47, XXX (Trisomy X)

47, XXX (Trisomy X) is a disorder that affects females and is characterized by the presence of an additional X chromosome. Normally, females have two X chromosomes, but females with 47, XXX have three X chromosomes. The characteristics (phenotype) associated with this chromosomal disorder varies widely, but most commonly includes language-based learning disabilities, developmental dyspraxia, tall stature, low muscle tone (hypotonia) and abnormal bending or curving of the pinkies toward the ring fingers (clinodactyly). 47, XXX occurs randomly due to errors during the division of reproductive cells in one of the parents. This disorder occurs in one in 900 to 1,000 livebirths.

The severity of symptoms associated with 47, XXX may vary greatly from one person to another, but it is thought that many females are mildly affected or asymptomatic, as about 75% of girls remain undiagnosed for their whole lives (Frith, 2024). It is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals should talk to their specialists and medical team about their specific case, associated symptoms and overall prognosis.

47, XXX is a chromosomal abnormality characterized by the presence of an extra X chromosome in females. Chromosomes are found in the nucleus of all the cells in the body and these chromosomes carry the genetic characteristics of all individuals. There are 23 pairs of human chromosomes with the 23rd pair determining the sex of an individual. Typical males have one X and one Y chromosome (46, XY) while typical females have two X chromosomes (46, XX).

47, XXX is a chromosomal disorder that affects only females. Reported estimates of frequency have varied with the most common estimate being one in 1,000 female births. Since many females with the disorder may have few or no symptoms, researchers believe that the disorder is substantially underdiagnosed and that the reported number of affected females is inappropriately low (about 10%). With increased diagnosis, more in depth studies may be conducted and more girls with 47, XXX can be appropriately treated.

Symptoms of the following disorders can be similar to those of 47, XXX. Researchers currently think each additional X is associated with a more severe phenotypic outcome. Comparisons may be useful for a differential diagnosis.

47, XXX may be suspected based upon the identification of characteristic neurodevelopmental, behavioral or learning disabilities. A diagnosis may be confirmed by specialized tests such as chromosomal microarray analysis performed on blood or buccal samples that can reveal the presence of an extra X chromosome in the body’s cells.


47,XYY 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.

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.

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.

There is an estimated incidence of 48, XXYY in 1/18,000 to 1/50,000 male births.

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.

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.


MTHFS-related developmental delay-microcephaly-short stature-epilepsy syndrome

neurodevelopmental disorder with microcephaly, epilepsy and hypomyelination

The first signs of MTHFS deficiency are developmental delay, global failure to thrive and microcephaly. Affected children start to show signs of rigidity and spasticity as they develop. Seizures may not be noticeable right away but affected children will eventually be diagnosed with different types of epilepsy. An MRI will show cerebral hypomyelination. Some patients have more severe disabilities than others.

5,10-methenyltetrahydrofolate synthetase deficiency is caused by changes (disease-causing variants) in the MTHFS gene. This gene is responsible for producing the 5-MTHF protein. This protein plays an essential role in metabolizing the carbon chains of folinic acid and turning them into L-methyl folate. Disease-causing variants in the MTHFS gene affect the breakdown of folinic acid, causing folinic acid to build up and preventing the formation of myelin.

MTHFS deficiency is a rare disorder, but the frequency is not known. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. This disorder has been reported around the globe (Iran, Haiti, United States; with ancestry from the British Isles, France, Portugal, Italy, Austria, Czech Republic).

Many other neurodevelopmental disorders can cause signs and symptoms that are similar to MTHFS deficiency.

MTHFS deficiency may be suspected based on symptoms including failure to thrive, global developmental delay and microcephaly.


Aarskog-Scott 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.

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.

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.

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.

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.)


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.

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.

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.

Symptoms of the following disorders can be similar to those of abetalipoproteinemia. Comparisons may be useful for a differential diagnosis.

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.


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).

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.

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.

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.

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.


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.

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.

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.

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.

Symptoms of the following disorders can be similar to those of aceruloplasminemia. Comparisons may be useful for a differential diagnosis.

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.


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.

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.

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.

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.

Symptoms of the following disorders can be similar to those of achalasia. Comparisons may be useful for a differential diagnosis:


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.

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.

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.

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.

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.


Achondroplasia

Achondroplasia is caused by a specific change (pathogenic variant) in the FGFR3 gene. About 98% of cases result from the exact same change in the DNA in this gene.

Achondroplasia appears to affect males and females in equal numbers. This disorder begins in the developing fetus and is the most common form of skeletal dysplasia that causes dwarfism. The estimated frequency of achondroplasia has ranged from about one in 20,000 to one in 30,000 live births.

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). Short stature often is not recognized until early to mid-childhood or, in some people, as late as adulthood. Affected individuals may also develop bowing of the legs during early childhood that often improves with age. 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 features. In about 10 percent of patients, mild cognitive delays may be present. Hypochondroplasia can occur sporadically with no apparent family history. In other cases, the condition is follows autosomal dominant inheritance. Hypochondroplasia and achondroplasia may result from different variants of the FGFR3 gene. (For more information on this disorder, choose Hypochondroplasia as your search term in the Rare Disease Database.)


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.

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.

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.

Symptoms of the following disorders can be similar to those of ASMD. Comparisons may be useful for a differential diagnosis.

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.

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.


Vestibular schwannoma

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.

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.

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.

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.

Symptoms of the following disorders can be similar to those of acoustic neuromas. Comparisons may be useful for a differential diagnosis.

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).


Idiopathic 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.

Most cases of acquired aplastic anemia occur unrelated to any identifiable causes, or for unknown reasons (idiopathic). Researchers believe that most are due to the immune system mistakenly targeting the bone marrow (autoimmunity). Autoimmune disorders are caused when the body’s natural defenses against foreign or invading organisms begin to attack healthy tissue for unknown reasons. Tests to confirm this in any individual case are not readily available, but there is much evidence to support this pathogenic mechanism.

Acquired aplastic anemia affects males and females in about equal numbers. Most cases affect older children, teenagers or young adults. The incidence of aplastic anemia in Europe and Israel is two new cases among 1 million people per year. The incidence rate is two or three times greater in Asia. The exact incidence rates exist for the United States is unknown although some sources say that approximately 500-1,000 new cases of aplastic anemia are diagnosed each year.

Symptoms of the following disorders can be similar to those of acquired aplastic anemia. Comparisons may be useful for a differential diagnosis:

Myelodysplastic syndromes (myelodysplasias, MDS) are a rare group of blood disorders that occur as a result of improper development of blood cells within the bone marrow. The three main types of blood cells (i.e., red blood cells, white blood cells and platelets) are affected. Red blood cells deliver oxygen to the body, white blood cells help fight infections, and platelets assist in clotting to stop blood loss. These improperly developed blood cells fail to develop normally and enter the bloodstream. As a result, individuals with MDS have abnormally low blood cell levels (low blood counts). It is sometimes difficult to distinguish acquired aplastic anemia from MDS. In MDS, patients often suffer due to failure of the bone marrow to produce blood cell, and some MDS can develop into an acute leukemia. In MDS, there are often typical abnormalities of chromosomes of marrow cells and/or harmful mutations in specific genes present in hematopoietic stem. (For more information on this disorder, choose myelodysplastic syndromes as your search term in the Rare Disease Database.)


Acquired Hemophilia

The symptoms of AH develop because the blood cannot clot properly. Clotting is the process by which blood clumps together to plug the site of a wound. Clotting factors, such as factor VIII, are specialized proteins that are essential for the blood to clot properly.

AH is an autoimmune disorder. It occurs when the immune system produces antibodies that mistakenly attack healthy tissue, specifically specialized proteins known as clotting factors, most often clotting factor VIII.

AH develops in individuals with no previous history of bleeding disorder with approximately equal numbers of males and females affected. In the United States, the disorder is estimated to affect approximately .2-1 individuals per 1,000,000/year in the general population. In the United Kingdom, the disorder is estimated to affect 1.4 per 1,000,000/year. However, affected individuals may go undiagnosed or misdiagnosed, making it difficult to determine the  true frequency of the disorder in the general population.

Symptoms of the following disorders can be similar to those of AH. Comparisons may be useful for a differential diagnosis. Hemophilia is a general term for a group of rare bleeding disorders. Most forms of hemophilia are inherited blood clotting (coagulation) disorder caused by inactive or deficient blood proteins. There are three major forms of inherited hemophilia: hemophilia A (also known as classical hemophilia, factor VIII deficiency or antihemophilic globulin [AHG] deficiency), the most common form; hemophilia B (Christmas disease or factor IX deficiency); and hemophilia C (factor XI deficiency). Hemophilia A and B are inherited as X-linked recessive genetic disorders, while hemophilia C is inherited as an autosomal recessive genetic disorder. Hemophilia A and B are mostly expressed in males, but females can also be affected. Hemophilia C affects males and females in equal numbers. Hemophilia may be classified as mild, moderate, or severe; the level of severity is determined by the percentage of active clotting factor in the blood (normal percentage ranges from 50 to 150 percent). People who have severe hemophilia have less than one percent of active clotting factor in their blood. (For more information on these disorders, choose hemophilia as your search term in the Rare Disease Database.)

AH should be suspected by the clinical picture and confirmed by an abnormal coagulation test. A diagnosis should be considered in patients with a recent onset of abnormal bleeding and an isolated prolongation of the activated partial thromboplastin time (aPTT), especially the elderly and peri- and post-partum women.


Acquired Lipodystrophy

Acquired lipodystrophy encompasses several subtypes. The specific symptoms present, severity, and prognosis can vary greatly depending upon the specific type of acquired lipodystrophy and the presence and extent of associated symptoms. The specific symptoms and severity can also vary among individuals with the same subtype. It is important to note that affected individuals will not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms, and overall prognosis.

Acquired lipodystrophies can be caused by medications, autoimmune reactions or other unknown mechanisms. Acquired lipodystrophies do not have a direct genetic basis. Some researchers have speculated that individuals may have a genetic predisposition to developing certain forms of acquired lipodystrophy, however, this remains unproven and controversial. Most likely, several different underlying mechanisms are involved in the development of acquired lipodystrophies.

AGL and APL generally affect women more than men, although this may be due in part to ascertainment bias because women tend to be more severely affected and more easily recognized. APL has been reported in approximately 250 individuals with a male to female ratio of 1:4. It has been reported in individuals of various different ethnicities. AGL has been reported in approximately 100 individuals with a male to female ratio of 1:3. Most cases have been reported in Caucasians. LD-HIV is estimated to affect approximately 100,000 individuals in the United States. Consistent with the increase prevalence of HIV in males, LD-HIV is also more prevalent in males.

Symptoms of the following disorders can be similar to those of acquired lipodystrophy. Comparisons may be useful for a differential diagnosis.

A diagnosis of acquired lipodystrophies is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. AGL may be suspected in individuals who have a generalized lack of subcutaneous fat and overall muscular appearance during childhood.


Isaacs syndrome

Acquired neuromyotonia is an inflammatory disorder characterized by abnormal nerve impulses from the peripheral nerves that result in continuous muscle fiber activity. Affected individuals often experience progressive muscle stiffness and cramping especially in the hands and feet, increased sweating (hyperhidrosis), and delayed muscle relaxation. Symptoms may persist even during sleep or under general anesthesia.

Acquired neuromyotonia is characterized by involuntary continuous muscle fiber activity (fasciculations, doublet and triplet discharges on electromyography) that cause stiffness and delayed relaxation in the affected muscles. Muscle twitching with a rippling appearance (myokymia) may occur along with these symptoms. Affected individuals may, at times, be unable to coordinate voluntary muscle movement and find difficulty in walking (ataxia). Other symptoms may include staggering and reeling (titubation), stiffness, and lack of balance in response to being startled. There may be diminished spontaneous gross motor activity.

Acquired neuromyotonia is an autoimmune disease in which the immune system malfunctions so that it damages parts of one’s own body. Approximately 40% of affected individuals have antibodies to voltage-gated potassium channels (VGKC’s) that affect the points at which the signals from the nerve fiber meet the muscle cell (neuromuscular junction).

Aquired neuromyotonia is a rare disorder affecting males and females but is slightly more common among men. Disease onset is usually between the ages of 15 and 60 years but has also been reported in childhood.

Symptoms of the following disorders can be similar to those of acquired neuromyotonia. Comparisons may be useful for a differential diagnosis:

Amyotrophic lateral sclerosis (ALS) is one of a group of disorders known as motor neuron diseases. It is characterized by the progressive degeneration and eventual death of nerve cells (motor neurons) in the brain, brainstem and spinal cord that facilitate communication between the nervous system and voluntary muscles of the body. Ordinarily, motor neurons in the brain (upper motor neurons) sent messages to motor neurons in the spinal cord (lower motor neurons) and then to various muscles. ALS affects both the upper and lower motor neurons, so that the transmission of messages is interrupted, and muscles gradually weaken and waste away. As a result, the ability to initiate and control voluntary movement is lost. Ultimately, ALS leads to respiratory failure because affected individuals lose the ability to control muscles in the chest and diaphragm. ALS is often called Lou Gehrig’s disease. (For more information on these disorders, choose ALS as your search terms in the Rare Disease Database.)


Acrocallosal Syndrome, Schinzel Type

Absence of Corpus Callosum, Schinzel Type

Acrocallosal syndrome, Schinzel type is a rare genetic disorder that is apparent at birth (congenital). Associated symptoms and findings may be variable, including among affected members of the same family (kindred). However, the disorder is typically characterized by underdevelopment (hypoplasia) or absence (agenesis) of the thick band of nerve fibers joining the two hemispheres of the brain (corpus callosum) and moderate to severe mental retardation. In addition, many affected individuals have malformations of the skull and facial (craniofacial) region and/or distinctive abnormalities of the fingers and toes (digits). Characteristic craniofacial abnormalities may include an unusually large head (macrocephaly) with a prominent forehead, widely spaced eyes (ocular hypertelorism), downslanting eyelid folds (palpebral fissures), a small nose with a broad nasal bridge; and malformed (dysplastic) ears. Most affected individuals also have distinctive digital malformations, such as the presence of extra (supernumerary) fingers and toes (polydactyly) and webbing or fusion (syndactyly) of certain digits. Additional physical abnormalities may also be present, including growth retardation, resulting in short stature. Although autosomal recessive inheritance has been suggested, acrocallosal syndrome often appears to occur randomly for unknown reasons (sporadically).

In individuals with acrocallosal syndrome, Schinzel type, the range and severity of associated findings may be extremely variable.  However, in all reported cases to date, the disorder has been characterized by underdevelopment (hypoplasia) or absence (agenesis) of the thick band of nerve fibers joining the two hemispheres of the brain (corpus callosum) as well as moderate to severe mental retardation.  In some cases, brain malformations may be associated with additional complications, such as sudden episodes of uncontrolled electrical activity in the brain (seizures) or hydrocephalus, a condition in which impaired flow or absorption of the fluid that circulates through cavities (ventricles) of the brain and the spinal canal (cerebrospinal fluid [CSF]) potentially leads to increasing fluid pressure in the brain.  Individuals with acrocallosal syndrome may also have abnormally diminished muscle tone (hypotonia) and experience severe psychomotor retardation–or marked delays in the development of certain physical, mental, or behavioral skills that are typically acquired at particular stages (i.e, developmental milestones).  Over 50 percent of affected individuals also have abnormal growth delays, often resulting in short stature.

According to many investigators, acrocallosal syndrome, Schinzel type may be inherited as an autosomal recessive trait.  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.

Acrocallosal syndrome, Schinzel type appears to affect males and females in relatively equal numbers.  The disorder was originally reported in 1979 (A. Schinzel).  Over 25 cases have been recorded in the medical literature.

Symptoms of the following disorders may be similar to those of acrocallosal syndrome, Schinzel type.  Comparisons may be useful for a differential diagnosis:

Greig cephalopolysyndactyly syndrome is a rare genetic disorder characterized by distinctive abnormalities of the skull and facial (craniofacial) region, the hands, and the feet.  Craniofacial abnormalities may include an abnormally large head (macrocephaly) with a high, prominent forehead; widely spaced eyes (ocular hypertelorism); and a broad nasal root.  In many cases, there is also duplication of the great toes (preaxial polydactyly) as well as webbing or fusion (syndactyly) of certain toes, primarily the first to the third toes.  Abnormalities of the hands may include unusually broad thumbs; duplication of certain fingers toward the pinky side of the hands (postaxial polydactyly); and webbing or fusion of certain fingers, particularly the third and fourth fingers.  Rarely, malformation or absence of the corpus callosum; as well as mental retardation, have been reported in association with Greig cephalopolysyndactyly syndrome.  In most cases, the disorder appears to be inherited as an autosomal dominant trait.  (For more information on this disorder, choose Greig cephalopolysyndactyly as your search term in the Rare Disease Database.)


Autoimmune encephalitis

Acrodermatitis enteropathica (AE) is a disorder of zinc metabolism that occurs in one of three forms: an inborn (congenital) form and two acquired forms. The inborn form of AE is a rare genetic disorder characterized by intestinal abnormalities that lead to the inability to absorb zinc from the intestine. The lack of zinc presents, characteristically, as: (1) skin inflammation with pimples (pustular dermatitis) occurring around the mouth and/or anus, (2) diarrhea, and (3) abnormal nails (nail dystrophy). In the acute phase, irritability and emotional disturbances are evident due to wasting (atrophy) of the brain cortex. It is important to recognize and treat this disorder.

Acrodermatitis enteropathica is characterized by chronic diarrhea which may be mild or severe, and the presence of fatty substances in the feces (steatorrhea). In the congenital form symptoms start gradually, frequently at the time of weaning of an infant. The skin around body openings such as the mouth, anus, and eyes, and the skin on elbows, knees, hands, and feet become inflamed. Skin lesions are usually blistered (vesicobullous) and after drying out become psoriasis-like. The skin around the nails may also be inflamed and the nail may be abnormal due to malnourished tissue. Hair loss on the scalp, eyelids, and eyebrows may be total (alopecia). Inflammation of the membrane that lines the eyelid (conjunctivitis), usually also occurs.

The congenital form of acrodermatitis enteropathica is transmitted as an autosomal recessive genetic disorder. It appears to be the result of mutations in the SLC39A4 gene.

The congenital form of arodermatitis enteropathica is a rare disorder beginning during infancy. The incidence is about 1 in 500,000 births and the condition affects males and females in equal numbers. Healthy breast-fed infants of female patients with the disorder can also become affected. The acquired form of AE is rare because in recent years zinc supplements have been added to the parenteral nutrition regimen, although acquired forms are more common in some regions such as Southeast Asia and sub-Saharan Africa where gastro-intestinal malabsorption syndrome are more frequent.

Symptoms of the following disorder can be similar to those of acrodermatitis enteropathica. Comparisons may be useful for a differential diagnosis:

Celiac sprue (gluten enteropathy) is a chronic, hereditary, intestinal malabsorption disorder caused by intolerance to dietary gluten. The illness is characterized by a flat mucous lining of the jejunum (part of the small intestine). Symptoms include weight loss, chronic diarrhea, abdominal cramping and bloating, intestinal gas, and muscle wasting. Clinical and/or histologic improvement of symptoms, follow withdrawal of dietary gluten. (For more information on this disorder, choose Celiac Sprue as your search term in the Rare Disease Database.)

Acrodermatitis enteropathica is treated with zinc supplements in the form of zinc sulfate. These supplements should be given as soon as diagnosis of the disorder is made and they have to be continued for life. The drug Diodoquin (iodoquinol) is another treatment that usually clears up symptoms within a week. If the disorder is caused by intravenous feeding, adding zinc supplements to the nutritional regimen can prevent and/or clear up manifestations of AE.


Acrodysostosis

acrodysostosis with or without hormone resistance

Although researchers have been able to establish a clear syndrome with characteristic or core symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physicians and medical team about their specific case, associated symptoms and overall prognosis.

Acrodysostosis is caused by a mutation in either the PRKAR1A gene or the PDE4D 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.

Acrodysostosis affects males and females in equal numbers. The disorder is present at birth (congenital) but may not be apparent until years after birth. The exact incidence and prevalence of the disorder is unknown. Because many cases can go misdiagnosed or undiagnosed, determining the true frequency of acrodysostosis in the general population is difficult.

Symptoms of the following disorders can be similar to those of acrodysostosis. Comparisons may be useful for a differential diagnosis.

A diagnosis of acrodysostosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including X-rays.


Acromegaly

Acromegaly is a rare, slowly progressive, acquired disorder that affects adults. It occurs when the pituitary gland produces too much growth hormone (GH). The pituitary gland is a small gland located near the base of the skull that stores several hormones and releases them into the bloodstream as needed by the body. These hormones regulate many different bodily functions. In most patients, acromegaly is caused by the growth of a benign tumor (adenoma), arising from the pituitary gland. Symptoms of acromegaly include abnormal enlargement in bones of the hands, arms, feet, legs and head. Enlargement of the bones in the jaws and in the front of the skull are typically the most apparent bony changes. Acromegaly may also cause thickening of the soft tissues of the body, including the heart, lips and tongue. If untreated, acromegaly can potentially cause serious illness and life-threatening complications. When excessive secretion of growth hormone occurs before puberty, the disorder is known as gigantism, not acromegaly.

The symptoms of acromegaly generally occur slowly and become more noticeable as affected individuals age. The specific symptoms that develop may vary greatly from one person to another. Acromegaly can potentially cause a wide variety of symptoms and physical findings.

Acromegaly is a rare disorder that is caused by excess levels of growth hormone (GH) in the body. In most patients, excess levels of GH are causes by a benign (noncancerous) tumor in the pituitary gland (pituitary adenoma). Most adenomas form from excessive growth of a pituitary cell called a somatotrope cell (the pituitary cell that normally secretes GH). In the overwhelming majority of patients, the disease is sporadic and not due to an inherited genetic mutation.

Acromegaly is a rare disorder that affects males and females in equal numbers. This disorder occurs in approximately 50 to 70 people per million. Researchers estimate that three to eleven people out of every million develop the disorder each year. However, because the symptoms of acromegaly may develop slowly, the disorder may often remain unrecognized and may therefore be underdiagnosed, making it difficult to determine the true frequency of acromegaly in the general population.

Symptoms of the following disorders can be similar to those of acromegaly. Comparisons may be useful for a differential diagnosis:

Gigantism is an abnormal condition characterized by excessive height and size. This disorder typically occurs before puberty as a result of the over secretion of growth hormone by the pituitary gland. Gigantism is associated with enlarged soft tissues and late closure of the epiphyses (heads of the long bones), which results in excessive growth during childhood. Height may reach 7 or 8 feet. Low levels of gonadotropin (gonad stimulating) hormones may be secreted by the pituitary gland later in the course of this disorder and result in low levels of hormone secretions by the ovaries or testes. Sexual development may be normal or it may be affected by the low levels of circulating sex hormones. Some children with gigantism may experience tingling and/or burning sensations in the arms and/or legs (peripheral neuropathy).


Acromesomelic dysplasia, Hunter-Thompson type

Acromesomelic dysplasia is an extremely rare, inherited, progressive skeletal disorder that results in a particular form of short stature known as short-limb dwarfism. The disorder is characterized by acromelia and mesomelia. Mesomelia describes the shortening of the bones of the forearms and lower legs relative to the upper parts of those limbs. Acromelia is the shortening of the bones of the hands and feet. Thus, the short stature of affected individuals is the result of unusually short forearms and abnormal shortening of bones of the lower legs. The very short hands, fingers, feet, and toes are characteristic. These findings are apparent during the first years of life.

Acromesomelic dysplasia (AMD) is characterized by inhibition of growth of certain long bones (i.e. bones of the forearms and lower legs). As a result, affected individuals exhibit unusually short forearms and lower legs and short stature (short-limbed dwarfism). These findings typically become apparent during the first years of life. Abnormal cartilage and bone development also affect other bones, particularly those of the hands and feet (i.e. metacarpals, phalanges, metatarsals).

There are thought to be five types of acromesomelic dysplasia. Each is extremely rare, and each is inherited as an autosomal recessive genetic trait, except for AMD Osebold-Remondini type, which appears to be autosomal dominant. The Maroteaux type has been traced to chromosome 9 at gene map locus 9p13-12. Grebe dysplasia (including AMD Hunter-Thompson type) and Du Pan syndrome all have each been mapped to chromosome 20 at gene map locus 20q11.2. Acromesomelic dysplasia with genital anomalies maps to 4q23-24. Osebold-Remondini type has not been genetically mapped yet.

As of 2005, there were about 10 affected individuals of Hunter-Thompson type ADM and about 40 to 50 patients of Maroteaux type AMD reported in the medical literature. The number of cases of Grebe type ADM is not known, but that type is believed to be almost entirely limited to persons living in Brazil.

Achondroplasia is the most common disorder of short-limbed dwarfism. Affected individuals have arms and legs that are very short, while the torso is more nearly normal in size. During fetal development and childhood, cartilage normally develops into bone, except in a few places, such as the nose and ears. In individuals with achondroplasia, something goes wrong during this process, especially in the long bones (such as those of the upper arms and thighs). The rate at which cartilage cells in the growth plates of the long bones turn into bone is slow, leading to short bones and reduced height. This syndrome is caused by specific mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Achondroplasia differs from AMD in that the upper bones of the arms and legs (the humerus and femur) are the most affected in achondroplasia, while it is the lower bones (radius and ulna in the arm, tibia and fibula in the leg) and the hands and the feet that are the most affected in AMD. (For more information on this disorder, choose  Achondroplasia  as your search term in the Rare Disease Database.)

In most patients, acromesomelic dysplasia is diagnosed within the first few years of life based upon a thorough clinical evaluation, detailed patient history, identification of characteristic findings, and advanced imaging techniques. Although the hands and feet may appear unusually short and broad at birth, the progressive abnormalities associated with the disorder (e.g. abnormal shortening of bones in the forearms and lower legs and short stature, further shortening and broadening of bones of the hands and feet, progressive vertebral abnormalities, limited elbow and arm extension, etc.) typically do not become apparent until late infancy or early childhood.


Acromicric Dysplasia

Acromicric Dysplasia is an extremely rare inherited disorder characterized by abnormally short hands and feet, growth retardation and delayed bone maturation leading to short stature, and mild facial abnormalities. Most cases have occurred randomly for no apparent reason (sporadically). However, autosomal dominant inheritance has not been ruled out.

Acromicric Dysplasia is an extremely rare inherited disorder that usually becomes apparent during late infancy. It is characterized by abnormally short hands and feet, growth delays leading to short stature, and mild facial abnormalities.

Acromicric Dysplasia is an extremely rare disorder that, in most cases, appears to occur randomly for no apparent reason (sporadically).  However, autosomal dominant inheritance has not been ruled out.

Acromicric Dysplasia is an extremely rare disorder that, in theory, affects males and females in equal numbers. Only a very small number of cases have been reported in the medical literature.

Symptoms of the following disorders can be similar to those of Acromicric Dysplasia.  Comparisons may be useful for a differential diagnosis:

Acromicric Dysplasia may be diagnosed based upon a thorough clinical evaluation, characteristic physical findings (e.g., abnormally short hands), a detailed patient history, and a variety of specialized tests such as advanced imaging techniques. X-rays may reveal characteristic abnormalities of the bones in the hands and feet (e.g., abnormally short broad phalanges, metacarpals, and metatarsals; epiphyseal coning of the phalanges in the toes; pointing of the last four metacarpals; and the presence of an abnormal notch on the radial side of the 2nd metacarpal and ulnar side of the 5th metacarpal). The removal and study of cartilage cells (biopsy) under a microscope may reveal distinctive abnormalities affecting the growth cartilage. These abnormalities may include disorganization of the growing portion of certain bones, especially abnormal organization of cells that form cartilage (chondrocytes) and of a protein substance (collagen) that forms fibers within the ligaments, tendons, and connective tissue. In addition, an abnormally high number of such cells may demonstrate degeneration.


ACTH Deficiency

迟发性单独促肾上腺皮质激素缺乏症

adrenocorticotropic hormone deficiency, isolated

ACTH deficiency arises as a result of decreased or absent production of adrenocorticotropic hormone (ACTH) by the pituitary gland. A decline in the concentration of ACTH in the blood leads to a reduction in the secretion of adrenal hormones, resulting in adrenal insufficiency (hypoadrenalism). Adrenal insufficiency leads to weight loss, lack of appetite (anorexia), weakness, nausea, vomiting, and low blood pressure (hypotension). Because these symptoms are so general, the diagnosis is sometimes delayed or missed entirely. For that reason, some clinicians believe the disorder to be more common than previously thought.

ACTH deficiency can either be congenital or acquired, and its manifestations are clinically indistinguishable from those of glucocorticoid deficiency. Symptoms include weight loss, lack of appetite (anorexia), muscle weakness, nausea and vomiting, and low blood pressure (hypotension). Low blood levels of sugar and dilutional hyponatremia (low blood sodium levels) may occur; however, blood potassium levels are typically normal as affected patients are deficient in glucocorticoids and not mineralocorticoids due to their intact renin-angiotensin-aldosterone system. The pituitary hormone ACTH may be undetectable in blood tests, and the level of the adrenal hormone cortisol is abnormally low. Concentrations of 17-hydroxycorticosteroids and 17-ketosteroids, produced from the adrenal cortex, are also abnormally low in the urine. Some adrenal hormones that are decreased are precursors of male sex hormones and are also known as pre-androgens.

The exact cause(s) of ACTH deficiency remain unknown. A defect in the brain’s hypothalamus or in the pituitary gland may cause the deficiency. Also, there is a congenital (present at birth) form of ACTH deficiency that has been tracked to mutations of the T-box 19 (TBX19) gene (also referred to as TPIT) on the long arm of chromosome one (1q23-q24) and the corticotropin releasing hormone (CRH) gene on the long arm of chromosome eight (8q13). The inheritance pattern is thought to be autosomal recessive.

Symptoms of ACTH deficiency most often occur in adults, but the disorder may also be diagnosed in infancy. The disorder affects males and females in equal numbers.

Symptoms of the following disorders may be similar to those of ACTH Deficiency. Comparisons may be useful for a differential diagnosis:

Congenital adrenal hyperplasia (CAH) is a group of disorders resulting from defective synthesis of the corticosteroid hormones of the adrenal gland. The adrenal gland becomes enlarged. In certain forms of CAH, the adrenal gland produces excessive amounts of male sex hormones (pre-androgens) in both males and females. The external genitals of some females with this disorder become masculinized to various degrees. Lack of glucocorticoids, especially cortisol, causes various metabolic problems. Lack of mineralocorticoids, primarily aldosterone, causes salt and water imbalances which may be life threatening. (For more information on this disorder, choose Congenital Adrenal Hyperplasia as your search term in the Rare Disease Database.)


Acute disseminated encephalomyelitis

Symptoms of ADEM can present within days to weeks following an infection. In a subset of patients, there is no identifiable infectious trigger for ADEM. Most commonly, ADEM occurs only once in a particular individual, meaning the disease is most often considered a monophasic disorder; however, a small percentage of patients may exhibit future attacks of ADEM (termed multiphasic ADEM).

The exact cause of ADEM is not known but it may be associated with an atypical immune response following an infectious trigger. An initial illness or infection is observed in 70-80% of patients with ADEM. For instance, ADEM can develop following an upper respiratory tract viral infection. Other ADEM inducing infections include influenza, measles, mumps, rubella, varicella-zoster, Epstein Barr virus, cytomegalovirus and herpes simplex virus.

ADEM can develop at any age but is much more frequent in younger children. Outcomes and severity of ADEM are typically worse in adults than in children. Males and females are affected, but males may be affected more often. In children, the mean age of onset is between 5-8 years old, but ADEM has been diagnosed in children as young as 7 months.

Symptoms of the following disorders can be similar to those of ADEM.

A diagnosis of ADEM is made based on the identification of characteristic symptoms, a detailed patient history, thorough clinical evaluation and a variety of specialized tests including imaging techniques such as magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues and can demonstrate characteristic brain lesions in individuals with ADEM. Additional tests such as spinal fluid testing may be needed to exclude other conditions.


Acute Eosinophilic Pneumonia

特发性急性嗜酸粒细胞肺炎

AEP is characterized by a sudden, rapid onset of symptoms usually within 1-7 days. However, in some cases, symptoms may develop less rapidly over the course of up to one month. AEP often develops in young, otherwise healthy individuals. Associated symptoms are nonspecific and can include fever, cough, difficulty breathing (dyspnea) and chest pain. Less common symptoms include fatigue, muscle pain (myalgia), joint aches, and abdominal discomfort or pain.

The cause of IAEP is unknown (idiopathic). Researchers believe that AEP develops due to an unidentified, nonspecific triggering agent that causes the body to produce eosinophils and recruit them to the lungs. The exact reason for the overproduction and accumulation of eosinophils is unknown.

AEP affects males approximately twice as often as females. Fewer than 200 cases have been reported in the medical literature and the exact prevalence is unknown. AEP can affect individuals of any age, but occurs most often in individuals between 20-40 years of age.

Symptoms of the following disorders can be similar to those of AEP. Comparisons may be useful for a differential diagnosis.

A diagnosis of AEP is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests especially bronchoalveolar lavage (BAL). The presence of other causes of pulmonary eosinophilia such as parasitic infections or exposure to certain drugs must be systematically investigated.


Autoimmune pancreatitis

AIP can be associated with a range of symptoms and physical findings that can potentially involve multiple organ systems of the body. The course and severity of attacks is highly variable from one person to another. In some cases, particularly those without proper diagnosis and treatment, the disorder can potentially cause life-threatening complications. It is important to note the highly variable nature of AIP and that affected individuals may not have all of the symptoms discussed below. Affected individuals and parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

AIP is a multifactorial disorder, which means that several different factors such as genetic and environmental factors occurring in combination are necessary for developing symptoms of the disorder. Individuals with AIP have a mutation in the HMBS 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.

In Europe the prevalence of symptomatic AIP is reported to be 5.9 per million people in the general population., It is likely to be similar elsewhere in the world apart from Sweden where it is higher due to a founder effect. Recent population based genetic studies have shown that approximately 1 in 2000 of the population inherit a disease causing (pathogenic) mutation in the HMBS gene. This suggests that only 1% of those who inherit a pathogenic mutation will ever experience porphyria symptoms. AIP can occur in individuals of all ethnic backgrounds, although it may be less frequently reported in African-American individuals. Women are affected by symptomatic AIP more often than men. The disorder is most common in young or middle-aged women.

Symptoms of the following disorders can be similar to those of AIP. Comparisons may be useful for a differential diagnosis.

A diagnosis of AIP can be difficult because most symptoms are nonspecific and occur episodically. A diagnosis is usually based upon identification of characteristic symptoms from a detailed patient history, a thorough clinical evaluation and certain specialized tests. AIP should be suspected in individuals with unexplained abdominal pain, especially repeated episodes and when occurring along with psychological symptoms, neurological findings with muscle weakness or unexplained hyponatraemia. Dark or reddish urine in such individuals is also suggestive of AIP. However, absence of this feature does not exclude AIP.


Acute myeloid leukemia

Some symptoms of acute myeloid leukemia result from disruption of the normal formation of blood cells. There are three main types of blood cells – red blood cells, white blood cells, and platelets. These cells are formed in the bone marrow and they arise from hematopoietic stem cells, a type of adult stem cell.

Leukemias are clonal disorders, which means that cancer arises from a change in one original cell. In AML, this occurs in a hematopoietic stem cell, specifically a myeloblast. A myeloblast is an immature precursor cell found in the bone marrow. This means that a myeloblast will change (mature or differentiate) into a healthy white blood cell called an agranulocyte or a monocyte. In AML, myeloblasts do not mature, and grow and multiply out-of-control. Because myeloblasts are immature cells, they cannot perform the normal functions of mature blood cells. These abnormal cells build up in the bone marrow, preventing the development of healthy red blood cells, white blood cells, and platelets. Leukemic myeloblasts also survive better than normal blood cells. People with AML eventually develop pancytopenia, a condition in which they lack healthy red and white blood cells and platelets.

Acute myeloid leukemia is the most common form of acute leukemia in adults, making up about 80% of people with acute leukemia. In the United States, it is estimated that 3-5 people per every 100,000 people in the general population has the disease. More than half the people diagnosed with AML are 65 years of age or older. Slightly more men than women are affected by the disease, and it occurs with slightly more frequency in people of European heritage.

Symptoms of the following disorders can be similar to those of acute myeloid leukemia. Comparisons may be useful for a differential diagnosis.

A diagnosis of acute myeloid leukemia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. During a complete physical examination, physicians may feel (i.e., palpate) the lymph nodes in certain regions to detect any swelling.


Acute promyelocytic leukemia

APL most commonly occurs in middle-aged individuals. The median age at diagnosis is around 40 years, meaning that half of cases occur in people under that age and the other half in people above that age. In APL, the bone marrow is overcrowded with malignant cells and eventually fails to produce normal blood cells required for normal functioning. Depletion of red blood cells (anemia) leads to symptoms such as fatigue and pallor, while a decreased number of functional white blood cells predispose affected individuals to infections. A decreased number of platelets (thrombocytopenia) increases the risk of bleeding and bruising.

APL is caused by the uncontrolled proliferation of promyelocytes, a type of immature cell from the myeloid lineage of blood cells. The hallmark of APL is genetic alterations involving the retinoic acid receptor alpha (RARA) gene. Retinoic acid (a derivative of vitamin A) is critical in the process of cellular maturation and specialization (differentiation) of many cells, including myeloid precursors. In normal cells, the RARA protein is bound to proteins and forms a complex that prevents genes involved in cellular differentiation from being read; this is called transcriptional repression. When retinoic acid binds to this protein complex, transcriptional repression is relieved, genes involved in cellular differentiation can be read, and promyelocytes can continue their maturation and differentiation process into mature granulocytes. In most patients with  APL, RARA gene alterations occur due to exchange of genetic material (translocation) between chromosomes 15 and 17, where the RARA and PML genes are located, respectively. This translocation results in a fusion gene termed PML/RARA, which leads to an abnormal retinoic acid receptor that blocks the differentiation process that is normally induced by retinoic acid. The myeloid precursors are therefore stuck in the promyelocyte stage and accumulate in the bone marrow, and eventually the blood. The fusion gene PML/RARA that leads to APL is an acquired mutation and is not inherited. When patients enter a remission, cells containing the PML/RARA fusion gene are no longer detectable.

APL comprises 5 to 10% of all cases of adult acute myeloid leukemia. Each year in the United States, it develops in around 2.2 people per million, for a total of 600 to 800 individuals. Although APL can occur at any age, middle-aged adults are most commonly affected; the median age at diagnosis is around 40. Epidemiological studies have shown that APL is slightly more common in Hispanics and slightly less common in African Americans compared to other ethnic groups. In very rare cases, APL can occur after chemotherapy or radiation therapy for other cancers, especially when therapy involves a class of medication known as topoisomerase II inhibitors; this is called therapy-related APL.

The symptoms of APL are often nonspecific and difficult to recognize. The following disorders are among those that most commonly present with symptoms resembling those of APL. Comparisons may be useful for a differential diagnosis.

The diagnosis of APL is based on a combination of patient history, physical examination and numerous laboratory tests. In cases where patients present with symptoms such as fever, fatigue and bruising or bleeding, a complete blood count (CBC) is usually performed to evaluate the number of red blood cells (erythrocytes), white blood cells (leukocytes) and platelets (thrombocytes). In APL, platelets and red blood cells are often low, and white blood cells might be low, normal or elevated (however, the number of functional white blood cells is usually decreased). The combination of low platelets (thrombocytopenia), red blood cells (anemia) and white blood cells (leukopenia) is known as pancytopenia and is a warning sign that requires further speedy investigation. The cells taken from a blood sample can also be evaluated by a physician specialized in disorders related to the blood (hematologist) to see if they are abnormal and potentially leukemic. Further evaluation usually requires bone marrow examination to assess for the presence of abnormal cells. Bone marrow samples are obtained by bone marrow aspiration and biopsy, which are respectively used to collect the liquid and solid portions of the bone marrow. The location of choice for bone marrow aspiration and biopsy is the hip bone (pelvic bone).


Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a type of severe, acute lung dysfunction affecting all or most of both lungs that occurs as a result of illness or injury. Although it is sometimes called adult respiratory distress syndrome, it may also affect children. ARDS is a buildup of fluid in the small air sacs (alveoli) in the lungs. This makes it difficult for oxygen to get into the bloodstream. Major symptoms may include breathing difficulties (dyspnea), rapid breathing (tachypnea), excessively deep and rapid breathing (hyperventilation) and insufficient levels of oxygen in the circulating blood (hypoxemia). ARDS may develop in conjunction with widespread infection in the body (sepsis) or as a result of pneumonia, trauma, shock, severe burns, aspiration of food into the lung, multiple blood transfusions, and inhalation of toxic fumes, among other things. It usually develops within 24 to 48 hours after the original illness or injury and is considered a medical emergency. It may progress to involvement of other organs.

Typically, ARDS develops within 24 to 48 hours of the original illness or injury. It may become a life-threatening condition characterized by inflammation of the lungs, which may begin in one lung but eventually affects both, and leads to damage to the air sacs (alveoli) and surrounding small blood vessels. The damaged alveoli close down or fill up with fluid (lung edema), thereby losing their ability to oxygenate the blood and eliminate carbon dioxide. Patients experience increasingly severe respiratory distress, associated with decreasing oxygen levels in arterial blood and tissues.

The incidence of ARDS varies widely, due to the different definitions of the disease, as well as demographic, cultural, and healthcare system related differences across countries. Acute respiratory distress syndrome can affect persons of any age who suffer acute injury or illness affecting the lungs. The incidence increases with age, ranging from 16 affected individuals per 100,000 persons aged 15-19 to 306 affected individuals per 100,000 persons between the ages of 75 and 84. There is no difference in the incidence between male and females when ARDS is associated with sepsis and most other causes. However, the incidence is slightly higher among females when trauma is the underlying cause leading to ARDS.

Symptoms of the following disorders can be similar to those of acute respiratory distress syndrome. Comparisons may be useful for a differential diagnosis:

Severe acute respiratory syndrome (SARS) is a respiratory illness that began to be reported in Asia, North America and Europe in the spring of 2003. It begins with a fever greater than 100.4 degrees F. Other symptoms may include headache, an overall feeling of discomfort, body aches, and mild respiratory symptoms. After two to seven days, SARS patients may develop a dry, hacking cough and have trouble breathing. SARS appears to be spread by close person-to-person contact. For additional information on SARS, contact the Centers for Disease Control and Prevention or the World Health Organization.


Adams-Oliver syndrome

Adams-Oliver syndrome (AOS) is a rare inherited condition present at birth that involves changes to the limbs and scalp. Symptoms may include areas of missing skin on the scalp, limb abnormalities, heart defects, neurological concerns, and issues with the eyes. AOS is caused by harmful changes (mutations) in the ARHGAP31, DLL4, DOCK6, EOGT, NOTCH1, or RBPJ genes. Some people with AOS do not have a mutation in one of these genes AOS has different inheritance patterns based on the gene involved. Mutations in these genes can follow either an autosomal dominant or recessive inheritance pattern. There is no cure for AOC. However, it can be managed by monitoring for and treating the symptoms. This is typically done by several different healthcare providers such as pediatricians, cardiologists, and plastic surgeons.

People with AOS may have the following symptoms: absence of areas of skin (aplasia cutis congenita); shortened or missing fingers, hands, toes and/or feet; heart problems present at birth; neurological concerns such as developmental delays and learning disabilities; kidney issues and eye problems.

AOS is known to be caused by harmful changes (mutations) in several genes: ARHGAP31, DLL4, DOCK6, EOGT, NOTCH1, or RBPJ. Symptoms vary based on which gene is involved. In about 50% of patients, no mutations in these genes are found.

AOS affects males and females in equal numbers. AOS occurs in about 44 out of every 10 million people and is present at birth.

Symptoms of the following conditions can be like those of AOS. Comparisons may be useful for a differential diagnosis:

Scalp-ear-nipple syndrome is a rare condition which involves areas of hairless skin on the scalp that is present at birth; ears are small and folded over; and underdeveloped or no nipples. Other symptoms of the condition include brittle nails, dental issues, kidney concerns and specific facial features such as a flat bridge of the nose and narrowed openings of the eyes.


ADCY5-Related Dyskinesia

家族性运动障碍与面肌颤搐

Although researchers have been able to establish a clear syndrome with characteristic or core symptoms, much about ADCY5-related dyskinesia is not fully understood. Several factors including the small number of identified patients, the lack of large clinical studies, and the possibility of other genes or additional factors influencing the disorder, prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below.

ADCY5-related dyskinesia is caused by a variation (mutation) in the ADCY5 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation in a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.

ADCY5-related dyskinesia affects males and females in equal numbers. The exact number of people who have this disorder is unknown. Rare disorders like ADCY5-dyskinesia often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. The disorder is almost certainly underrecognized and underdiagnosed.

Symptoms of the following disorders can be similar to those of ADCY5-related dyskinesia. Comparisons may be useful for a differential diagnosis.

A diagnosis of ADCY5-related dyskinesia is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. There are no published guidelines for diagnosis. A diagnosis is suspected in infants, children or adolescents with characteristic movement symptoms (e.g. choreiform, myoclonic, dystonic movements) who do not have a structural abnormality of the brain. Clues which may be helpful in diagnosis include facial abnormalities and nocturnal disturbances, but not all individuals experience or have these symptoms. A diagnosis is confirmed through molecular genetic testing.


Addison disease

The symptoms of Addison’s disease can vary from one individual to another. Symptoms usually develop slowly over time and are usually vague and common to many conditions (nonspecific). This often leads to delays in the proper diagnosis of Addison’s disease. In rare cases, the symptoms of Addison’s disease can develop rapidly causing a condition called acute adrenal failure.

Most cases of Addison’s disease occur due to damage or destruction of the adrenal cortex, the outermost layers of the adrenal glands (zona fasciulata, which secretes cortisol and zona glomerulosa, which secretes aldosterone). Symptoms usually do not develop until 90 percent of the adrenal cortex has been damaged.

Addison’s disease affects males and females in equal numbers. Approximately 1 in 100,000 people in United States have Addison’s disease. The overall prevalence is estimated to be between 40 and 60 people per million of the general population. Because cases of Addison’s disease may go undiagnosed, it is difficult to determine its true frequency in the general population. Addison’s disease can potentially affect individuals of any age, but usually occurs in individuals between 30-50 years of age. Addison’s disease was first identified in the medical literature in 1855 by a physician named Thomas Addison.

Symptoms of the following disorders can be similar to those of Addison’s disease. Comparisons may be useful for a differential diagnosis.

A diagnosis of Addison’s disease is suspected based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. Often a diagnosis is made incidentally during a routine exam when a blood test shows low levels of sodium or high levels of potassium. A diagnosis may be confirmed through a variety of specialized tests including the ACTH stimulation test, insulin-induced hypoglycemia test and x-ray examination.


Adrenocortical carcinoma

Adenoid cystic carcinoma (ACC) is a relatively rare form of cancer that most commonly develops in the salivary glands or other regions of the head and neck. ACC can occur in other parts of the body, such as the breast, skin, cervix in females, prostate gland in males and various other areas. ACC tumors are characterized by a distinctive histological pattern of abnormal nests or cords of certain cells (epithelial cells) that surround and/or infiltrate ducts or glandular structures within the affected organ. These structures are typically filled with a mucous-like material or contain abnormal fibrous membranes. Such characteristics are apparent during microscopic evaluation of tumor cells from a biopsy sample. ACC is considered a low-grade malignancy that has a history of slow growth. ACC can be aggressively invasive and infiltrate nearby lymph nodes as well as the sheaths or coatings surrounding nerve fibers (perineural spaces). This form of cancer can recur later at the site where it first developed (local recurrence) or spread to distant body sites (metastatic disease), particularly the lungs, in approximately 50% of patients. ACC typically occurs during adulthood, around the ages of 40 to 60, but has also been diagnosed in children and adolescents.

There are three histological tumor growth patterns common to ACC: cribriform, tubular and solid. The cribriform growth pattern is most common and appears as a Swiss cheese pattern in histological stains. The cribriform and tubular growth patterns are less aggressive. Tumors exhibiting a solid pattern are more likely to spread, have been associated with activating pathogenic variants (mutations) in the NOTCH1 gene and have a worse prognosis.

The exact cause of adenoid cystic carcinoma is unknown. However, current research suggests that genetic changes (chromosomal rearrangements, pathogenic variants in genes or other DNA alterations) are the underlying basis of cellular malignant transformation in many cancers, including ACC.

Every year, about 1,200 individuals are diagnosed with ACC in the United States. 58% of ACC patients exhibit tumors in the oral cavity, salivary glands and pharynx, 17% in the respiratory system, 12% in the breast and the remaining 13% of tumors occur in other areas of the body such as on the skin, lacrimal glands, prostate, etc. ACC makes up 10% of all tumors of the head and neck region.

Depending upon the tumor site, some benign (noncancerous) growths may appear similar to primary ACC tumor development. However, ACC typically exhibits additional symptoms that distinguish it from benign growths. Microscopic examination of tumor cells and other diagnostic testing are essential in differentiating between the two.

The diagnosis of adenoid cystic carcinoma is based upon a thorough clinical evaluation, characteristic symptoms and physical findings, a detailed patient history and a variety of specialized tests. Such testing includes microscopic evaluation of tumor cells.


Adenylosuccinate lyase deficiency

腺苷酸琥珀酸裂解酶缺乏症

Three categories of adenylosuccinate lyase deficiency have been recognized. The first is the fatal neonatal form, where babies have encephalopathy with lack of spontaneous movement, respiratory failure and intractable seizures. There may be some prenatal indications such as the fetus being small in size (IUGR), having a small head (microcephaly), a low level of fetal movement (hypokinesia) and a loss of fetal heart rate variability.

Adenylosuccinate lyase deficiency (ASLD) is a type of metabolic disorder. Metabolism is the process in which organisms take in various organic materials, use them to build cellular structures and for energy, and expel any waste products. Adenylosuccinate lyase is important in the production of purines (guanine and adenine), which are molecules that are important for the structure of genetic information and in providing sources of energy. ASLD is caused when the enzyme adenylosuccinate lyase is less functional than normal.

All forms of adenylosuccinate lyase deficiency affect males and females in equal numbers. The age of onset and frequency is different between the different types. People with the fatal neonatal form and type I begin showing symptoms within the first few months of life. In type II, people begin showing symptoms within the first few years of life. Of known cases of ASLD, 5-10% of cases are the neonatal form, 70-80% are type I, and 15-20% are type II (Donti, 2016).

A diagnosis of adenylosuccinate lyase deficiency should be considered in infants with seizures, delayed milestones, muscle weakness and/or autistic features. The diagnosis is based on elevated levels of two compounds in body fluids such as plasma, urine and cerebrospinal fluid (the fluid that surrounds the spinal nerves). These two compounds are called succinylaminoimidazole carboxamide riboside (SAICA riboside) and succinyladenosine, and they are not usually detectable in these fluids. Sequencing of the ADSL gene can identify the disease-causing genetic change (pathogenic variant).


Holmes-Adie syndrome

Adie syndrome, or Holmes-Adie syndrome, is a rare neurological disorder affecting the pupil of the eye. In most patients the pupil is larger than normal (dilated) and slow to react in response to direct light. Absent or poor tendon reflexes are also associated with this disorder. In most individuals, the cause is unknown (idiopathic), but Adie syndrome can occur as due to other conditions such as trauma, surgery, lack of blood flow (ischemia) or infection. In rare cases localized disturbance of sweat secretion is associated with Adie syndrome (Ross syndrome). Adie syndrome involves a usually non progressive and limited damage to the autonomic nervous system, which is the portion of the nervous system that controls or regulates certain involuntary body functions including the reaction of the pupils to stimuli.

Normally the pupil gets smaller (constricts) in the presence of light or when focusing on nearby objects. The pupil normally opens wider (dilates) in dim light or darkness, when focusing on far away objects, or when a person is excited.

In most instances, the exact cause of Adie syndrome is unknown (idiopathic). It is believed that most cases result from inflammation or damage to the ciliary ganglion, a cluster of nerve cells found in the eye socket (orbit) just behind the eyes, or damage to the post-ganglionic nerves. The ciliary ganglion is part of the parasympathetic nervous system, which is itself part of the autonomic nervous system. The parasympathetic nervous system relaxes the body and inhibits or slows down high energy functions.

Adie syndrome affects females more often than males by a ratio by some estimates of 2.6:1 for cases where the cause is unknown. Young adults usually between the ages of 25 to 45 are most commonly affected. The prevalence of Adie’s pupil (not the full syndrome) is approximately 2 people per 1,000 in the general population. The exact incidence or prevalence of Adie syndrome itself is unknown.

Symptoms of the following disorders can be similar to those of Adie syndrome. Comparisons may be useful for a differential diagnosis:

Ross syndrome is a variant of Adie syndrome in which affected individuals experience an impaired ability to sweat normally (anhidrosis) in association with Adie pupil and loss of deep tendon reflexes. The inability to sweat properly may result in the body attempting to compensate, resulting in certain areas of the body sweating excessively. Affected individuals may experience heat intolerance due to the sweating abnormalities. More than 40 cases of Ross syndrome have been reported in the medical literature. The exact underlying cause of this disorder is unknown.

In most instances, treatment will not be necessary. Glasses may be prescribed to correct blurred vision; sunglasses can help individuals with sensitivity to light. Therapy using dilute pilocarpine may improve poor depth perception and relieve glare in some patients. The loss of deep tendon reflexes is permanent.


ADNP syndrome

ADNP-related intellectual disability, autism-related spectrum disorder

Although researchers have established a clear syndromic presentation with characteristic or core symptoms associated with pathogenic variants in the ADNP gene, much about the disorder is not fully understood. Several factors have impeded the identification of a complete picture of the associated symptoms and prognosis; these include the small number of identified children, the lack of large clinical studies, and a lack of understanding of moderating effects of genetic background, the presence of additional gene variants, or environmental contributions. Therefore, it is important to note that every child is unique and that affected individuals may not have all of the symptoms discussed below.

ADNP syndrome is caused by a change (mutation) in the activity-dependent neuroprotective protein (ADNP) 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, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.

ADNP syndrome affects females and males in equal numbers. The exact number of people who have this disorder is unknown. According to one estimate, about 1 in 20,000 people in the general population in the United States and Europe have the disorder. Rare disorders like ADNP syndrome often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. ADNP syndrome is believed to account for about .17% of individuals with autism, making it one of the most common, single-gene causes of an autism spectrum disorder. Approximately 205 affected children have been identified worldwide in the medical literature and as reported by the ADNP Kids Research Foundation as of January 2019.

Symptoms of the following disorders can be similar to those of ADNP syndrome. Comparisons may be useful for a differential diagnosis.

A diagnosis of ADNP syndrome may be suspected based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Premature tooth eruption and abnormal tooth development when occurring along with developmental delays or intellectual disabilities and autism symptoms can also lead to a suspicion of ADNP syndrome.


Adult Neuronal Ceroid Lipofuscinosis

成人神经元蜡样质脂褐质沉积症

ANCL or Kufs disease was generally broken down into type A and type B. The signs and symptoms of these two subtypes often overlap and the distinction between the two is not always clear. Symptoms typically become worse over time. Generally, type A is associated with progressive myoclonic epilepsy (PME). PME is a condition characterized by both muscle contractions (myoclonus) and seizures (epilepsy). Some individuals experience difficulties in coordinating voluntary movements (ataxia) or difficulty speaking (dysarthria).

Changes (mutations) in several different genes can cause adult neuronal ceroid lipofuscinosis. These include the CLN6 gene for type A and the CTSF gene for type B. There are also people with adult onset of neuronal ceroid lipofuscinosis due to changes in the PPT1 gene, the CLN5 gene, CTSD gene, and the GRN gene. Adult onset disease that affects vision or the heart has been found to be caused by changes in the CLN3 gene, and the MFSD8 gene. Some very specific changes in the DNAJC5 gene can also cause adult onset neuronal ceroid lipofuscinoses.

Adult neuronal ceroid lipofuscinoses are extremely rare disorders. The prevalence is estimated to be about 1.5 people per 9,000,000 in the general population. Prevalence is the total numbers of individuals with a disease at a given time. Studies into the incidence of ANCL have varied based on the country conducting the study. Estimates range from 1.5-7 infants per 100,000 live births. Incidence is the number of new people born with a disorder in a given year.

Symptoms of the following disorders can be similar to those of adult neuronal ceroid lipofuscinosis. Comparisons may be useful for a differential diagnosis.

A diagnosis of adult neuronal ceroid lipofuscinosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The tests used may be different based on the specific subtype of ANCL. These tests can include enzyme assays, the study of affected tissue under an electron microscope, and molecular genetic testing to identify changes in genes that can cause disease.


Adult polyglucosan body disease

成人葡聚糖多聚体神经病变

Symptoms and severity can vary greatly from one person to another. Typically, symptoms develop around the fifth decade of life. The initial sign is many times related to neurogenic bladder: specifically, an increased need to urinate that may eventually progress to cause a near complete loss of bladder control (urinary incontinence). In some cases, urinary difficulties may precede other symptoms by one or two decades.

APBD is caused by a mutation in the GBE1 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 domain, this can affect many organ systems of the body, including the brain.

Adult polyglucosan body disease is a rare disorder that appears to affect males and females in equal proportions. Familial clustering is observed in about 30% of cases especially among Ashkenazi Jewish populations. More than 50 cases have been reported in the medical literature.

A wide variety of disorders can be mistaken for APBD. Such disorders include multiple sclerosis, hereditary spastic paraplegia, adrenomyeloneuropathy, amyotrophic lateral sclerosis, metachromatic leukodystrophy, and Pelizaeus-Merzbacher disease. Men with primarily urinary symptoms may be mistaken for having an enlarged prostate (prostate hypertrophy).

A diagnosis is made based upon a thorough clinical evaluation, identification of characteristic findings, a detailed patient history, and a variety of specialized tests.