminemia |
nord_6_2 | Causes of Aceruloplasminemia | Aceruloplasminemia is caused by mutations of the ceruloplasmin (CP) gene and is inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. In most recessive conditions, individuals with one working gene and one gene for the disease (carriers) do not develop symptoms, however, in aceruloplasminemia carriers may, in rare cases develop cerebellar ataxia (problems coordinating movements).The CP gene contains instructions for producing the enzyme ceruloplasmin. This enzyme is essential for the proper function and transport of iron within the body. Mutations of the CP gene result in deficient levels of functional ceruloplasmin, which ultimately results in the accumulation of iron in the brain and other organs of the body. Iron accumulation damages the tissue of affected organs causing the characteristic symptoms of aceruloplasminemia.Iron is a critical mineral that is found in all cells of the body and is essential for the body to function and grow properly. Iron is found many types of food including red meat, poultry, eggs and vegetables. Iron levels must remain in a specific range within the body, otherwise they can cause anemia (due to low iron levels) or damage affected organs (due to high iron levels).In most individuals with aceruloplasminemia, iron accumulates within the basal ganglia, a part of the brain that consists of three clusters of brain cells (neurons). The basal ganglia processes information involved in involuntary movements, coordination and cognition. The specific neurological symptoms that develop in aceruloplasminemia depend on the exact location and extent of iron accumulation within the brain.Diabetes associated with aceruloplasminemia results from iron accumulation in the pancreas. Iron can also accumulate elsewhere in the body such as the retinas or liver. Liver damage does not occur in aceruloplasminemia. | Causes of Aceruloplasminemia. Aceruloplasminemia is caused by mutations of the ceruloplasmin (CP) gene and is inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. In most recessive conditions, individuals with one working gene and one gene for the disease (carriers) do not develop symptoms, however, in aceruloplasminemia carriers may, in rare cases develop cerebellar ataxia (problems coordinating movements).The CP gene contains instructions for producing the enzyme ceruloplasmin. This enzyme is essential for the proper function and transport of iron within the body. Mutations of the CP gene result in deficient levels of functional ceruloplasmin, which ultimately results in the accumulation of iron in the brain and other organs of the body. Iron accumulation damages the tissue of affected organs causing the characteristic symptoms of aceruloplasminemia.Iron is a critical mineral that is found in all cells of the body and is essential for the body to function and grow properly. Iron is found many types of food including red meat, poultry, eggs and vegetables. Iron levels must remain in a specific range within the body, otherwise they can cause anemia (due to low iron levels) or damage affected organs (due to high iron levels).In most individuals with aceruloplasminemia, iron accumulates within the basal ganglia, a part of the brain that consists of three clusters of brain cells (neurons). The basal ganglia processes information involved in involuntary movements, coordination and cognition. The specific neurological symptoms that develop in aceruloplasminemia depend on the exact location and extent of iron accumulation within the brain.Diabetes associated with aceruloplasminemia results from iron accumulation in the pancreas. Iron can also accumulate elsewhere in the body such as the retinas or liver. Liver damage does not occur in aceruloplasminemia. | 6 | Aceruloplasminemia |
nord_6_3 | Affects of Aceruloplasminemia | Aceruloplasminemia is an extremely rare disorder that affects males and females in equal numbers. The exact incidence of aceruloplasminemia is unknown. It may be more prevalent in Japan, where it is estimated to affect 1 individual per 2,000,000 in the general population. Because many cases of aceruloplasminemia go undiagnosed or misdiagnosed, determining the disorder’s true frequency in the general population is difficult. Aceruloplasminemia was first described in the medical literature in 1992. | Affects of Aceruloplasminemia. Aceruloplasminemia is an extremely rare disorder that affects males and females in equal numbers. The exact incidence of aceruloplasminemia is unknown. It may be more prevalent in Japan, where it is estimated to affect 1 individual per 2,000,000 in the general population. Because many cases of aceruloplasminemia go undiagnosed or misdiagnosed, determining the disorder’s true frequency in the general population is difficult. Aceruloplasminemia was first described in the medical literature in 1992. | 6 | Aceruloplasminemia |
nord_6_4 | Related disorders of Aceruloplasminemia | Symptoms of the following disorders can be similar to those of aceruloplasminemia. Comparisons may be useful for a differential diagnosis.Neurodegeneration with brain iron accumulation (NBIA) is a general term for a rare group of genetic disorders characterized by the accumulation of iron in the brain. These disorders may develop during childhood (early-onset, rapid progression) or adulthood (late-onset, slow progression) and iron accumulation most often occurs in the basal ganglia. A variety of neurological symptoms may develop. In addition to aceruloplasminemia, NBIAs include pantothenate kinase associated neurodegeneration (formerly Hallervorden-Spatz disease) and infantile neuroaxonal dystrophy (Seitelberger disease), which are childhood onset recessive conditions, and neuroferritinopathy, which is an autosomal dominant adult onset disorder. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)Wilson’s disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain, and corneas of the eyes. The disease is progressive and, if left untreated, it may cause liver (hepatic) disease, central nervous system dysfunction, and death. Early diagnosis and treatment may prevent serious long-term disability and life threatening complications. Treatment is aimed at reducing the amount of copper that has accumulated in the body and maintaining normal copper levels thereafter. (For more information on this disorder, choose “Wilson” as your search term in the Rare Disease Database.)Iron overload disorders are a group of disorders characterized by the accumulation of iron in the body, especially in internal organs such as the liver and heart. Aceruloplasminemia is considered a type of iron overload disorder, although, in the other disorders in this group, the brain is not usually affected. These disorders include hemochromatosis, neonatal hemochromatosis, astransferrinemia, and African iron overload disease. (For more information choose the specific disorder name as your search term in the Rare Disease Database.)A variety of neurological disorders have symptoms that are similar to aceruloplasminemia including Parkinson’s disease, dystonia, hereditary ataxias, Huntington’s disease, multiple system atrophy, and dentatorubral-pallidoluysian atrophy. (For more information choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Aceruloplasminemia. Symptoms of the following disorders can be similar to those of aceruloplasminemia. Comparisons may be useful for a differential diagnosis.Neurodegeneration with brain iron accumulation (NBIA) is a general term for a rare group of genetic disorders characterized by the accumulation of iron in the brain. These disorders may develop during childhood (early-onset, rapid progression) or adulthood (late-onset, slow progression) and iron accumulation most often occurs in the basal ganglia. A variety of neurological symptoms may develop. In addition to aceruloplasminemia, NBIAs include pantothenate kinase associated neurodegeneration (formerly Hallervorden-Spatz disease) and infantile neuroaxonal dystrophy (Seitelberger disease), which are childhood onset recessive conditions, and neuroferritinopathy, which is an autosomal dominant adult onset disorder. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)Wilson’s disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain, and corneas of the eyes. The disease is progressive and, if left untreated, it may cause liver (hepatic) disease, central nervous system dysfunction, and death. Early diagnosis and treatment may prevent serious long-term disability and life threatening complications. Treatment is aimed at reducing the amount of copper that has accumulated in the body and maintaining normal copper levels thereafter. (For more information on this disorder, choose “Wilson” as your search term in the Rare Disease Database.)Iron overload disorders are a group of disorders characterized by the accumulation of iron in the body, especially in internal organs such as the liver and heart. Aceruloplasminemia is considered a type of iron overload disorder, although, in the other disorders in this group, the brain is not usually affected. These disorders include hemochromatosis, neonatal hemochromatosis, astransferrinemia, and African iron overload disease. (For more information choose the specific disorder name as your search term in the Rare Disease Database.)A variety of neurological disorders have symptoms that are similar to aceruloplasminemia including Parkinson’s disease, dystonia, hereditary ataxias, Huntington’s disease, multiple system atrophy, and dentatorubral-pallidoluysian atrophy. (For more information choose the specific disorder name as your search term in the Rare Disease Database.) | 6 | Aceruloplasminemia |
nord_6_5 | Diagnosis of Aceruloplasminemia | A diagnosis of aceruloplasminemia is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood tests can reveal certain findings associated with aceruloplasminemia including absent blood ceruloplasmin and low concentrations of copper and iron in serum. Magnetic resonance imaging (MRI) of the brain and liver can reveal characteristic findings that indicate the accumulation of iron. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. A genetic test to demonstrate mutations in the CP gene is the definitive diagnostic test. | Diagnosis of Aceruloplasminemia. A diagnosis of aceruloplasminemia is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood tests can reveal certain findings associated with aceruloplasminemia including absent blood ceruloplasmin and low concentrations of copper and iron in serum. Magnetic resonance imaging (MRI) of the brain and liver can reveal characteristic findings that indicate the accumulation of iron. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. A genetic test to demonstrate mutations in the CP gene is the definitive diagnostic test. | 6 | Aceruloplasminemia |
nord_6_6 | Therapies of Aceruloplasminemia | Treatment
The treatment of aceruloplasminemia is directed toward the specific symptoms that are apparent in each individual. Individuals with aceruloplasminemia may be treated with a drug called desferrioxamine, an iron chelator. Iron chelators are drugs that bind to the excess iron in the body allowing it to be dissolved in water and excreted from the body through the kidneys. It has not been conclusively established that iron chelation improves symptoms in aceruloplasminemia. Individuals with aceruloplasminemia should avoid substances that increase the levels of iron in the body.Other treatment is symptomatic and supportive. Of particular importance is management of diabetes, with appropriate diet, tablets and insulin injects as needed.Genetic counseling is recommended for affected individuals and their families. | Therapies of Aceruloplasminemia. Treatment
The treatment of aceruloplasminemia is directed toward the specific symptoms that are apparent in each individual. Individuals with aceruloplasminemia may be treated with a drug called desferrioxamine, an iron chelator. Iron chelators are drugs that bind to the excess iron in the body allowing it to be dissolved in water and excreted from the body through the kidneys. It has not been conclusively established that iron chelation improves symptoms in aceruloplasminemia. Individuals with aceruloplasminemia should avoid substances that increase the levels of iron in the body.Other treatment is symptomatic and supportive. Of particular importance is management of diabetes, with appropriate diet, tablets and insulin injects as needed.Genetic counseling is recommended for affected individuals and their families. | 6 | Aceruloplasminemia |
nord_7_0 | Overview of Achalasia | Achalasia is a rare disorder of the esophagus, the tube that carries food from the throat to the stomach. It is characterized by impaired ability to push food down toward the stomach (peristalsis), failure of the ring-shaped muscle at the bottom of the esophagus, the lower esophageal sphincter (LES), to relax. It is the contraction and relaxation of the sphincter that moves food through the tube. | Overview of Achalasia. Achalasia is a rare disorder of the esophagus, the tube that carries food from the throat to the stomach. It is characterized by impaired ability to push food down toward the stomach (peristalsis), failure of the ring-shaped muscle at the bottom of the esophagus, the lower esophageal sphincter (LES), to relax. It is the contraction and relaxation of the sphincter that moves food through the tube. | 7 | Achalasia |
nord_7_1 | Symptoms of Achalasia | The symptoms of achalasia typically appear gradually. Most people with this disorder experience an impairment in the ability to swallow (dysphagia) as a major and early symptom. There may also be mild chest pain that comes and goes. Some affected individuals experience pain that is very intense.Retention of saliva and ingested food in the esophagus may often cause regurgitation of these contents; in addition, such contents may also be propelled into the lungs during breathing (tracheobronchial aspiration). Other symptoms of this disorder may include a cough during the night and significant weight loss, because of difficulty in swallowing, in cases that remain untreated. Dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) are not unusual in patients with achalasia.The aspiration of saliva and food contents by people with achalasia may cause pneumonia, other pulmonary infections, or even death. The incidence of esophageal cancer is significantly increased in patients with achalasia. | Symptoms of Achalasia. The symptoms of achalasia typically appear gradually. Most people with this disorder experience an impairment in the ability to swallow (dysphagia) as a major and early symptom. There may also be mild chest pain that comes and goes. Some affected individuals experience pain that is very intense.Retention of saliva and ingested food in the esophagus may often cause regurgitation of these contents; in addition, such contents may also be propelled into the lungs during breathing (tracheobronchial aspiration). Other symptoms of this disorder may include a cough during the night and significant weight loss, because of difficulty in swallowing, in cases that remain untreated. Dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) are not unusual in patients with achalasia.The aspiration of saliva and food contents by people with achalasia may cause pneumonia, other pulmonary infections, or even death. The incidence of esophageal cancer is significantly increased in patients with achalasia. | 7 | Achalasia |
nord_7_2 | Causes of Achalasia | The exact cause of achalasia is not known. Some clinical researchers suspect that the condition may be caused by the degeneration of a group of nerves located in the chest (Auerbach’s plexus). It is believed that there may be a rare, inherited form of achalasia, but this is not yet well understood at this time. | Causes of Achalasia. The exact cause of achalasia is not known. Some clinical researchers suspect that the condition may be caused by the degeneration of a group of nerves located in the chest (Auerbach’s plexus). It is believed that there may be a rare, inherited form of achalasia, but this is not yet well understood at this time. | 7 | Achalasia |
nord_7_3 | Affects of Achalasia | Achalasia is a rare disorder that typically affects adults between the ages of 25 and 60 years. However, this disorder may occur at any age, including during childhood. Achalasia affects males and females in equal numbers except in cases that appear to reflect an inherited form. In those cases, it appears that males are twice as likely as females to be diagnosed with this disorder. | Affects of Achalasia. Achalasia is a rare disorder that typically affects adults between the ages of 25 and 60 years. However, this disorder may occur at any age, including during childhood. Achalasia affects males and females in equal numbers except in cases that appear to reflect an inherited form. In those cases, it appears that males are twice as likely as females to be diagnosed with this disorder. | 7 | Achalasia |
nord_7_4 | Related disorders of Achalasia | Symptoms of the following disorders can be similar to those of achalasia. Comparisons may be useful for a differential diagnosis:Esophageal cancer
The symptoms of esophageal cancer resemble those associated with achalasia. Esophageal cancer may begin at almost any point in the tube. Small cancers may be asymptomatic or may be present without symptoms. As the tumor grows, the first sign may be difficulty in swallowing and/or pain upon swallowing and/or feeling as if food were stuck behind the breastbone. Difficulty in swallowing may be accompanied by indigestion, heartburn and choking. Weight loss is not uncommon.Swallowing disorders
Swallowing disorders come in a variety of forms. Some are the result of disturbances of the brain such as Parkinson’s disease, multiple sclerosis or amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease). Others are the result of malfunctioning of parts of the throat involved in swallowing. For example, the pharynx may malfunction after a stroke. | Related disorders of Achalasia. Symptoms of the following disorders can be similar to those of achalasia. Comparisons may be useful for a differential diagnosis:Esophageal cancer
The symptoms of esophageal cancer resemble those associated with achalasia. Esophageal cancer may begin at almost any point in the tube. Small cancers may be asymptomatic or may be present without symptoms. As the tumor grows, the first sign may be difficulty in swallowing and/or pain upon swallowing and/or feeling as if food were stuck behind the breastbone. Difficulty in swallowing may be accompanied by indigestion, heartburn and choking. Weight loss is not uncommon.Swallowing disorders
Swallowing disorders come in a variety of forms. Some are the result of disturbances of the brain such as Parkinson’s disease, multiple sclerosis or amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease). Others are the result of malfunctioning of parts of the throat involved in swallowing. For example, the pharynx may malfunction after a stroke. | 7 | Achalasia |
nord_7_5 | Diagnosis of Achalasia | X-ray examination (radiology) is frequently useful in the diagnosis of achalasia. Radiological examination, especially with the use of barium, may show enlargement (dilation) of the esophagus and the retention of food and secretions within the esophagus. Devices that measure fluid pressure (manometers) within the esophagus are used to confirm the diagnosis of achalasia. | Diagnosis of Achalasia. X-ray examination (radiology) is frequently useful in the diagnosis of achalasia. Radiological examination, especially with the use of barium, may show enlargement (dilation) of the esophagus and the retention of food and secretions within the esophagus. Devices that measure fluid pressure (manometers) within the esophagus are used to confirm the diagnosis of achalasia. | 7 | Achalasia |
nord_7_6 | Therapies of Achalasia | TreatmentThe treatment of achalasia is aimed at removing obstructions caused by the failure of the lower esophageal sphincter muscle to relax. This may be done with the administration of drugs, expanding the cross-section (manual dilation) of the sphincter muscle, or through surgery.The drug isosorbide, (a long-acting nitrate) or nifedipine (a calcium channel blocker) may provide some relief for people with achalasia.Approximately 70 percent of cases of achalasia may be treated effectively by the enlargement of the lower esophageal sphincter muscle through a procedure known as pneumatic balloon dilation. In many people, repeated dilations may be necessary to obtain improvement of symptoms.Surgical treatments of achalasia may be effective in approximately 85-90 percent of cases. During these procedures, the muscle fibers in the lower esophageal sphincter are cut (laparoscopic Heller myotomy or peroral endoscopic myotomy). About 15 percent of people with achalasia experience the symptoms of gastroesophageal reflux after this surgical procedure. | Therapies of Achalasia. TreatmentThe treatment of achalasia is aimed at removing obstructions caused by the failure of the lower esophageal sphincter muscle to relax. This may be done with the administration of drugs, expanding the cross-section (manual dilation) of the sphincter muscle, or through surgery.The drug isosorbide, (a long-acting nitrate) or nifedipine (a calcium channel blocker) may provide some relief for people with achalasia.Approximately 70 percent of cases of achalasia may be treated effectively by the enlargement of the lower esophageal sphincter muscle through a procedure known as pneumatic balloon dilation. In many people, repeated dilations may be necessary to obtain improvement of symptoms.Surgical treatments of achalasia may be effective in approximately 85-90 percent of cases. During these procedures, the muscle fibers in the lower esophageal sphincter are cut (laparoscopic Heller myotomy or peroral endoscopic myotomy). About 15 percent of people with achalasia experience the symptoms of gastroesophageal reflux after this surgical procedure. | 7 | Achalasia |
nord_8_0 | Overview of Achard Thiers Syndrome | Achard-Thiers syndrome is a rare disorder that occurs primarily in postmenopausal women and is characterized by type 2 (insulin-resistant) diabetes mellitus and signs of androgen excess. The exact cause of this syndrome is unknown. | Overview of Achard Thiers Syndrome. Achard-Thiers syndrome is a rare disorder that occurs primarily in postmenopausal women and is characterized by type 2 (insulin-resistant) diabetes mellitus and signs of androgen excess. The exact cause of this syndrome is unknown. | 8 | Achard Thiers Syndrome |
nord_8_1 | Symptoms of Achard Thiers Syndrome | The original description and usual emphasis in this syndrome is on the affected individual as a bearded woman with diabetes mellitus. In older women, the first clinical symptoms are often those associated with classic diabetes and may include abnormally high blood glucose due to the body's inability to utilize insulin properly.Those affected may also have abnormally high levels of glucose in the urine, frequent urination, excessive thirst and hunger, and weight loss. Other signs of the syndrome are directly due to the overproduction of androgens, and may include an increase in body hair, particularly on the face, chest, back, and other areas, receding hairline, deepening of the voice, enlargement of the clitoris; infertility; and obesity. Typically, a detailed patient history shows the development of infrequent or very light menstrual periods in someone who has previously had normal menstruation (oligomenorrhea) or the absence of menstrual periods (amenorrhea) soon after the first menstrual period (menarche), commonly followed by development of excess body hair (hirsutism) and rapid weight gain. Many women with the disorder have acanthosis nigricans.The constellation of clinical androgen excess and failure of the blood sugar control system to work properly (hyperinsulinemia) is now commonly identified earlier in a woman's life, typically during adolescence and young adulthood, as polycystic ovary syndrome or PCOS. | Symptoms of Achard Thiers Syndrome. The original description and usual emphasis in this syndrome is on the affected individual as a bearded woman with diabetes mellitus. In older women, the first clinical symptoms are often those associated with classic diabetes and may include abnormally high blood glucose due to the body's inability to utilize insulin properly.Those affected may also have abnormally high levels of glucose in the urine, frequent urination, excessive thirst and hunger, and weight loss. Other signs of the syndrome are directly due to the overproduction of androgens, and may include an increase in body hair, particularly on the face, chest, back, and other areas, receding hairline, deepening of the voice, enlargement of the clitoris; infertility; and obesity. Typically, a detailed patient history shows the development of infrequent or very light menstrual periods in someone who has previously had normal menstruation (oligomenorrhea) or the absence of menstrual periods (amenorrhea) soon after the first menstrual period (menarche), commonly followed by development of excess body hair (hirsutism) and rapid weight gain. Many women with the disorder have acanthosis nigricans.The constellation of clinical androgen excess and failure of the blood sugar control system to work properly (hyperinsulinemia) is now commonly identified earlier in a woman's life, typically during adolescence and young adulthood, as polycystic ovary syndrome or PCOS. | 8 | Achard Thiers Syndrome |
nord_8_2 | Causes of Achard Thiers Syndrome | These syndromes appear to be transmitted within families. Approximately 50% of the sisters of women with PCOS have some form of the syndrome. The exact mechanism of genetic transmission is unknown. | Causes of Achard Thiers Syndrome. These syndromes appear to be transmitted within families. Approximately 50% of the sisters of women with PCOS have some form of the syndrome. The exact mechanism of genetic transmission is unknown. | 8 | Achard Thiers Syndrome |
nord_8_3 | Affects of Achard Thiers Syndrome | Achard-Thiers Syndrome is a rare disorder that affects females after menopause. The incidence of this disorder in the general population is not known. | Affects of Achard Thiers Syndrome. Achard-Thiers Syndrome is a rare disorder that affects females after menopause. The incidence of this disorder in the general population is not known. | 8 | Achard Thiers Syndrome |
nord_8_4 | Related disorders of Achard Thiers Syndrome | Symptoms of the following disorders can be similar to those of Achard-Thiers. Comparisons may be useful for a differential diagnosis:Acquired adrenogenital syndrome is a rare endocrine disorder that occurs because of a tumor in the adrenal glands which causes the overproduction of androgens. In an adult female the symptoms may include a male pattern of hair growth, loss of hair on the head, acne, deepening voice, and abnormally large muscles.Empty sella syndrome is a rare brain disorder that may be inherited or acquired. The acquired form of the disease may occur as a result of a tumor in the pituitary gland or radiation to that area. Symptoms may include headaches, impaired vision, and/or obesity. Some people with empty sella syndrome cannot tolerate cold temperatures and may also have abnormally high blood pressure (hypertension). In women this disorder is associated with an increase in body hair and a male pattern of hair growth. (For more information on this disorder, choose “Empty Sella” as your search term in the Rare Disease Database.)Diabetes is a complex endocrine disease that occurs when the pancreas does not produce enough insulin or the body is not able to use insulin properly. There are two main groups of diabetes: Type I (insulin-dependent) and type II (noninsulin-dependent). The symptoms of diabetes usually include frequent urination, extreme thirst, constant hunger, and unexplained weight loss. Long-term complications of diabetes may affect many organs of the body including the nervous system, heart, kidneys, and eyes. (For more information on this disorder, choose “Diabetes” as your search term in the Rare Disease Database.)Polycystic ovary syndrome (PCOS) affects women and is a complex of symptoms that are not necessarily all present in all cases. Some, but not all, affected women have multiple cysts on the ovaries. Other characteristics include absent or irregular menstruation, failure of the ovary to release eggs (anovulation), elevated levels of the male hormones known as androgens (hyperandrogenism), excessive amounts of body hair (hirsutism), a high rate of miscarriage, and infertility. Three criteria often used for a diagnosis are menstrual irregularity, hyperandrogenism, and exclusion of other disease. There is some evidence that PCOS is an inherited condition. | Related disorders of Achard Thiers Syndrome. Symptoms of the following disorders can be similar to those of Achard-Thiers. Comparisons may be useful for a differential diagnosis:Acquired adrenogenital syndrome is a rare endocrine disorder that occurs because of a tumor in the adrenal glands which causes the overproduction of androgens. In an adult female the symptoms may include a male pattern of hair growth, loss of hair on the head, acne, deepening voice, and abnormally large muscles.Empty sella syndrome is a rare brain disorder that may be inherited or acquired. The acquired form of the disease may occur as a result of a tumor in the pituitary gland or radiation to that area. Symptoms may include headaches, impaired vision, and/or obesity. Some people with empty sella syndrome cannot tolerate cold temperatures and may also have abnormally high blood pressure (hypertension). In women this disorder is associated with an increase in body hair and a male pattern of hair growth. (For more information on this disorder, choose “Empty Sella” as your search term in the Rare Disease Database.)Diabetes is a complex endocrine disease that occurs when the pancreas does not produce enough insulin or the body is not able to use insulin properly. There are two main groups of diabetes: Type I (insulin-dependent) and type II (noninsulin-dependent). The symptoms of diabetes usually include frequent urination, extreme thirst, constant hunger, and unexplained weight loss. Long-term complications of diabetes may affect many organs of the body including the nervous system, heart, kidneys, and eyes. (For more information on this disorder, choose “Diabetes” as your search term in the Rare Disease Database.)Polycystic ovary syndrome (PCOS) affects women and is a complex of symptoms that are not necessarily all present in all cases. Some, but not all, affected women have multiple cysts on the ovaries. Other characteristics include absent or irregular menstruation, failure of the ovary to release eggs (anovulation), elevated levels of the male hormones known as androgens (hyperandrogenism), excessive amounts of body hair (hirsutism), a high rate of miscarriage, and infertility. Three criteria often used for a diagnosis are menstrual irregularity, hyperandrogenism, and exclusion of other disease. There is some evidence that PCOS is an inherited condition. | 8 | Achard Thiers Syndrome |
nord_8_5 | Diagnosis of Achard Thiers Syndrome | The diagnosis of Achard-Thiers syndrome should be suspected based on the clinical findings. Because affected women are hyperinsulinemic, a two-hour oral glucose tolerance test shows abnormally elevated levels of glucose in the blood. | Diagnosis of Achard Thiers Syndrome. The diagnosis of Achard-Thiers syndrome should be suspected based on the clinical findings. Because affected women are hyperinsulinemic, a two-hour oral glucose tolerance test shows abnormally elevated levels of glucose in the blood. | 8 | Achard Thiers Syndrome |
nord_8_6 | Therapies of Achard Thiers Syndrome | TreatmentDiabetes may be managed by diet and/or insulin or other medications, as required. Cosmetic measures (for example, waxing and electrolysis) can be used to facilitate hair removal. For younger women with PCOS, treatment with an oral contraceptive is the most common therapy, whereas for postmenopausal women with Achard-Thiers syndrome, hormone replacement therapy is usually recommended. Antiandrogens have also been used. | Therapies of Achard Thiers Syndrome. TreatmentDiabetes may be managed by diet and/or insulin or other medications, as required. Cosmetic measures (for example, waxing and electrolysis) can be used to facilitate hair removal. For younger women with PCOS, treatment with an oral contraceptive is the most common therapy, whereas for postmenopausal women with Achard-Thiers syndrome, hormone replacement therapy is usually recommended. Antiandrogens have also been used. | 8 | Achard Thiers Syndrome |
nord_9_0 | Overview of Achondrogenesis | SummaryAchondrogenesis is a group of rare skeletal dysplasias characterized by extreme shortening of the arms and legs in relation to the trunk, abnormal development of ribs, vertebra and other skeletal abnormalities. The health problems associated with these conditions are life-threatening and most affected infants are stillborn or die shortly after birth due to respiratory failure. All types of achondrogenesis are genetic conditions; type IA and type IB, are autosomal recessive disorders, whereas achondrogenesis type II is an autosomal dominant disorder. All types of achondrogenesis are very severe skeletal dysplasias usually detected by prenatal ultrasound examination as early as week 14-17 of gestational age.IntroductionThe term achondrogenesis was first used in the medical literature in 1952 by an Italian pathologist named Marco Fraccaro. Achondrogenesis is derived from Greek and means “not producing cartilage.” Achondrogenesis belongs to group of skeletal dysplasias, (also called osteochondrodysplasias), a broad term for a group of disorders (about 450 clinical diagnoses) characterized by abnormal growth or development of cartilage and bone. | Overview of Achondrogenesis. SummaryAchondrogenesis is a group of rare skeletal dysplasias characterized by extreme shortening of the arms and legs in relation to the trunk, abnormal development of ribs, vertebra and other skeletal abnormalities. The health problems associated with these conditions are life-threatening and most affected infants are stillborn or die shortly after birth due to respiratory failure. All types of achondrogenesis are genetic conditions; type IA and type IB, are autosomal recessive disorders, whereas achondrogenesis type II is an autosomal dominant disorder. All types of achondrogenesis are very severe skeletal dysplasias usually detected by prenatal ultrasound examination as early as week 14-17 of gestational age.IntroductionThe term achondrogenesis was first used in the medical literature in 1952 by an Italian pathologist named Marco Fraccaro. Achondrogenesis is derived from Greek and means “not producing cartilage.” Achondrogenesis belongs to group of skeletal dysplasias, (also called osteochondrodysplasias), a broad term for a group of disorders (about 450 clinical diagnoses) characterized by abnormal growth or development of cartilage and bone. | 9 | Achondrogenesis |
nord_9_1 | Symptoms of Achondrogenesis | Achondrogenesis is characterized by premature birth, abnormal accumulation of fluid in the body (hydrops fetalis), and a head that may be abnormal in shape and less ossified. The head may look disproportionately large, because the body is small. In addition, affected individuals have extremely short limbs and ribs, short neck, flat vertebrae and many other bones of the skeleton are not properly developed. In infants born with this disorder the abdomen is prominent and the thoracic cage is small. Other abnormalities are incomplete closure of the roof of the mouth (cleft palate), corneal clouding, and ear deformities. The disorder is life-threatening either before birth or shortly after birth usually due to underdeveloped thorax and small lungs.Achondrogenesis type IA (Houston-Harris type) is characterized by varying facial abnormalities (flat face, protruding eyes and protruding tongue or only minor facial anomalies), short trunk and limbs, short beaded ribs and thin skull bones (deficient ossification of the skull). Bone formation is abnormal in the spine, pelvis and extremities, but the degree of the severity of skeletal involvement may be variable. However, small thorax leads to underdevelopment of lungs and death soon after birth.Achondrogenesis type IB (Fraccaro type) is characterized by short trunk and limbs, narrow chest, and prominent abdomen. Affected infants may have a protrusion around the belly-button (umbilical hernia), or near the groin (inguinal hernia), and have short fingers and toes with feet turned inward. The face may be flat, the palate may be cleft and the neck is usually short. In some cases, the soft tissue of the neck may be abnormally thickened. Achondrogenesis type IB is sub-classified as a sulfation disorder, a small group of disorders associated with mutations in the gene SLC26A2. This group includes diastrophic dysplasia and recessive multiple epiphyseal dysplasia, which are milder conditions. It is important to note that one diagnosis does not change to another while the baby is developing, even if the genetic changes are located in the same gene.Achondrogenesis type II (Langer-Saldino type) is characterized by a narrow chest, abnormally small or short bones in the arms and/or legs, thin ribs, flat vertebra or deficient ossification of vertebral bodies, underdeveloped lungs, small chin, cleft palate and club feet. Bone formation is abnormal in the spine and pelvis. Abnormal accumulation of fluid may occur (hydrops fetalis) and the abdomen may be enlarged. | Symptoms of Achondrogenesis. Achondrogenesis is characterized by premature birth, abnormal accumulation of fluid in the body (hydrops fetalis), and a head that may be abnormal in shape and less ossified. The head may look disproportionately large, because the body is small. In addition, affected individuals have extremely short limbs and ribs, short neck, flat vertebrae and many other bones of the skeleton are not properly developed. In infants born with this disorder the abdomen is prominent and the thoracic cage is small. Other abnormalities are incomplete closure of the roof of the mouth (cleft palate), corneal clouding, and ear deformities. The disorder is life-threatening either before birth or shortly after birth usually due to underdeveloped thorax and small lungs.Achondrogenesis type IA (Houston-Harris type) is characterized by varying facial abnormalities (flat face, protruding eyes and protruding tongue or only minor facial anomalies), short trunk and limbs, short beaded ribs and thin skull bones (deficient ossification of the skull). Bone formation is abnormal in the spine, pelvis and extremities, but the degree of the severity of skeletal involvement may be variable. However, small thorax leads to underdevelopment of lungs and death soon after birth.Achondrogenesis type IB (Fraccaro type) is characterized by short trunk and limbs, narrow chest, and prominent abdomen. Affected infants may have a protrusion around the belly-button (umbilical hernia), or near the groin (inguinal hernia), and have short fingers and toes with feet turned inward. The face may be flat, the palate may be cleft and the neck is usually short. In some cases, the soft tissue of the neck may be abnormally thickened. Achondrogenesis type IB is sub-classified as a sulfation disorder, a small group of disorders associated with mutations in the gene SLC26A2. This group includes diastrophic dysplasia and recessive multiple epiphyseal dysplasia, which are milder conditions. It is important to note that one diagnosis does not change to another while the baby is developing, even if the genetic changes are located in the same gene.Achondrogenesis type II (Langer-Saldino type) is characterized by a narrow chest, abnormally small or short bones in the arms and/or legs, thin ribs, flat vertebra or deficient ossification of vertebral bodies, underdeveloped lungs, small chin, cleft palate and club feet. Bone formation is abnormal in the spine and pelvis. Abnormal accumulation of fluid may occur (hydrops fetalis) and the abdomen may be enlarged. | 9 | Achondrogenesis |
nord_9_2 | Causes of Achondrogenesis | Each type of achondrogenesis is caused by a mutation in a specific 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.The gene mutations that cause achondrogenesis type IA and type IB are inherited in an autosomal recessive manner. 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 is a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to 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 is 25%. The risk is the same for males and females.All individuals carry several abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than non-consanguineous parents to carry the same abnormal gene, which increases the risk to have children with a rare recessive genetic disorder.Achondrogenesis type IA is caused by mutations in the TRIP11 gene. Achondrogenesis type IB is caused by mutations in the SLC26A2 gene. These two genes are required for the efficient cellular transport of certain cartilage proteins needed to build skeleton and other tissues. Mutations of the TRIP11 gene results in deficiency of the Golgi microtubule associated protein 210. This protein is found in most cell types of the body. The protein product of the SLC26A2 gene is a sulfate transporter that is involved in the proper development and function of cartilage. Cartilage is the specialized tissue that serves as a buffer or cushion at joints. Most of the skeleton of an embryo consists of cartilage, which is slowly converted into bone.The gene mutation that causes achondrogenesis type II is caused by so called autosomal dominant change in the COL2A1 gene. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. Most cases of achondrogenesis type II are caused by a new (de novo) mutation in the COL2A1 gene, which means that risk for the parents of an affected infant to get another child with the same disease is not higher then 1%. This gene encodes collagen type II. Collagen is one of the most abundant proteins in the body and a major building block of connective tissue, which is the material between cells of the body that gives the tissue form and strength. There are many different types of collagen, which are indicated by Roman numerals. Collagen type II is most prevalent in cartilage and the jelly-like fluid that fills the center of the eye (vitreous). Collagen is also found in bone.There are very rare cases where siblings of infants with achondrogenesis type II have been affected. This is most likely due to the presence of more than one cell line in the egg or sperm from a parent (germline mosaicism). In germline mosaicism, some of a parent’s reproductive cells (germ cells) carry the COL2A1 gene mutation, while other germ cells contain normal COL2A1 genes (“mosaicism”). The other cells in the parent’s body do not have the mutation, so these parents are unaffected. As a result, one or more of the parent’s children may inherit the germ cell gene COL2A1 mutation, leading to the development of achondrogenesis II, while the parent does not have this disorder (asymptomatic carrier). Germline mosaicism may be suspected when apparently unaffected parents have more than one child with the same autosomal dominant genetic condition. The likelihood of a parent passing on a mosaic germline mutation to a child depends upon the percentage of the parent’s germ cells that have the mutation versus the percentage that do not. There is no test for germline mutation prior to pregnancy. Testing during early pregnancy may be available and is best discussed directly with a genetic specialist. | Causes of Achondrogenesis. Each type of achondrogenesis is caused by a mutation in a specific 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.The gene mutations that cause achondrogenesis type IA and type IB are inherited in an autosomal recessive manner. 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 is a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to 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 is 25%. The risk is the same for males and females.All individuals carry several abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than non-consanguineous parents to carry the same abnormal gene, which increases the risk to have children with a rare recessive genetic disorder.Achondrogenesis type IA is caused by mutations in the TRIP11 gene. Achondrogenesis type IB is caused by mutations in the SLC26A2 gene. These two genes are required for the efficient cellular transport of certain cartilage proteins needed to build skeleton and other tissues. Mutations of the TRIP11 gene results in deficiency of the Golgi microtubule associated protein 210. This protein is found in most cell types of the body. The protein product of the SLC26A2 gene is a sulfate transporter that is involved in the proper development and function of cartilage. Cartilage is the specialized tissue that serves as a buffer or cushion at joints. Most of the skeleton of an embryo consists of cartilage, which is slowly converted into bone.The gene mutation that causes achondrogenesis type II is caused by so called autosomal dominant change in the COL2A1 gene. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. Most cases of achondrogenesis type II are caused by a new (de novo) mutation in the COL2A1 gene, which means that risk for the parents of an affected infant to get another child with the same disease is not higher then 1%. This gene encodes collagen type II. Collagen is one of the most abundant proteins in the body and a major building block of connective tissue, which is the material between cells of the body that gives the tissue form and strength. There are many different types of collagen, which are indicated by Roman numerals. Collagen type II is most prevalent in cartilage and the jelly-like fluid that fills the center of the eye (vitreous). Collagen is also found in bone.There are very rare cases where siblings of infants with achondrogenesis type II have been affected. This is most likely due to the presence of more than one cell line in the egg or sperm from a parent (germline mosaicism). In germline mosaicism, some of a parent’s reproductive cells (germ cells) carry the COL2A1 gene mutation, while other germ cells contain normal COL2A1 genes (“mosaicism”). The other cells in the parent’s body do not have the mutation, so these parents are unaffected. As a result, one or more of the parent’s children may inherit the germ cell gene COL2A1 mutation, leading to the development of achondrogenesis II, while the parent does not have this disorder (asymptomatic carrier). Germline mosaicism may be suspected when apparently unaffected parents have more than one child with the same autosomal dominant genetic condition. The likelihood of a parent passing on a mosaic germline mutation to a child depends upon the percentage of the parent’s germ cells that have the mutation versus the percentage that do not. There is no test for germline mutation prior to pregnancy. Testing during early pregnancy may be available and is best discussed directly with a genetic specialist. | 9 | Achondrogenesis |
nord_9_3 | Affects of Achondrogenesis | Achondrogenesis affect males and females in equal numbers. Achondrogenesis type IA and type IB are very rare disorders and prevalence for them is unknown. Achondrogenesis type II occurs in approximately 1/40,000-1/60,000 newborns. | Affects of Achondrogenesis. Achondrogenesis affect males and females in equal numbers. Achondrogenesis type IA and type IB are very rare disorders and prevalence for them is unknown. Achondrogenesis type II occurs in approximately 1/40,000-1/60,000 newborns. | 9 | Achondrogenesis |
nord_9_4 | Related disorders of Achondrogenesis | Skeletal dysplasias (osteochondrodysplasias) are a general term for a group of disorders characterized by abnormal growth or development or cartilage and bone. Some forms cause life-threatening complications shortly after birth, while others are only may or may not cause life-threatening complications. Some forms do not cause life-threatening complications early in life. Skeletal dysplasias can be associated with short-limbed short stature or with more proportional shortening of the trunk and limbs. Various additional abnormalities may be present depending upon the specific disorder. There are approximately 450 types of skeletal dysplasias with more than 360 causative genes. Several forms are discussed below; the differentiation among them is made by radiographic and molecular means.Kniest dysplasia is one of several forms of skeletal dysplasias that are caused by a change (mutation) in the COL2A1 gene. This gene is involved in the production of a particular protein that forms collagen type II, which is essential for the normal development of bones and other connective tissue. Changes in the composition of collagen type II lead to abnormal skeletal growth and, thus, to a variety of congenital skeletal diseases known as skeletal dysplasias. Some of the signs and symptoms of Kniest dysplasia, such as short stature, enlarged knees, and cleft palate, are usually present at birth. Other symptoms develop with age. (For more information on this disorder, choose “Kniest” as your search term in the Rare Disease Database.)Campomelic syndrome is a rare congenital disorder in which multiple anomalies are present. It is caused by mutations in the SOX9 gene and characterized by bowing and angular shape of the long bones of the legs, especially the tibiae; multiple minor anomalies of the face; cleft palate; other skeletal anomalies such as abnormalities of the shoulder and pelvic area and eleven pairs of ribs instead of the usual twelve; underdevelopment of the trachea; developmental delay in some cases and incomplete development of genitalia in males such that they appear to be females. (For more information on this disorder, choose “campomelic” as your search term in the Rare Disease Database.)Hypophosphatasia is an inborn metabolic disorder of the bones characterized by skeletal defects resembling those of rickets. The symptoms result from a failure of bone mineral to be deposited in young, uncalcified bone (osteoid), and in the cartilage at the end of the long bones (epiphyses) during early years. The activity of the enzyme alkaline phosphatase in blood serum and bone cells is lower than normal. Urinary excretion and blood plasma concentrations of phosphoethanolamine and inorganic pyrophosphate are abnormally high. Hypophosphatasia does respond to treatment with Strensig (For more information on this disorder, choose “hypophosphatasia” as your search term in the Rare Disease Database.)Thanatophoric dysplasia is one of the most common forms of lethal skeletal dysplasias. It is characterized by an enlarged head, short and eventually bowed bones in the arms and legs, small, short ribs, narrow thorax and flattened vertebrae. There is an abnormally large amount of amniotic fluid. Thanatophoric dysplasia is caused by mutations in the FGFR3 gene.Short-rib-polydactyly syndrome includes several types of skeletal dysplasias. The infant may have cleft lip and palate, deformed ears, and a narrow chest with short ribs. The kidneys are often deformed (cystic), as are the sex organs. There may be brain malformations and an absence of a gallbladder. This disorder is often life-threatening as a result of insufficient lung development. | Related disorders of Achondrogenesis. Skeletal dysplasias (osteochondrodysplasias) are a general term for a group of disorders characterized by abnormal growth or development or cartilage and bone. Some forms cause life-threatening complications shortly after birth, while others are only may or may not cause life-threatening complications. Some forms do not cause life-threatening complications early in life. Skeletal dysplasias can be associated with short-limbed short stature or with more proportional shortening of the trunk and limbs. Various additional abnormalities may be present depending upon the specific disorder. There are approximately 450 types of skeletal dysplasias with more than 360 causative genes. Several forms are discussed below; the differentiation among them is made by radiographic and molecular means.Kniest dysplasia is one of several forms of skeletal dysplasias that are caused by a change (mutation) in the COL2A1 gene. This gene is involved in the production of a particular protein that forms collagen type II, which is essential for the normal development of bones and other connective tissue. Changes in the composition of collagen type II lead to abnormal skeletal growth and, thus, to a variety of congenital skeletal diseases known as skeletal dysplasias. Some of the signs and symptoms of Kniest dysplasia, such as short stature, enlarged knees, and cleft palate, are usually present at birth. Other symptoms develop with age. (For more information on this disorder, choose “Kniest” as your search term in the Rare Disease Database.)Campomelic syndrome is a rare congenital disorder in which multiple anomalies are present. It is caused by mutations in the SOX9 gene and characterized by bowing and angular shape of the long bones of the legs, especially the tibiae; multiple minor anomalies of the face; cleft palate; other skeletal anomalies such as abnormalities of the shoulder and pelvic area and eleven pairs of ribs instead of the usual twelve; underdevelopment of the trachea; developmental delay in some cases and incomplete development of genitalia in males such that they appear to be females. (For more information on this disorder, choose “campomelic” as your search term in the Rare Disease Database.)Hypophosphatasia is an inborn metabolic disorder of the bones characterized by skeletal defects resembling those of rickets. The symptoms result from a failure of bone mineral to be deposited in young, uncalcified bone (osteoid), and in the cartilage at the end of the long bones (epiphyses) during early years. The activity of the enzyme alkaline phosphatase in blood serum and bone cells is lower than normal. Urinary excretion and blood plasma concentrations of phosphoethanolamine and inorganic pyrophosphate are abnormally high. Hypophosphatasia does respond to treatment with Strensig (For more information on this disorder, choose “hypophosphatasia” as your search term in the Rare Disease Database.)Thanatophoric dysplasia is one of the most common forms of lethal skeletal dysplasias. It is characterized by an enlarged head, short and eventually bowed bones in the arms and legs, small, short ribs, narrow thorax and flattened vertebrae. There is an abnormally large amount of amniotic fluid. Thanatophoric dysplasia is caused by mutations in the FGFR3 gene.Short-rib-polydactyly syndrome includes several types of skeletal dysplasias. The infant may have cleft lip and palate, deformed ears, and a narrow chest with short ribs. The kidneys are often deformed (cystic), as are the sex organs. There may be brain malformations and an absence of a gallbladder. This disorder is often life-threatening as a result of insufficient lung development. | 9 | Achondrogenesis |
nord_9_5 | Diagnosis of Achondrogenesis | Achondrogenesis is diagnosed by physical features, X-ray (radiographic) findings and examination of tissue samples under a microscope (histology). Molecular genetic tests for mutations in the SLC26A2 gene can be used to confirm the diagnosis of achondrogenesis type 1B.Prenatal diagnosis of achondrogenesis by ultrasound is possible after 14-15 weeks gestation. Prenatal diagnosis by chorionic villus sampling (10-12 weeks gestation) or amniocentesis (15-18 weeks gestation) is possible if the specific gene mutations have been identified in a family member. | Diagnosis of Achondrogenesis. Achondrogenesis is diagnosed by physical features, X-ray (radiographic) findings and examination of tissue samples under a microscope (histology). Molecular genetic tests for mutations in the SLC26A2 gene can be used to confirm the diagnosis of achondrogenesis type 1B.Prenatal diagnosis of achondrogenesis by ultrasound is possible after 14-15 weeks gestation. Prenatal diagnosis by chorionic villus sampling (10-12 weeks gestation) or amniocentesis (15-18 weeks gestation) is possible if the specific gene mutations have been identified in a family member. | 9 | Achondrogenesis |
nord_9_6 | Therapies of Achondrogenesis | TreatmentTreatment of achondrogenesis is symptomatic and supportive and involves palliative care, in which physicians attempt to reduce or minimize pain, stress and specific symptoms associated with the disorder. Genetic counseling is recommended for families with an affected child. Psychosocial support for the entire family is essential as well. | Therapies of Achondrogenesis. TreatmentTreatment of achondrogenesis is symptomatic and supportive and involves palliative care, in which physicians attempt to reduce or minimize pain, stress and specific symptoms associated with the disorder. Genetic counseling is recommended for families with an affected child. Psychosocial support for the entire family is essential as well. | 9 | Achondrogenesis |
nord_10_0 | Overview of Achondroplasia | SummaryAchondroplasia is the most commonly occurring abnormality of bone growth (skeletal dysplasia), occurring in approximately 1 in 20,000-30,000 live births. This genetic disorder is caused by a change (mutation) in the fibroblast growth factor receptor 3 (FGFR3) gene. Achondroplasia occurs as a result of a spontaneous genetic mutation in approximately 80 percent of patients; in the remaining 20 percent it is inherited from a parent. This genetic disorder is characterized by an unusually large head (macrocephaly), short upper arms (rhizomelic dwarfism), and short stature (adult height of approximately 4 feet). Achondroplasia does not typically cause impairment or deficiencies in mental abilities. If the bones that join the head and neck do not compress the brainstem or upper spinal cord (craniocervical junction compression), life expectancy is near normal. | Overview of Achondroplasia. SummaryAchondroplasia is the most commonly occurring abnormality of bone growth (skeletal dysplasia), occurring in approximately 1 in 20,000-30,000 live births. This genetic disorder is caused by a change (mutation) in the fibroblast growth factor receptor 3 (FGFR3) gene. Achondroplasia occurs as a result of a spontaneous genetic mutation in approximately 80 percent of patients; in the remaining 20 percent it is inherited from a parent. This genetic disorder is characterized by an unusually large head (macrocephaly), short upper arms (rhizomelic dwarfism), and short stature (adult height of approximately 4 feet). Achondroplasia does not typically cause impairment or deficiencies in mental abilities. If the bones that join the head and neck do not compress the brainstem or upper spinal cord (craniocervical junction compression), life expectancy is near normal. | 10 | Achondroplasia |
nord_10_1 | Symptoms of Achondroplasia | General
This rare genetic disorder is characterized by distinctive features: short stature (usually under 4 feet 6 inches); an unusually large head (macrocephaly) with a prominent forehead (frontal bossing) and flat (depressed) nasal bridge; short arms and legs; prominent abdomen and buttocks (due to inward curve of the spine); and short hands with fingers that assume a “trident” or three-pronged position during extension. Infancy
Infants born with achondroplasia typically have a “dome-like” (vaulted) skull, and a very broad forehead. In a small proportion there is excessive accumulation of fluid around the brain (hydrocephalus). Low muscle tone (hypotonia) in infancy is typical of achondroplasia. Acquisition of developmental motor milestones may be delayed. | Symptoms of Achondroplasia. General
This rare genetic disorder is characterized by distinctive features: short stature (usually under 4 feet 6 inches); an unusually large head (macrocephaly) with a prominent forehead (frontal bossing) and flat (depressed) nasal bridge; short arms and legs; prominent abdomen and buttocks (due to inward curve of the spine); and short hands with fingers that assume a “trident” or three-pronged position during extension. Infancy
Infants born with achondroplasia typically have a “dome-like” (vaulted) skull, and a very broad forehead. In a small proportion there is excessive accumulation of fluid around the brain (hydrocephalus). Low muscle tone (hypotonia) in infancy is typical of achondroplasia. Acquisition of developmental motor milestones may be delayed. | 10 | Achondroplasia |
nord_10_2 | Causes of Achondroplasia | Achondroplasia results from specific changes (mutations) of a gene known as fibroblast growth factor receptor 3 (FGFR3). For most patients, there is no apparent family history of the condition. Increased age of the father (advanced paternal age) may be a contributing factor in cases of sporadic achondroplasia.Less commonly, familial cases of achondroplasia follow an autosomal dominant pattern of inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disorder. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. | Causes of Achondroplasia. Achondroplasia results from specific changes (mutations) of a gene known as fibroblast growth factor receptor 3 (FGFR3). For most patients, there is no apparent family history of the condition. Increased age of the father (advanced paternal age) may be a contributing factor in cases of sporadic achondroplasia.Less commonly, familial cases of achondroplasia follow an autosomal dominant pattern of inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disorder. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. | 10 | Achondroplasia |
nord_10_3 | Affects of Achondroplasia | Achondroplasia appears to affect males and females in equal numbers. This disorder begins in the developing fetus and is one of the most common forms of skeletal dysplasia that causes dwarfism. The estimated frequency of achondroplasia has ranged from about one in 15,000 to one in 35,000 births. | Affects of Achondroplasia. Achondroplasia appears to affect males and females in equal numbers. This disorder begins in the developing fetus and is one of the most common forms of skeletal dysplasia that causes dwarfism. The estimated frequency of achondroplasia has ranged from about one in 15,000 to one in 35,000 births. | 10 | Achondroplasia |
nord_10_4 | Related disorders of Achondroplasia | Symptoms of the following disorders may be similar to those of Achondroplasia. Comparisons may be useful for a differential diagnosis:Hypochrondroplasia is a genetic disorder characterized by small stature and disproportionately short arms, legs, hands, and feet (i.e., short-limbed dwarfism). In those with the disorder, short stature often is not recognized until early to mid-childhood or, in some cases, as late as adulthood. Affected individuals may also develop bowing of the legs during early childhood that often improves spontaneously with age. In some cases, additional abnormalities may be present, such as an unusually large head (macrocephaly), a relatively prominent forehead, limited extension and rotation of the elbows, and/or other physical findings. In addition, in about 10 percent of cases, mild mental retardation may be present. In some instances, hypochondroplasia appears to occur randomly for unknown reasons (sporadically) with no apparent family history. In other cases, the disorder is familial with autosomal dominant inheritance. As noted above (see “Causes”), hypochondroplasia and achondroplasia may result from different mutations of the same gene (i.e., FGFR3). (For more information on this disorder, choose “Hypochondroplasia” as your search term in the Rare Disease Database.)Additional disorders may be characterized by small stature and disproportionately short arms and legs (short-limbed dwarfism), abnormal enlargement of the head (macrocephaly), additional malformations of the skull and facial (craniofacial) region, and/or other symptoms and findings similar to those potentially associated with achondroplasia. Achondroplasia may be distinguished from other forms of short-limbed dwarfism through thorough clinical examination, x-ray studies, and/or additional diagnostic techniques. (For more information on these disorders, choose “dwarfism” or the exact disease name in question as your search term in the Rare Disease Database.) | Related disorders of Achondroplasia. Symptoms of the following disorders may be similar to those of Achondroplasia. Comparisons may be useful for a differential diagnosis:Hypochrondroplasia is a genetic disorder characterized by small stature and disproportionately short arms, legs, hands, and feet (i.e., short-limbed dwarfism). In those with the disorder, short stature often is not recognized until early to mid-childhood or, in some cases, as late as adulthood. Affected individuals may also develop bowing of the legs during early childhood that often improves spontaneously with age. In some cases, additional abnormalities may be present, such as an unusually large head (macrocephaly), a relatively prominent forehead, limited extension and rotation of the elbows, and/or other physical findings. In addition, in about 10 percent of cases, mild mental retardation may be present. In some instances, hypochondroplasia appears to occur randomly for unknown reasons (sporadically) with no apparent family history. In other cases, the disorder is familial with autosomal dominant inheritance. As noted above (see “Causes”), hypochondroplasia and achondroplasia may result from different mutations of the same gene (i.e., FGFR3). (For more information on this disorder, choose “Hypochondroplasia” as your search term in the Rare Disease Database.)Additional disorders may be characterized by small stature and disproportionately short arms and legs (short-limbed dwarfism), abnormal enlargement of the head (macrocephaly), additional malformations of the skull and facial (craniofacial) region, and/or other symptoms and findings similar to those potentially associated with achondroplasia. Achondroplasia may be distinguished from other forms of short-limbed dwarfism through thorough clinical examination, x-ray studies, and/or additional diagnostic techniques. (For more information on these disorders, choose “dwarfism” or the exact disease name in question as your search term in the Rare Disease Database.) | 10 | Achondroplasia |
nord_10_5 | Diagnosis of Achondroplasia | Clinical and radiologic features of achondroplasia are well-characterized. Those with typical findings generally do not need molecular genetic testing to confirm the diagnosis. When clinical features raise suspicion in a newborn, X-ray (radiography) findings can be used to help confirm the diagnosis. However, if there is uncertainty, identification of the genetic variant of the FGFR3 gene by molecular genetic testing can be used to establish the diagnosis. Below is a list adapted from Pauli and Legare (2018) that provides clinical signs that may be used in the diagnosis of achondroplasia. | Diagnosis of Achondroplasia. Clinical and radiologic features of achondroplasia are well-characterized. Those with typical findings generally do not need molecular genetic testing to confirm the diagnosis. When clinical features raise suspicion in a newborn, X-ray (radiography) findings can be used to help confirm the diagnosis. However, if there is uncertainty, identification of the genetic variant of the FGFR3 gene by molecular genetic testing can be used to establish the diagnosis. Below is a list adapted from Pauli and Legare (2018) that provides clinical signs that may be used in the diagnosis of achondroplasia. | 10 | Achondroplasia |
nord_10_6 | Therapies of Achondroplasia | Treatment
Recommendations for managing children with achondroplasia are outlined by the American Academy of Pediatrics Committee on Genetics, which are designed to supplement guidelines for children with average stature.As outlined in Pauli and Legare (2018), the recommendations for the manifestations of achondroplasia include:In 2021, Voxzogo (vosoritide) was approved for children five years of age and older with achondroplasia and open epiphyses (growth plates), allowing the potential for growth. | Therapies of Achondroplasia. Treatment
Recommendations for managing children with achondroplasia are outlined by the American Academy of Pediatrics Committee on Genetics, which are designed to supplement guidelines for children with average stature.As outlined in Pauli and Legare (2018), the recommendations for the manifestations of achondroplasia include:In 2021, Voxzogo (vosoritide) was approved for children five years of age and older with achondroplasia and open epiphyses (growth plates), allowing the potential for growth. | 10 | Achondroplasia |
nord_11_0 | Overview of Acid Sphingomyelinase Deficiency | SummaryAcid sphingomyelinase deficiency (ASMD) is a rare progressive genetic disorder that results from a deficiency of the enzyme acid sphingomyelinase, which is required to break down (metabolize) a fatty substance (lipid) called sphingomyelin. Consequently, sphingomyelin and other substances accumulate in various tissues of the body. ASMD is highly variable and the age of onset, specific symptoms and severity of the disorder can vary dramatically from one person to another, sometimes even among members of the same family. The disorder may be best thought of as a spectrum of disease. At the severe end of the spectrum is a fatal neurodegenerative disorder that presents in infancy (Niemann-Pick disease type A). At the mild end of the spectrum, affected individuals have no or only minimal neurological symptoms and survival into adulthood is common (Niemann-Pick disease type B). Intermediate forms of the disorder exist as well. ASMD is caused by mutations in the SMPD1 gene and is inherited in an autosomal recessive manner.IntroductionThere are three disorders known as Niemann-Pick disease, types A, B, and C. These disorders were initially grouped together because similar symptoms, but we now know that they are different diseases. NPD types A and B are due to mutations in the SMPD1 gene, which causes a deficiency of a specific enzyme, acid sphingomyelinase (ASM). NPD type C is due to mutations in one of two different genes and does not involve a deficient enzyme. NPD type C is now considered a separate disorder, distinct from Niemann-Pick disease types A and B. NORD has an individual report on NPD type C in the Rare Disease Database. ASMD is also known as acid sphingomyelinase-deficient Niemann-Pick disease.ASMD has traditionally been broken down into two subgroups – neuronopathic (type A) and non-neuronopathic (type B). Neuronopathic refers to disorders that damage brain cells (neurons). Type A generally causes severe neurodegenerative disease during infancy, while type B is generally not considered to be a neurologic disease. However, since cases fall in between these two extremes, such broad designations can be misleading. Some researchers use acid sphingomyelinase disease type B to refer to all mild and intermediate forms, which can include those that have neurological findings. | Overview of Acid Sphingomyelinase Deficiency. SummaryAcid sphingomyelinase deficiency (ASMD) is a rare progressive genetic disorder that results from a deficiency of the enzyme acid sphingomyelinase, which is required to break down (metabolize) a fatty substance (lipid) called sphingomyelin. Consequently, sphingomyelin and other substances accumulate in various tissues of the body. ASMD is highly variable and the age of onset, specific symptoms and severity of the disorder can vary dramatically from one person to another, sometimes even among members of the same family. The disorder may be best thought of as a spectrum of disease. At the severe end of the spectrum is a fatal neurodegenerative disorder that presents in infancy (Niemann-Pick disease type A). At the mild end of the spectrum, affected individuals have no or only minimal neurological symptoms and survival into adulthood is common (Niemann-Pick disease type B). Intermediate forms of the disorder exist as well. ASMD is caused by mutations in the SMPD1 gene and is inherited in an autosomal recessive manner.IntroductionThere are three disorders known as Niemann-Pick disease, types A, B, and C. These disorders were initially grouped together because similar symptoms, but we now know that they are different diseases. NPD types A and B are due to mutations in the SMPD1 gene, which causes a deficiency of a specific enzyme, acid sphingomyelinase (ASM). NPD type C is due to mutations in one of two different genes and does not involve a deficient enzyme. NPD type C is now considered a separate disorder, distinct from Niemann-Pick disease types A and B. NORD has an individual report on NPD type C in the Rare Disease Database. ASMD is also known as acid sphingomyelinase-deficient Niemann-Pick disease.ASMD has traditionally been broken down into two subgroups – neuronopathic (type A) and non-neuronopathic (type B). Neuronopathic refers to disorders that damage brain cells (neurons). Type A generally causes severe neurodegenerative disease during infancy, while type B is generally not considered to be a neurologic disease. However, since cases fall in between these two extremes, such broad designations can be misleading. Some researchers use acid sphingomyelinase disease type B to refer to all mild and intermediate forms, which can include those that have neurological findings. | 11 | Acid Sphingomyelinase Deficiency |
nord_11_1 | Symptoms of Acid Sphingomyelinase Deficiency | Because ASMD is a highly variable disorder, it is important to note that affected individuals will not have all of the symptoms described below and that every individual case is unique. Some children will develop severe, life-threatening complications early in life; others have mild disease that may go undiagnosed well into adulthood. Parents should talk to their child’s physician and medical team about the specific symptoms and overall prognosis. NIEMANN-PICK DISEASE TYPE A
The severe, infantile form of ASMD, known as Niemann-Pick disease type A, can be distinguished from more mild forms, which have later onset. The initial symptom in most infantile cases is abnormal enlargement of the liver and/or spleen (hepatosplenomegaly), which can progressively worsen until the liver and spleen become massive. Significant accumulation of fluid in the abdomen (ascites) can also occur. Yellowing of the skin and whites of the eyes (jaundice) may occur during the newborn period. Additional symptoms during infancy include feeding problems, constipation, nausea, vomiting, significant gastrointestinal reflux, irritability, loss of reflexes, and progressive loss of muscle tone (hypotonia). Feeding difficulties and other abnormalities (e.g. frequent vomiting) can result in failure to thrive. The accumulation of sphingomyelin in the lungs can result in recurrent respiratory infections and difficulty breathing, potentially resulting in life-threatening respiratory failure. Most infants develop a condition known as cherry red spots in the eyes. A cherry red spot affects the macula, which is the region of the retina that contains light-sensing cells necessary for central vision. It is normally yellow. A cherry red spot is not always present in affected individuals. The attainment of developmental milestones and overall development may be normal in the first several months. However, often by 9 to 12 months of age, development plateaus and affected infants lose previously acquired motor skills. Affected infants may experience profound neurologic deterioration and increased muscle tone and stiffness of muscles (spasticity), and the disorder is often fatal by 3 years of age. NIEMANN-PICK DISEASE TYPE B
Individuals with later onset forms of ASMD can develop symptoms from infancy to adulthood. Sometimes, these forms are collectively referred to as Niemann-Pick disease type B; they are, generally, milder than Niemann-Pick disease type A (infantile form). Individuals with mild forms can live until late adulthood and some may go undiagnosed until well into adulthood. Niemann-Pick disease type B is associated with systemic disease that can vary widely in severity and extent. Hepatosplenomegaly is a common initial symptom and can range from mild to massive enlargement. Progressive enlargement of the spleen can cause low levels of platelets and white blood cells. White blood cells help to fight infection and a reduced number of these cells can leave an affected individual susceptible to infection. Platelets are specialized blood cells that allow the body to form clots to stop bleeding. A reduced number of platelets, known as thrombocytopenia, can lead to episodes of prolonged bleeding. Abdominal pain can result from enlargement of the liver and spleen. An enlarged spleen is at risk of rupturing, potentially resulting in life threatening bleeding into the abdominal cavity.Some degree of liver disease is present in most individuals with type B disease. The majority have abnormal liver blood tests and some scarring in the liver. The scarring can range from mild without symptoms, to frank cirrhosis and liver failure. Some affected individuals experience a gradual deterioration in lung function. For some individuals, lung involvement may be mild with no noticeable symptoms. Some individuals may develop difficulty breathing upon exertion (dyspnea). Other individuals may experience continued deterioration in breathing (respiratory) function with severe limitations in activity levels and oxygen dependence. Recurrent pneumonia may occur. Individuals with late-infantile or later onset of ASMD usually do not develop neurological symptoms, but may develop mild symptoms, or, in rare cases, may develop clinically significant neurological symptoms. Some affected children and adolescents may develop rapid, involuntary eye movements (nystagmus) and cerebellar signs, which includes unsteady manner of walking and clumsiness. Intellectual disability and psychiatric disorders have also been reported. Abnormalities of the retina, the nerve-rich membrane lining the back of the eyes, and peripheral neuropathy may occur. Peripheral neuropathy is a general term for any disease affecting the nerves outside the central nervous system. Common symptoms include the loss of sensation or abnormal sensations such as tingling, burning, or pricking along the affected nerves.Most affected children experience growth delays and low weight, although most eventually reach a near normal adult height. Delayed puberty and skeletal maturation may also occur. Most individuals have osteopenia, or thinning of the bones. (Wasserstein et al, JIMD, 2013). Limb and bone pain have been reported. A common finding in affected individuals is abnormal levels of lipids in the blood serum (dyslipidemia), specifically low levels of high density lipoprotein (HDL-cholesterol, aka “good cholesterol”), high serum concentrations of low density lipoprotein-cholesterol (LDL-C) and high triglyceride levels (hypertriglyceridemia). Affected individuals may be at risk early coronary artery disease. | Symptoms of Acid Sphingomyelinase Deficiency. Because ASMD is a highly variable disorder, it is important to note that affected individuals will not have all of the symptoms described below and that every individual case is unique. Some children will develop severe, life-threatening complications early in life; others have mild disease that may go undiagnosed well into adulthood. Parents should talk to their child’s physician and medical team about the specific symptoms and overall prognosis. NIEMANN-PICK DISEASE TYPE A
The severe, infantile form of ASMD, known as Niemann-Pick disease type A, can be distinguished from more mild forms, which have later onset. The initial symptom in most infantile cases is abnormal enlargement of the liver and/or spleen (hepatosplenomegaly), which can progressively worsen until the liver and spleen become massive. Significant accumulation of fluid in the abdomen (ascites) can also occur. Yellowing of the skin and whites of the eyes (jaundice) may occur during the newborn period. Additional symptoms during infancy include feeding problems, constipation, nausea, vomiting, significant gastrointestinal reflux, irritability, loss of reflexes, and progressive loss of muscle tone (hypotonia). Feeding difficulties and other abnormalities (e.g. frequent vomiting) can result in failure to thrive. The accumulation of sphingomyelin in the lungs can result in recurrent respiratory infections and difficulty breathing, potentially resulting in life-threatening respiratory failure. Most infants develop a condition known as cherry red spots in the eyes. A cherry red spot affects the macula, which is the region of the retina that contains light-sensing cells necessary for central vision. It is normally yellow. A cherry red spot is not always present in affected individuals. The attainment of developmental milestones and overall development may be normal in the first several months. However, often by 9 to 12 months of age, development plateaus and affected infants lose previously acquired motor skills. Affected infants may experience profound neurologic deterioration and increased muscle tone and stiffness of muscles (spasticity), and the disorder is often fatal by 3 years of age. NIEMANN-PICK DISEASE TYPE B
Individuals with later onset forms of ASMD can develop symptoms from infancy to adulthood. Sometimes, these forms are collectively referred to as Niemann-Pick disease type B; they are, generally, milder than Niemann-Pick disease type A (infantile form). Individuals with mild forms can live until late adulthood and some may go undiagnosed until well into adulthood. Niemann-Pick disease type B is associated with systemic disease that can vary widely in severity and extent. Hepatosplenomegaly is a common initial symptom and can range from mild to massive enlargement. Progressive enlargement of the spleen can cause low levels of platelets and white blood cells. White blood cells help to fight infection and a reduced number of these cells can leave an affected individual susceptible to infection. Platelets are specialized blood cells that allow the body to form clots to stop bleeding. A reduced number of platelets, known as thrombocytopenia, can lead to episodes of prolonged bleeding. Abdominal pain can result from enlargement of the liver and spleen. An enlarged spleen is at risk of rupturing, potentially resulting in life threatening bleeding into the abdominal cavity.Some degree of liver disease is present in most individuals with type B disease. The majority have abnormal liver blood tests and some scarring in the liver. The scarring can range from mild without symptoms, to frank cirrhosis and liver failure. Some affected individuals experience a gradual deterioration in lung function. For some individuals, lung involvement may be mild with no noticeable symptoms. Some individuals may develop difficulty breathing upon exertion (dyspnea). Other individuals may experience continued deterioration in breathing (respiratory) function with severe limitations in activity levels and oxygen dependence. Recurrent pneumonia may occur. Individuals with late-infantile or later onset of ASMD usually do not develop neurological symptoms, but may develop mild symptoms, or, in rare cases, may develop clinically significant neurological symptoms. Some affected children and adolescents may develop rapid, involuntary eye movements (nystagmus) and cerebellar signs, which includes unsteady manner of walking and clumsiness. Intellectual disability and psychiatric disorders have also been reported. Abnormalities of the retina, the nerve-rich membrane lining the back of the eyes, and peripheral neuropathy may occur. Peripheral neuropathy is a general term for any disease affecting the nerves outside the central nervous system. Common symptoms include the loss of sensation or abnormal sensations such as tingling, burning, or pricking along the affected nerves.Most affected children experience growth delays and low weight, although most eventually reach a near normal adult height. Delayed puberty and skeletal maturation may also occur. Most individuals have osteopenia, or thinning of the bones. (Wasserstein et al, JIMD, 2013). Limb and bone pain have been reported. A common finding in affected individuals is abnormal levels of lipids in the blood serum (dyslipidemia), specifically low levels of high density lipoprotein (HDL-cholesterol, aka “good cholesterol”), high serum concentrations of low density lipoprotein-cholesterol (LDL-C) and high triglyceride levels (hypertriglyceridemia). Affected individuals may be at risk early coronary artery disease. | 11 | Acid Sphingomyelinase Deficiency |
nord_11_2 | Causes of Acid Sphingomyelinase Deficiency | Acid sphingomyelinase deficiency is caused by a mutation in the sphingomyelin phophodiesterase-1 (SMPD1) 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.The SMPD1 gene is located on the short arm (p) of chromosome 11 (11p15.4). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. The SMPD1 gene creates (encodes) an enzyme known as acid sphingomyelinase (ASM). A mutation in this gene leads to deficient levels of functional copies of the ASM enzyme. This enzyme is essential to break down (metabolize) certain fatty substances (lipids) in the body. Reduced or absent activity of the ASM enzyme results in the abnormal accumulation sphingomyelin in various tissues of the body. Sphingomyelin is a fatty substance that is a component of most cell membranes. The abnormal accumulation of sphingomyelin within certain tissues of the body causes the signs and symptoms of acid sphingomyelinase deficiency. ASMD is a genetic disease, which means that it is inherited from the parents and might be present in other family members. In general, human beings receive two copies of most genes, one inherited from the mother, and one from the father. Recessive genetic disorders such as ASMD occur when an individual inherits changes, or mutations, in both copies of a particular gene (in this case, the SMPD1 gene.). If an individual receives one normal copy of a gene and one altered copy, 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 copy of the gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal copies of the gene from both parents and be neither affected nor a carrier for that particular trait is 25%. The risk is the same for males and females. | Causes of Acid Sphingomyelinase Deficiency. Acid sphingomyelinase deficiency is caused by a mutation in the sphingomyelin phophodiesterase-1 (SMPD1) 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.The SMPD1 gene is located on the short arm (p) of chromosome 11 (11p15.4). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. The SMPD1 gene creates (encodes) an enzyme known as acid sphingomyelinase (ASM). A mutation in this gene leads to deficient levels of functional copies of the ASM enzyme. This enzyme is essential to break down (metabolize) certain fatty substances (lipids) in the body. Reduced or absent activity of the ASM enzyme results in the abnormal accumulation sphingomyelin in various tissues of the body. Sphingomyelin is a fatty substance that is a component of most cell membranes. The abnormal accumulation of sphingomyelin within certain tissues of the body causes the signs and symptoms of acid sphingomyelinase deficiency. ASMD is a genetic disease, which means that it is inherited from the parents and might be present in other family members. In general, human beings receive two copies of most genes, one inherited from the mother, and one from the father. Recessive genetic disorders such as ASMD occur when an individual inherits changes, or mutations, in both copies of a particular gene (in this case, the SMPD1 gene.). If an individual receives one normal copy of a gene and one altered copy, 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 copy of the gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal copies of the gene from both parents and be neither affected nor a carrier for that particular trait is 25%. The risk is the same for males and females. | 11 | Acid Sphingomyelinase Deficiency |
nord_11_3 | Affects of Acid Sphingomyelinase Deficiency | ASMD affects males and females in equal numbers. The exact incidence and prevalence of the disorder is unknown, but has been estimated at 1 in 250,000 individuals in the general population. However, because some cases go misdiagnosed or undiagnosed, determining the true frequency of ASMD in the general population is difficult. The severe, infantile form (Niemann-Pick type A) can affect different ethnic groups, but occurs with greater frequency in individuals of Ashkenazi Jewish descent. Later-onset forms (Niemann-Pick type B) can affect all ethnic groups. | Affects of Acid Sphingomyelinase Deficiency. ASMD affects males and females in equal numbers. The exact incidence and prevalence of the disorder is unknown, but has been estimated at 1 in 250,000 individuals in the general population. However, because some cases go misdiagnosed or undiagnosed, determining the true frequency of ASMD in the general population is difficult. The severe, infantile form (Niemann-Pick type A) can affect different ethnic groups, but occurs with greater frequency in individuals of Ashkenazi Jewish descent. Later-onset forms (Niemann-Pick type B) can affect all ethnic groups. | 11 | Acid Sphingomyelinase Deficiency |
nord_11_4 | Related disorders of Acid Sphingomyelinase Deficiency | Symptoms of the following disorders can be similar to those of ASMD. Comparisons may be useful for a differential diagnosis.There are several types of metabolic disorders in which there is secondary accumulation of certain substances like fats and carbohydrates including the mucopolysaccharidoses and other lysosomal storage disorders. These disorders include galactosemia, sialidosis, Niemann-Pick disease type C, Gaucher disease, galactosialidosis, Wolman disease, cholesteryl ester storage deficiency, (For more information on these disorders, choose the specific lysosomal storage disorder name as your search term in the Rare Disease Database.) | Related disorders of Acid Sphingomyelinase Deficiency. Symptoms of the following disorders can be similar to those of ASMD. Comparisons may be useful for a differential diagnosis.There are several types of metabolic disorders in which there is secondary accumulation of certain substances like fats and carbohydrates including the mucopolysaccharidoses and other lysosomal storage disorders. These disorders include galactosemia, sialidosis, Niemann-Pick disease type C, Gaucher disease, galactosialidosis, Wolman disease, cholesteryl ester storage deficiency, (For more information on these disorders, choose the specific lysosomal storage disorder name as your search term in the Rare Disease Database.) | 11 | Acid Sphingomyelinase Deficiency |
nord_11_5 | Diagnosis of Acid Sphingomyelinase Deficiency | A diagnosis of ASMD is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Clinical Testing and Workup
Individuals suspected of ASMD will be tested to determine whether the activity of the enzyme, ASM, is reduced or absent. Peripheral blood leukocytes or cultured skin fibroblasts are examined to assess residual ASM activity. A diagnosis is confirmed when a suspected sample demonstrates less than 10% that of a control sample. Peripheral blood leukocytes are white blood cells that are drawn from the blood. Cultured fibroblasts are connective tissue cells obtained from a skin sample and grown in a laboratory. Molecular genetic testing can confirm a diagnosis of ASMD. Molecular genetic testing can detect mutations in the SMPD1 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories. | Diagnosis of Acid Sphingomyelinase Deficiency. A diagnosis of ASMD is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Clinical Testing and Workup
Individuals suspected of ASMD will be tested to determine whether the activity of the enzyme, ASM, is reduced or absent. Peripheral blood leukocytes or cultured skin fibroblasts are examined to assess residual ASM activity. A diagnosis is confirmed when a suspected sample demonstrates less than 10% that of a control sample. Peripheral blood leukocytes are white blood cells that are drawn from the blood. Cultured fibroblasts are connective tissue cells obtained from a skin sample and grown in a laboratory. Molecular genetic testing can confirm a diagnosis of ASMD. Molecular genetic testing can detect mutations in the SMPD1 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories. | 11 | Acid Sphingomyelinase Deficiency |
nord_11_6 | Therapies of Acid Sphingomyelinase Deficiency | The treatment of ASMD may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, hepatologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan a child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families. Current therapies are directed toward the specific symptoms that are apparent in each individual. In Niemann-Pick type A, physical and occupational therapy and periodic nutritional assessment may be recommended. Ensuring proper nutritional intake may require the implantation of a feeding (gastronomy) tube. With this procedure, a thin tube is placed into the stomach via a small incision in the abdomen, allowing for direct intake of food and/or medicine. The sleep issues associated with the disorder can be treated with nocturnal sedatives. Treatment for dyslipidemia may be required in some adults with type B disease. Nutritional support is also encouraged for individuals with type B disease to guide sufficient high quality caloric intake, ensure proper calcium and vitamin D intake because of the risk of osteopenia, and reduce the risk of dyslipidemia in adults. Blood transfusions may be required for individuals with Niemann-Pick type B who experience prolonged bleeding due to thrombocytopenia. Individuals with lung disease may require supplemental oxygen. Individuals with an enlarged spleen are advised to avoid contact sports to prevent the spleen from rupturing. Adults with hyperlipidemia should be treatment to correct cholesterol levels. Liver transplantation has been reported in some adults with liver failure due to Niemann-Pick B. In 2022, Olipudase alfa (Xenpozyme) was approved by the U.S Food and Drug Administration (FDA) to treat pediatric and adult patients with ASMD. This is the first approved medication to treat symptoms that are not related to the central nervous system in patients with ASMD. Olipudase is an enzyme replacement therapy (ERT) that replaces the missing enzyme, acid sphingomyelinase, with a genetically engineered (recombinant) form and helps reduce sphingomyelin accumulation in the liver, spleen and lung. | Therapies of Acid Sphingomyelinase Deficiency. The treatment of ASMD may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, hepatologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan a child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families. Current therapies are directed toward the specific symptoms that are apparent in each individual. In Niemann-Pick type A, physical and occupational therapy and periodic nutritional assessment may be recommended. Ensuring proper nutritional intake may require the implantation of a feeding (gastronomy) tube. With this procedure, a thin tube is placed into the stomach via a small incision in the abdomen, allowing for direct intake of food and/or medicine. The sleep issues associated with the disorder can be treated with nocturnal sedatives. Treatment for dyslipidemia may be required in some adults with type B disease. Nutritional support is also encouraged for individuals with type B disease to guide sufficient high quality caloric intake, ensure proper calcium and vitamin D intake because of the risk of osteopenia, and reduce the risk of dyslipidemia in adults. Blood transfusions may be required for individuals with Niemann-Pick type B who experience prolonged bleeding due to thrombocytopenia. Individuals with lung disease may require supplemental oxygen. Individuals with an enlarged spleen are advised to avoid contact sports to prevent the spleen from rupturing. Adults with hyperlipidemia should be treatment to correct cholesterol levels. Liver transplantation has been reported in some adults with liver failure due to Niemann-Pick B. In 2022, Olipudase alfa (Xenpozyme) was approved by the U.S Food and Drug Administration (FDA) to treat pediatric and adult patients with ASMD. This is the first approved medication to treat symptoms that are not related to the central nervous system in patients with ASMD. Olipudase is an enzyme replacement therapy (ERT) that replaces the missing enzyme, acid sphingomyelinase, with a genetically engineered (recombinant) form and helps reduce sphingomyelin accumulation in the liver, spleen and lung. | 11 | Acid Sphingomyelinase Deficiency |
nord_12_0 | Overview of Acidemia, Methylmalonic | The methylmalonic acidemias are organic acidemias caused by an enzymatic defect in the metabolism of four amino acids (methionine, threonine, isoleucine and valine). This results in an abnormally high level of acid in the blood (academia) and body tissues. In the acute form, drowsiness, coma, and seizures may occur. Mental retardation is a long-term consequence. The disorder may be caused by a deficiency of one or more of the enzymes methylmalonyl CoA mutase, methylmalonyl racemase, or adenosylcobalamin synthetic enzymes. Excretion of methylmalonate, a product of amino acid metabolism, in the urine is abnormally high and therefore is a marker of the disorder. All known organic acidemias are inherited as autosomal recessive traits. | Overview of Acidemia, Methylmalonic. The methylmalonic acidemias are organic acidemias caused by an enzymatic defect in the metabolism of four amino acids (methionine, threonine, isoleucine and valine). This results in an abnormally high level of acid in the blood (academia) and body tissues. In the acute form, drowsiness, coma, and seizures may occur. Mental retardation is a long-term consequence. The disorder may be caused by a deficiency of one or more of the enzymes methylmalonyl CoA mutase, methylmalonyl racemase, or adenosylcobalamin synthetic enzymes. Excretion of methylmalonate, a product of amino acid metabolism, in the urine is abnormally high and therefore is a marker of the disorder. All known organic acidemias are inherited as autosomal recessive traits. | 12 | Acidemia, Methylmalonic |
nord_12_1 | Symptoms of Acidemia, Methylmalonic | The onset of the Methylmalonic Acidemias usually occurs during the first few months of life although onset to late childhoods has been described. Symptoms may include lethargy, failure to thrive, recurrent vomiting, acidosis, dehydration, respiratory distress, diminished muscle tone, developmental retardation, seizures and/or an enlarged liver.Laboratory findings include an abnormally high amount of methylmalonic acid in the blood and urine. Metabolic acidosis also occurs. Elevated levels of ketone bodies such as acetone in the blood (ketonemia) or in the urine (ketonuria) may develop. An elevated level of ammonia in the blood (hyperammonemia) may also be present. Excessive levels of the amino acid, glycine in the blood (hyperglycinemia) and in the urine (hyperglycinuria) is found. The concentration of white blood cells, blood platelets and red blood cells may be lower than normal. Low blood sugar (hypoglycemia) may also occur. | Symptoms of Acidemia, Methylmalonic. The onset of the Methylmalonic Acidemias usually occurs during the first few months of life although onset to late childhoods has been described. Symptoms may include lethargy, failure to thrive, recurrent vomiting, acidosis, dehydration, respiratory distress, diminished muscle tone, developmental retardation, seizures and/or an enlarged liver.Laboratory findings include an abnormally high amount of methylmalonic acid in the blood and urine. Metabolic acidosis also occurs. Elevated levels of ketone bodies such as acetone in the blood (ketonemia) or in the urine (ketonuria) may develop. An elevated level of ammonia in the blood (hyperammonemia) may also be present. Excessive levels of the amino acid, glycine in the blood (hyperglycinemia) and in the urine (hyperglycinuria) is found. The concentration of white blood cells, blood platelets and red blood cells may be lower than normal. Low blood sugar (hypoglycemia) may also occur. | 12 | Acidemia, Methylmalonic |
nord_12_2 | Causes of Acidemia, Methylmalonic | Researchers at the University of Calgary and McGill University in Canada announced in December 2002 that they had identified genes that underlie two severe forms of methylmalonic academia. This discovery should make possible DNA testing for carriers and prenatal diagnosis, which is important because treatment can be started during pregnancy.All known organic acidemias are inherited as autosomal recessive traits. Human traits including the classic genetic diseases are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective 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 of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. On average, 50 percent of their children will be carriers of the disease but will not show symptoms of the disorder, while 25 percent will receive a normal copy of the gene from each parent. These risks are the same for each pregnancy. | Causes of Acidemia, Methylmalonic. Researchers at the University of Calgary and McGill University in Canada announced in December 2002 that they had identified genes that underlie two severe forms of methylmalonic academia. This discovery should make possible DNA testing for carriers and prenatal diagnosis, which is important because treatment can be started during pregnancy.All known organic acidemias are inherited as autosomal recessive traits. Human traits including the classic genetic diseases are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective 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 of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. On average, 50 percent of their children will be carriers of the disease but will not show symptoms of the disorder, while 25 percent will receive a normal copy of the gene from each parent. These risks are the same for each pregnancy. | 12 | Acidemia, Methylmalonic |
nord_12_3 | Affects of Acidemia, Methylmalonic | The Methylmalonic Acidemias occur at a rate of 1 in 50,000 to 1 in 100,000 live births. | Affects of Acidemia, Methylmalonic. The Methylmalonic Acidemias occur at a rate of 1 in 50,000 to 1 in 100,000 live births. | 12 | Acidemia, Methylmalonic |
nord_12_4 | Related disorders of Acidemia, Methylmalonic | Symptoms of the following disorders are similar to those of Methylmalonic Acidemias. Comparisons may be useful for a differential diagnosis.Ketotic Hyperglycinemia is a group of hereditary protein metabolism disorders. In each case, a defective enzyme prevents the breakdown of certain amino acids and lipids. High levels of the amino acid glycine and ketones accumulate in the blood and urine. Clinically, affected infants have feeding difficulties and developmental, neurological, digestive, and metabolic problems, as well as increased susceptibility to infections. Often, complications can be avoided with early treatment. The disorders are very rare, with only a few individual cases reported. Methylmalonic Acidemia is a form of Ketotic Hyperglycinemia. (For more information on this disorder, choose “Ketotic Hyperglycinemia” as your search term in the Rare Disease Database.)Propionic Acidemia is a very rare genetic form of Ketotic Hyperglycinemia. This disorder is caused by a deficiency of the enzyme propionyl CoA carboxylase, one of the enzymes necessary in the process of breaking down amino acids. (For more information on this disorder, choose “Propionic Acidemia” as your search term in the Rare Disease Database.) | Related disorders of Acidemia, Methylmalonic. Symptoms of the following disorders are similar to those of Methylmalonic Acidemias. Comparisons may be useful for a differential diagnosis.Ketotic Hyperglycinemia is a group of hereditary protein metabolism disorders. In each case, a defective enzyme prevents the breakdown of certain amino acids and lipids. High levels of the amino acid glycine and ketones accumulate in the blood and urine. Clinically, affected infants have feeding difficulties and developmental, neurological, digestive, and metabolic problems, as well as increased susceptibility to infections. Often, complications can be avoided with early treatment. The disorders are very rare, with only a few individual cases reported. Methylmalonic Acidemia is a form of Ketotic Hyperglycinemia. (For more information on this disorder, choose “Ketotic Hyperglycinemia” as your search term in the Rare Disease Database.)Propionic Acidemia is a very rare genetic form of Ketotic Hyperglycinemia. This disorder is caused by a deficiency of the enzyme propionyl CoA carboxylase, one of the enzymes necessary in the process of breaking down amino acids. (For more information on this disorder, choose “Propionic Acidemia” as your search term in the Rare Disease Database.) | 12 | Acidemia, Methylmalonic |
nord_12_5 | Diagnosis of Acidemia, Methylmalonic | Methylmalonic Acidemias can usually be diagnosed before birth (prenatally) by measuring the concentration of methylmalonic acid in amniotic fluid or activity of the deficient enzyme in fluid or tissue samples obtained from the fetus or uterus during pregnancy (amniocentesis or chorionic villus sampling [CVS]). During amniocentesis, a sample of fluid surrounding the developing fetus is removed and analyzed. CVS involves the removal and examination of tissue from a portion of the placenta. The disorder can be identified at birth through expanded newborn screening with tandem mass spectrometry.In most affected infants, the disorder is diagnosed or confirmed in the first weeks of life, based upon a thorough clinical evaluation, a detailed patient and family history, and a variety of specialized tests. Laboratory studies (assays) are typically conducted on certain white blood cells (leukocytes) or cultured skin cells (fibroblasts) to confirm deficient activity of the deficient enzyme. Additional laboratory studies may reveal excessive levels of acids and increased accumulations of ketone bodies in bodily tissues and fluids (ketoacidosis), increased levels of glycine in the blood and urine (hyperglycinemia and hyperglycinuria), high levels of ammonia in the blood (hyperammonemia), and/or decreased levels of circulating platelets and white blood cells (thrombocytopenia and neutropenia). | Diagnosis of Acidemia, Methylmalonic. Methylmalonic Acidemias can usually be diagnosed before birth (prenatally) by measuring the concentration of methylmalonic acid in amniotic fluid or activity of the deficient enzyme in fluid or tissue samples obtained from the fetus or uterus during pregnancy (amniocentesis or chorionic villus sampling [CVS]). During amniocentesis, a sample of fluid surrounding the developing fetus is removed and analyzed. CVS involves the removal and examination of tissue from a portion of the placenta. The disorder can be identified at birth through expanded newborn screening with tandem mass spectrometry.In most affected infants, the disorder is diagnosed or confirmed in the first weeks of life, based upon a thorough clinical evaluation, a detailed patient and family history, and a variety of specialized tests. Laboratory studies (assays) are typically conducted on certain white blood cells (leukocytes) or cultured skin cells (fibroblasts) to confirm deficient activity of the deficient enzyme. Additional laboratory studies may reveal excessive levels of acids and increased accumulations of ketone bodies in bodily tissues and fluids (ketoacidosis), increased levels of glycine in the blood and urine (hyperglycinemia and hyperglycinuria), high levels of ammonia in the blood (hyperammonemia), and/or decreased levels of circulating platelets and white blood cells (thrombocytopenia and neutropenia). | 12 | Acidemia, Methylmalonic |
nord_12_6 | Therapies of Acidemia, Methylmalonic | TreatmentThe diet of children with Methylmalonic Acidemias must be carefully controlled. Treatment includes a low-protein diet and avoidance of the amino acids isoleucine, valine, threonine and methionine. To assure a balanced diet, certain medical foods must be fed to affected children. Massive doses of vitamin B12 are indicated in the B12-responsive variants. In the disorders of cobalamin metabolism, administration of intramuscular and/or oral hydroxycobalamin may correct the defect and restore normal metabolism.Genetic counseling is recommended for the families of children with Methylmalonic Acidemias. | Therapies of Acidemia, Methylmalonic. TreatmentThe diet of children with Methylmalonic Acidemias must be carefully controlled. Treatment includes a low-protein diet and avoidance of the amino acids isoleucine, valine, threonine and methionine. To assure a balanced diet, certain medical foods must be fed to affected children. Massive doses of vitamin B12 are indicated in the B12-responsive variants. In the disorders of cobalamin metabolism, administration of intramuscular and/or oral hydroxycobalamin may correct the defect and restore normal metabolism.Genetic counseling is recommended for the families of children with Methylmalonic Acidemias. | 12 | Acidemia, Methylmalonic |
nord_13_0 | Overview of Acoustic Neuroma | An acoustic neuroma, also known as a vestibular schwannoma, is a rare benign (non-cancerous) growth that develops on the eighth cranial nerve. This nerve runs from the inner ear to the brain and is responsible for hearing and balance (equilibrium). Although there is no standard or typical pattern of symptom development, hearing loss in one ear (unilateral) is the initial symptom in approximately 90 percent of affected individuals. Additional common findings include ringing in the ears (tinnitus) and dizziness or imbalance. The symptoms of an acoustic neuroma occur from the tumor pressing against the eighth cranial nerve and disrupting its ability to transmit nerve signals to the brain. An acoustic neuroma is not cancerous (malignant); it does not spread to other parts of the body. The reason an acoustic neuroma forms is unknown. | Overview of Acoustic Neuroma. An acoustic neuroma, also known as a vestibular schwannoma, is a rare benign (non-cancerous) growth that develops on the eighth cranial nerve. This nerve runs from the inner ear to the brain and is responsible for hearing and balance (equilibrium). Although there is no standard or typical pattern of symptom development, hearing loss in one ear (unilateral) is the initial symptom in approximately 90 percent of affected individuals. Additional common findings include ringing in the ears (tinnitus) and dizziness or imbalance. The symptoms of an acoustic neuroma occur from the tumor pressing against the eighth cranial nerve and disrupting its ability to transmit nerve signals to the brain. An acoustic neuroma is not cancerous (malignant); it does not spread to other parts of the body. The reason an acoustic neuroma forms is unknown. | 13 | Acoustic Neuroma |
nord_13_1 | Symptoms of Acoustic Neuroma | Some individuals, especially those with small tumors, may not have any associated symptoms (asymptomatic). However, even small tumors, depending upon their location, can cause significant symptoms or physical findings.Acoustic neuromas are slow-growing tumors that can eventually cause a variety of symptoms by pressing against the eighth cranial nerve. Hearing loss in one ear (the ear affected by the tumor) is the initial symptom in approximately 90 percent of patients. Hearing loss is usually gradual, although in some rare cases it can be sudden. In some cases, hearing loss can also fluctuate (worsen and then improve). Hearing loss may be accompanied by ringing in the ears, a condition known as tinnitus, or by a feeling of fullness in the affected ear. In some cases, affected individuals may have difficulty understanding speech that is disproportional to the amount of hearing loss.Acoustic neuromas can also cause dizziness and problems with balance such as unsteadiness. In rare cases, dizziness or balance problems may occur before noticeable hearing loss. Because these tumors usually grow very slowly, the body can often compensate for these balance problems.Although slow-growing, acoustic neuromas can eventually become large enough to press against neighboring cranial nerves. While rare, symptoms resulting from the involvement of other cranial nerves include facial weakness or paralysis, facial numbness or tingling, and swallowing difficulties. Facial numbness or tingling can be constant or it may come and go (intermittent).In some patients, acoustic neuromas may grow large enough to press against the brainstem, preventing the normal flow of cerebrospinal fluid between the brain and spinal cord. This fluid can accumulate in the skull, leading to a phenomenon called hydrocephalus, which causes pressure on the tissues of brain and results in a variety of symptoms including headaches, an impaired ability to coordinate voluntary movements (ataxia), and mental confusion. Headaches may also occur in the absence of hydrocephalus and in some rare cases may be the first sign of an acoustic neuroma. In very rare cases, an untreated acoustic neuroma that presses on the brain can cause life-threatening complications. | Symptoms of Acoustic Neuroma. Some individuals, especially those with small tumors, may not have any associated symptoms (asymptomatic). However, even small tumors, depending upon their location, can cause significant symptoms or physical findings.Acoustic neuromas are slow-growing tumors that can eventually cause a variety of symptoms by pressing against the eighth cranial nerve. Hearing loss in one ear (the ear affected by the tumor) is the initial symptom in approximately 90 percent of patients. Hearing loss is usually gradual, although in some rare cases it can be sudden. In some cases, hearing loss can also fluctuate (worsen and then improve). Hearing loss may be accompanied by ringing in the ears, a condition known as tinnitus, or by a feeling of fullness in the affected ear. In some cases, affected individuals may have difficulty understanding speech that is disproportional to the amount of hearing loss.Acoustic neuromas can also cause dizziness and problems with balance such as unsteadiness. In rare cases, dizziness or balance problems may occur before noticeable hearing loss. Because these tumors usually grow very slowly, the body can often compensate for these balance problems.Although slow-growing, acoustic neuromas can eventually become large enough to press against neighboring cranial nerves. While rare, symptoms resulting from the involvement of other cranial nerves include facial weakness or paralysis, facial numbness or tingling, and swallowing difficulties. Facial numbness or tingling can be constant or it may come and go (intermittent).In some patients, acoustic neuromas may grow large enough to press against the brainstem, preventing the normal flow of cerebrospinal fluid between the brain and spinal cord. This fluid can accumulate in the skull, leading to a phenomenon called hydrocephalus, which causes pressure on the tissues of brain and results in a variety of symptoms including headaches, an impaired ability to coordinate voluntary movements (ataxia), and mental confusion. Headaches may also occur in the absence of hydrocephalus and in some rare cases may be the first sign of an acoustic neuroma. In very rare cases, an untreated acoustic neuroma that presses on the brain can cause life-threatening complications. | 13 | Acoustic Neuroma |
nord_13_2 | Causes of Acoustic Neuroma | The exact cause of an acoustic neuroma is unknown. Most cases seem to arise for no apparent reason (spontaneously). No specific risk factors for the development of these tumors have been identified.A variety of potential risk factors for acoustic neuroma have been studied including prior exposure to radiation to the head and neck area (as is done to treat certain cancers) or prolonged or sustained exposure to loud noises (as in an occupational setting). Research is under way to determine the specific cause and risk factors associated with an acoustic neuroma.In a small subset of cases, acoustic neuromas occur as part of a rare disorder known as neurofibromatosis type II. This rare genetic disorder is usually associated with acoustic neuromas affecting both ears at once (bilateral). (For more information on this disorder, choose “neurofibromatosis” as your search term in NORD’s Rare Disease Database.)An acoustic neuroma arises from a type of cell known as the Schwann cell. These cells form an insulating layer over all nerves of the peripheral nervous system (i.e., nerves outside of the central nervous system) including the eighth cranial nerve. The eighth cranial nerve is separated into two branches the cochlear branch, which transmits sound to the brain and the vestibular branch, which transmits balance information to the brain. Most acoustic neuromas occur on the vestibular portion of the eighth cranial nerve. Because these tumors are made up of Schwann cells and usually occur on the vestibular portion of the eighth cranial nerve, many physicians prefer the use of the term vestibular schwannoma. However, the term acoustic neuroma is still used more often in the medical literature. | Causes of Acoustic Neuroma. The exact cause of an acoustic neuroma is unknown. Most cases seem to arise for no apparent reason (spontaneously). No specific risk factors for the development of these tumors have been identified.A variety of potential risk factors for acoustic neuroma have been studied including prior exposure to radiation to the head and neck area (as is done to treat certain cancers) or prolonged or sustained exposure to loud noises (as in an occupational setting). Research is under way to determine the specific cause and risk factors associated with an acoustic neuroma.In a small subset of cases, acoustic neuromas occur as part of a rare disorder known as neurofibromatosis type II. This rare genetic disorder is usually associated with acoustic neuromas affecting both ears at once (bilateral). (For more information on this disorder, choose “neurofibromatosis” as your search term in NORD’s Rare Disease Database.)An acoustic neuroma arises from a type of cell known as the Schwann cell. These cells form an insulating layer over all nerves of the peripheral nervous system (i.e., nerves outside of the central nervous system) including the eighth cranial nerve. The eighth cranial nerve is separated into two branches the cochlear branch, which transmits sound to the brain and the vestibular branch, which transmits balance information to the brain. Most acoustic neuromas occur on the vestibular portion of the eighth cranial nerve. Because these tumors are made up of Schwann cells and usually occur on the vestibular portion of the eighth cranial nerve, many physicians prefer the use of the term vestibular schwannoma. However, the term acoustic neuroma is still used more often in the medical literature. | 13 | Acoustic Neuroma |
nord_13_3 | Affects of Acoustic Neuroma | Acoustic neuromas affect women more often than men. Most cases of acoustic neuroma develop in individuals between the ages of 30 and 60. Although quite rare, they can develop in children. Acoustic neuromas are estimated to affect about 1 in 100,000 people in the general population. Racial differences have been reported in which Black, Hispanic, and Asian Americans have relatively lower rates of acoustic neuroma diagnoses than White Americans. Approximately 2,500 new patients are diagnosed each year. The incidence has risen in the last several years, which some researchers attribute to the greater frequency in which small tumors are recognized. However, many individuals with small acoustic neuromas may remain undiagnosed, making it difficult to determine its true frequency in the general population. | Affects of Acoustic Neuroma. Acoustic neuromas affect women more often than men. Most cases of acoustic neuroma develop in individuals between the ages of 30 and 60. Although quite rare, they can develop in children. Acoustic neuromas are estimated to affect about 1 in 100,000 people in the general population. Racial differences have been reported in which Black, Hispanic, and Asian Americans have relatively lower rates of acoustic neuroma diagnoses than White Americans. Approximately 2,500 new patients are diagnosed each year. The incidence has risen in the last several years, which some researchers attribute to the greater frequency in which small tumors are recognized. However, many individuals with small acoustic neuromas may remain undiagnosed, making it difficult to determine its true frequency in the general population. | 13 | Acoustic Neuroma |
nord_13_4 | Related disorders of Acoustic Neuroma | Symptoms of the following disorders can be similar to those of acoustic neuromas. Comparisons may be useful for a differential diagnosis.Meniere’s disease is a rare disorder affecting the inner ear that is characterized by periodic episodes of rotary vertigo or dizziness; progressive, fluctuating, low-frequency (low-pitch) hearing loss; ringing in the ears (tinnitus); and a feeling of fullness or pressure in the ear. Symptoms may occur daily or only a couple times a year. Symptoms may develop suddenly. Over time hearing loss and tinnitus may become permanent. Vertigo can be severe and cause nausea, vomiting and sweating. The exact cause of Meniere’s disease is unknown (idiopathic). (For more information on this disorder, choose “Meniere” as your search term in the Rare Disease Database.)Bell’s palsy is a non-progressive neurological disorder of one of the facial nerves (7th cranial nerve). This disorder is characterized by the sudden onset of facial paralysis that may be preceded by a slight fever, pain behind the ear on the affected side, a stiff neck, and weakness and/or stiffness on one side of the face. Paralysis results from decreased blood supply (ischemia) and/or compression of the 7th cranial nerve. The exact cause of Bell’s palsy is not known. Viral (e.g., herpes zoster virus) and immune disorders are frequently implicated as a cause for this disorder. There may also be an inherited tendency toward developing Bell’s palsy. (For more information on this disorder, choose “Bell’s palsy” as your search term in the Rare Disease Database.)Meningioma is a rare and typically benign (non-cancerous) tumor that can mimic an acoustic neuroma. While they can occur in any area of the lining of the brain and spinal cord (dura), meningiomas can form adjacent to the hearing and balance nerves and cause symptoms of unilateral (one-sided) hearing loss, dizziness or imbalance, facial numbness, and/or swallowing difficulty. Magnetic resonance imaging (MRI) can often distinguish between an acoustic neuroma and a meningioma but there are times when even a skilled radiologist is unable to definitively differentiate between the two. If surgery is performed, a pathologist will make the final diagnosis based on the microscopic appearance (histology). | Related disorders of Acoustic Neuroma. Symptoms of the following disorders can be similar to those of acoustic neuromas. Comparisons may be useful for a differential diagnosis.Meniere’s disease is a rare disorder affecting the inner ear that is characterized by periodic episodes of rotary vertigo or dizziness; progressive, fluctuating, low-frequency (low-pitch) hearing loss; ringing in the ears (tinnitus); and a feeling of fullness or pressure in the ear. Symptoms may occur daily or only a couple times a year. Symptoms may develop suddenly. Over time hearing loss and tinnitus may become permanent. Vertigo can be severe and cause nausea, vomiting and sweating. The exact cause of Meniere’s disease is unknown (idiopathic). (For more information on this disorder, choose “Meniere” as your search term in the Rare Disease Database.)Bell’s palsy is a non-progressive neurological disorder of one of the facial nerves (7th cranial nerve). This disorder is characterized by the sudden onset of facial paralysis that may be preceded by a slight fever, pain behind the ear on the affected side, a stiff neck, and weakness and/or stiffness on one side of the face. Paralysis results from decreased blood supply (ischemia) and/or compression of the 7th cranial nerve. The exact cause of Bell’s palsy is not known. Viral (e.g., herpes zoster virus) and immune disorders are frequently implicated as a cause for this disorder. There may also be an inherited tendency toward developing Bell’s palsy. (For more information on this disorder, choose “Bell’s palsy” as your search term in the Rare Disease Database.)Meningioma is a rare and typically benign (non-cancerous) tumor that can mimic an acoustic neuroma. While they can occur in any area of the lining of the brain and spinal cord (dura), meningiomas can form adjacent to the hearing and balance nerves and cause symptoms of unilateral (one-sided) hearing loss, dizziness or imbalance, facial numbness, and/or swallowing difficulty. Magnetic resonance imaging (MRI) can often distinguish between an acoustic neuroma and a meningioma but there are times when even a skilled radiologist is unable to definitively differentiate between the two. If surgery is performed, a pathologist will make the final diagnosis based on the microscopic appearance (histology). | 13 | Acoustic Neuroma |
nord_13_5 | Diagnosis of Acoustic Neuroma | A diagnosis of an acoustic neuroma is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of specialized tests. Such tests include hearing exams, x-ray scans such as magnetic resonance imaging (MRI) or computed tomography (CT), a specialized test that evaluates balance (electronystagmography), and a brainstem auditory evoked response (BAER).An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. MRIs are the most sensitive study to confirm the presence of an acoustic neuroma.An electronystagmography test evaluates balance by detecting abnormal, involuntary eye movements, a condition known as nystagmus. Nystagmus may occur as a result of inner ear complications such as an acoustic neuroma.A BAER exam checks hearing and neurological function and interaction by recording the brain's response to certain sounds. Since an acoustic neuroma can disrupt the nerve pathway that relays sound from the ear to the brain, a positive result of a BAER exam could be caused by these tumors. | Diagnosis of Acoustic Neuroma. A diagnosis of an acoustic neuroma is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of specialized tests. Such tests include hearing exams, x-ray scans such as magnetic resonance imaging (MRI) or computed tomography (CT), a specialized test that evaluates balance (electronystagmography), and a brainstem auditory evoked response (BAER).An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. MRIs are the most sensitive study to confirm the presence of an acoustic neuroma.An electronystagmography test evaluates balance by detecting abnormal, involuntary eye movements, a condition known as nystagmus. Nystagmus may occur as a result of inner ear complications such as an acoustic neuroma.A BAER exam checks hearing and neurological function and interaction by recording the brain's response to certain sounds. Since an acoustic neuroma can disrupt the nerve pathway that relays sound from the ear to the brain, a positive result of a BAER exam could be caused by these tumors. | 13 | Acoustic Neuroma |
nord_13_6 | Therapies of Acoustic Neuroma | TreatmentThe treatment of an acoustic neuroma may involve observation (if the tumor is small and does not cause symptoms), surgical removal (microsurgery or excision) of the tumor, or the use of radiation to stop the tumor from growing (radiation therapy or radiosurgery).Observation
This option may be preferred in affected individuals where no associated symptoms are present or where a small tumor is not growing or growing at a slow rate. This period of observation may be called “watch and wait”. In elderly individuals who do not have symptoms, watch and wait may be appropriate because an acoustic neuroma may not require treatment during an individual's normal life expectancy and the inherent risks and complications of removal can be avoided.Watchful waiting is also appropriate if an individual with hearing in only one ear is found with an acoustic neuroma in that ear. The patient may choose to live with the acoustic neuroma as long as it is not a life-threatening condition rather than risk further hearing loss that can potentially occur from therapy.If an acoustic neuroma eventually causes symptoms, then radiation therapy or microsurgery may be necessary. There is not a single, “best” therapy for all affected individuals. The specific location and size of an acoustic neuroma as well as an affected individual's overall level of hearing and general health are all considered when determining which treatment method is used.Microsurgery
Surgery performed with specialized instruments under a microscope (microsurgery) may be necessary in some individuals with an acoustic neuroma. Microsurgery allows physicians to perform surgery on very small body parts.During microsurgery, a physician may remove all or part of an acoustic neuroma. Partial tumor removal is undertaken to reduce the risk of unwanted surgical complications. In other words, it may be easier and safer to take out part of the growth rather than the whole tumor. If the tumor is very large or if the person is older, partial removal may be more appropriate. Further surgery may be necessary in the future if partial tumor removal is performed.When total tumor removal is indicated, the objective of the procedure is to protect the facial nerve and avoid facial paralysis. In addition the surgeon tries to preserve hearing as much as possible in the affected ear.Three different surgical approaches are commonly used for individuals with an acoustic neuroma: retrosigmoid (suboccipital), middle fossa, and translabyrinthine. The size and location of the tumor as well as additional factors are all weighed when determining which approach is used.Radiation Therapy (Radiosurgery or Radiotherapy)
Three dimensional focusing of radiation has become more accurate in recent years so that affected individuals may be treated at one session on an outpatient basis or, alternatively, smaller doses may be delivered over several sessions. The objective is to aim so accurately that the tumor cells are affected and damage to surrounding cells is minimized. Radiation therapy has the ability to stop growth of a tumor. Radiation therapy provides a noninvasive treatment option for individuals with an acoustic neuroma, but in some patients it may take weeks, months or even a couple years to see significant effects from this treatment. Tumors treated with radiation therapy can start to grow again at some point later on.Complications
Post-treatment problems (from either surgery or radiation therapy) may include: cranial nerve deficits such facial weakness or numbness, hearing loss and dizziness. Headache, obstruction of fluid that surrounds the brain and spinal cord (cerebrospinal fluid), and/or decreased mental alertness due to blood clots or obstruction of flow of cerebrospinal fluid can also occur. Cerebrospinal fluid leakage or an infection that produces meningitis are rare complications of surgical therapy.The facial nerve may be damaged by the acoustic neuroma or as a result of surgery. In some affected individuals, it may be necessary for the surgeon to remove portions of the facial nerve, resulting in temporary or permanent facial paralysis. The regrowth of the nerve (regeneration) and restoration of function to the muscles of the face may take up to a year. If the facial paralysis persists, a second surgery may be performed to connect the healthy portion of the facial nerve to another nerve such as the hypoglossal nerve (nerve that controls the tongue) in the neck or the nerve to masseter (nerve that helps with chewing) in the face. This may bring some improvement in function to the muscles of the face. There are a number of other surgical procedures that can aid in reanimating the face that can improve the function and appearance of the weakened side of the face. Eye problems may develop in some individuals following surgical removal of an acoustic neuroma. Facial weakness can bring about incomplete eyelid closure on the affected side which may lead to irritation of the cornea. In rare instances, this has the potential to lead to blindness of the affected eye. The eye must be kept moist with frequent use of artificial tears, and a barrier applied during sleep, such as a moisture chamber, or taped closed. The use of an eye patch is discouraged as it may contribute to corneal damage.
Double vision (diplopia) may occur if there is pressure on the 6th cranial nerve, and there may be impairment of the muscles of the eyelids. Artificial tears or eye lubricants may be needed. Additionally, if prolonged facial paralysis is not treated, then it is possible that food may “get lost” in the mouth on the affected side, which could contribute to dental problems. | Therapies of Acoustic Neuroma. TreatmentThe treatment of an acoustic neuroma may involve observation (if the tumor is small and does not cause symptoms), surgical removal (microsurgery or excision) of the tumor, or the use of radiation to stop the tumor from growing (radiation therapy or radiosurgery).Observation
This option may be preferred in affected individuals where no associated symptoms are present or where a small tumor is not growing or growing at a slow rate. This period of observation may be called “watch and wait”. In elderly individuals who do not have symptoms, watch and wait may be appropriate because an acoustic neuroma may not require treatment during an individual's normal life expectancy and the inherent risks and complications of removal can be avoided.Watchful waiting is also appropriate if an individual with hearing in only one ear is found with an acoustic neuroma in that ear. The patient may choose to live with the acoustic neuroma as long as it is not a life-threatening condition rather than risk further hearing loss that can potentially occur from therapy.If an acoustic neuroma eventually causes symptoms, then radiation therapy or microsurgery may be necessary. There is not a single, “best” therapy for all affected individuals. The specific location and size of an acoustic neuroma as well as an affected individual's overall level of hearing and general health are all considered when determining which treatment method is used.Microsurgery
Surgery performed with specialized instruments under a microscope (microsurgery) may be necessary in some individuals with an acoustic neuroma. Microsurgery allows physicians to perform surgery on very small body parts.During microsurgery, a physician may remove all or part of an acoustic neuroma. Partial tumor removal is undertaken to reduce the risk of unwanted surgical complications. In other words, it may be easier and safer to take out part of the growth rather than the whole tumor. If the tumor is very large or if the person is older, partial removal may be more appropriate. Further surgery may be necessary in the future if partial tumor removal is performed.When total tumor removal is indicated, the objective of the procedure is to protect the facial nerve and avoid facial paralysis. In addition the surgeon tries to preserve hearing as much as possible in the affected ear.Three different surgical approaches are commonly used for individuals with an acoustic neuroma: retrosigmoid (suboccipital), middle fossa, and translabyrinthine. The size and location of the tumor as well as additional factors are all weighed when determining which approach is used.Radiation Therapy (Radiosurgery or Radiotherapy)
Three dimensional focusing of radiation has become more accurate in recent years so that affected individuals may be treated at one session on an outpatient basis or, alternatively, smaller doses may be delivered over several sessions. The objective is to aim so accurately that the tumor cells are affected and damage to surrounding cells is minimized. Radiation therapy has the ability to stop growth of a tumor. Radiation therapy provides a noninvasive treatment option for individuals with an acoustic neuroma, but in some patients it may take weeks, months or even a couple years to see significant effects from this treatment. Tumors treated with radiation therapy can start to grow again at some point later on.Complications
Post-treatment problems (from either surgery or radiation therapy) may include: cranial nerve deficits such facial weakness or numbness, hearing loss and dizziness. Headache, obstruction of fluid that surrounds the brain and spinal cord (cerebrospinal fluid), and/or decreased mental alertness due to blood clots or obstruction of flow of cerebrospinal fluid can also occur. Cerebrospinal fluid leakage or an infection that produces meningitis are rare complications of surgical therapy.The facial nerve may be damaged by the acoustic neuroma or as a result of surgery. In some affected individuals, it may be necessary for the surgeon to remove portions of the facial nerve, resulting in temporary or permanent facial paralysis. The regrowth of the nerve (regeneration) and restoration of function to the muscles of the face may take up to a year. If the facial paralysis persists, a second surgery may be performed to connect the healthy portion of the facial nerve to another nerve such as the hypoglossal nerve (nerve that controls the tongue) in the neck or the nerve to masseter (nerve that helps with chewing) in the face. This may bring some improvement in function to the muscles of the face. There are a number of other surgical procedures that can aid in reanimating the face that can improve the function and appearance of the weakened side of the face. Eye problems may develop in some individuals following surgical removal of an acoustic neuroma. Facial weakness can bring about incomplete eyelid closure on the affected side which may lead to irritation of the cornea. In rare instances, this has the potential to lead to blindness of the affected eye. The eye must be kept moist with frequent use of artificial tears, and a barrier applied during sleep, such as a moisture chamber, or taped closed. The use of an eye patch is discouraged as it may contribute to corneal damage.
Double vision (diplopia) may occur if there is pressure on the 6th cranial nerve, and there may be impairment of the muscles of the eyelids. Artificial tears or eye lubricants may be needed. Additionally, if prolonged facial paralysis is not treated, then it is possible that food may “get lost” in the mouth on the affected side, which could contribute to dental problems. | 13 | Acoustic Neuroma |
nord_14_0 | Overview of Acquired Aplastic Anemia | SummaryAcquired aplastic anemia is a rare, serious blood disorder, due to failure of the bone marrow failure to produce blood cells. Bone marrow is the spongy substance found in the center of the bones of the body, in adults mainly the spine, pelvis, and large bones of the legs. The bone marrow contains hematopoietic stem cells. Stem cells can produce more stem cells (self-renewal) and also differentiate and proliferate, giving rise to red blood cells (erythrocytes), white blood cells (leukocytes), and platelets. In acquired aplastic anemia, an almost complete absence of hematopoietic stem cells results in low levels of red and white blood cells and platelets (pancytopenia). Symptoms of aplastic anemia are those of anemia, bleeding, and infection. Although bone marrow failure can occur secondary to other disorders, most aplastic anemia is due to the immune system mistakenly targeting the bone marrow (autoimmunity). Indeed, most patients can respond to therapy that suppresses the immune system, usually ATG and cyclosporine.IntroductionAplastic anemia is classified as severe according to blood counts. Most of the discussion that follows relates to severe aplastic anemia. Patients with more moderately decreased blood counts; may not require treatment. Furthermore, some aplastic anemia that is genetically inherited may, first manifest in adulthood, sometimes without a family history of blood disease. | Overview of Acquired Aplastic Anemia. SummaryAcquired aplastic anemia is a rare, serious blood disorder, due to failure of the bone marrow failure to produce blood cells. Bone marrow is the spongy substance found in the center of the bones of the body, in adults mainly the spine, pelvis, and large bones of the legs. The bone marrow contains hematopoietic stem cells. Stem cells can produce more stem cells (self-renewal) and also differentiate and proliferate, giving rise to red blood cells (erythrocytes), white blood cells (leukocytes), and platelets. In acquired aplastic anemia, an almost complete absence of hematopoietic stem cells results in low levels of red and white blood cells and platelets (pancytopenia). Symptoms of aplastic anemia are those of anemia, bleeding, and infection. Although bone marrow failure can occur secondary to other disorders, most aplastic anemia is due to the immune system mistakenly targeting the bone marrow (autoimmunity). Indeed, most patients can respond to therapy that suppresses the immune system, usually ATG and cyclosporine.IntroductionAplastic anemia is classified as severe according to blood counts. Most of the discussion that follows relates to severe aplastic anemia. Patients with more moderately decreased blood counts; may not require treatment. Furthermore, some aplastic anemia that is genetically inherited may, first manifest in adulthood, sometimes without a family history of blood disease. | 14 | Acquired Aplastic Anemia |
nord_14_1 | Symptoms of Acquired Aplastic Anemia | The symptoms of acquired aplastic anemia occur as a consequence of the bone marrow failing to produce enough blood cells. Specific symptoms vary from case to case. Some individuals may have mild symptoms that remain stable for many years; others may have serious symptoms that can progress to life-threatening complications.Red and white blood cells and platelets are formed in the bone marrow. The cells are released into the bloodstream to travel throughout the body performing their specific functions. Red blood cells deliver oxygen to the body’s organs, white blood cells help in fighting infections, and platelets form clots to stop bleeding. A low level of circulating red blood cells is called anemia. A low level of white blood cells is known as leukopenia. A low level of platelets is known as thrombocytopenia.Individuals with anemia may experience tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing, and cardiac symptoms like chest pain. Individuals with leukopenia have an increase in risk of contracting bacterial and fungal infections. Individuals with thrombocytopenia are more susceptible to bruising following minimal injury and to spontaneous bleeding from the gums and nose. Women may have increased menstrual blood loss. Symptoms are dependent on the severity of the anemia, leukopenia, and thrombocytopenia.Some individuals with acquired aplastic anemia also have another disorder at the same time, called paroxysmal nocturnal hemoglobinuria (PNH). Acquired aplastic and PNH have a close relationship that is not fully understood by researchers. It is believed that PNH arises in the setting of autoimmune acquired aplastic anemia and bone marrow failure. Individuals affected with acquired aplastic anemia are also at risk that it will evolve into another similar disorder known as myelodysplasia. In a minority of cases, acquired aplastic anemia may eventually develop leukemia. PNH is caused by an acquired genetic defect affecting the PIGA gene, limited to marrow stem cells. The PIGA gene mutations cause blood cells to become sensitive to increased destruction by complement, a blood immunity protein. About half patients with aplastic anemia have evidence of PNH at presentation, as detected by flow cytometry. Furthermore, patients who respond following immunosuppressive therapy may recover with PNH. There are a minority of MDS patients with hypoplastic or low cellularity bone marrow, as seen in acquired aplastic anemia. These conditions are often mistaken for each other, so whether one is transformed to another is uncertain. (For more information on these disorders, see the Related Disorders section of this report.) | Symptoms of Acquired Aplastic Anemia. The symptoms of acquired aplastic anemia occur as a consequence of the bone marrow failing to produce enough blood cells. Specific symptoms vary from case to case. Some individuals may have mild symptoms that remain stable for many years; others may have serious symptoms that can progress to life-threatening complications.Red and white blood cells and platelets are formed in the bone marrow. The cells are released into the bloodstream to travel throughout the body performing their specific functions. Red blood cells deliver oxygen to the body’s organs, white blood cells help in fighting infections, and platelets form clots to stop bleeding. A low level of circulating red blood cells is called anemia. A low level of white blood cells is known as leukopenia. A low level of platelets is known as thrombocytopenia.Individuals with anemia may experience tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing, and cardiac symptoms like chest pain. Individuals with leukopenia have an increase in risk of contracting bacterial and fungal infections. Individuals with thrombocytopenia are more susceptible to bruising following minimal injury and to spontaneous bleeding from the gums and nose. Women may have increased menstrual blood loss. Symptoms are dependent on the severity of the anemia, leukopenia, and thrombocytopenia.Some individuals with acquired aplastic anemia also have another disorder at the same time, called paroxysmal nocturnal hemoglobinuria (PNH). Acquired aplastic and PNH have a close relationship that is not fully understood by researchers. It is believed that PNH arises in the setting of autoimmune acquired aplastic anemia and bone marrow failure. Individuals affected with acquired aplastic anemia are also at risk that it will evolve into another similar disorder known as myelodysplasia. In a minority of cases, acquired aplastic anemia may eventually develop leukemia. PNH is caused by an acquired genetic defect affecting the PIGA gene, limited to marrow stem cells. The PIGA gene mutations cause blood cells to become sensitive to increased destruction by complement, a blood immunity protein. About half patients with aplastic anemia have evidence of PNH at presentation, as detected by flow cytometry. Furthermore, patients who respond following immunosuppressive therapy may recover with PNH. There are a minority of MDS patients with hypoplastic or low cellularity bone marrow, as seen in acquired aplastic anemia. These conditions are often mistaken for each other, so whether one is transformed to another is uncertain. (For more information on these disorders, see the Related Disorders section of this report.) | 14 | Acquired Aplastic Anemia |
Subsets and Splits