A number sign (#) is used with this entry because alpha-mannosidosis (MANSA) is caused by homozygous or compound heterozygous mutation in the MAN2B1 gene (609458) on chromosome 19p13. Description Alpha-mannosidosis is an autosomal recessive lysosomal storage disease characterized by mental retardation, coarse facial features, skeletal abnormalities, hearing impairment, neurologic motor problems, and immune deficiency. Expression of the disease varies considerably, and there is a wide spectrum of clinical findings and severity. Affected children are often normal at birth and during early development. They present in early childhood with delayed psychomotor development, delayed speech, and hearing loss.

Summary Clinical characteristics. Alpha-mannosidosis encompasses a continuum of clinical findings from mild to severe. Three major clinical subtypes have been suggested: A mild form recognized after age ten years with absence of skeletal abnormalities, myopathy, and slow progression (type 1) A moderate form recognized before age ten years with presence of skeletal abnormalities, myopathy, and slow progression (type 2) A severe form manifested as prenatal loss or early death from progressive central nervous system involvement or infection (type 3) Individuals with a milder phenotype have mild-to-moderate intellectual disability, impaired hearing, characteristic coarse features, clinical or radiographic skeletal abnormalities, immunodeficiency, and primary central nervous system disease – mainly cerebellar involvement causing ataxia. Periods of psychiatric symptoms are common. Associated medical problems can include corneal opacities, hepatosplenomegaly, aseptic destructive arthritis, and metabolic myopathy. Alpha-mannosidosis is insidiously progressive; some individuals may live into the sixth decade. Diagnosis/testing. The diagnosis of alpha-mannosidosis is established in a proband by identification of deficient acid alpha-mannosidase enzyme activity in peripheral blood leukocytes or other nucleated cells such as fibroblasts.

Alpha-mannosidosis is a rare inherited disorder that causes problems in many organs and tissues of the body. Affected individuals may have intellectual disability, distinctive facial features, and skeletal abnormalities. Characteristic facial features can include a large head , prominent forehead , low hairline , rounded eyebrows, large ears, flattened bridge of the nose, protruding jaw , widely spaced teeth , overgrown gums, and large tongue . The skeletal abnormalities that can occur in this disorder include reduced bone density (osteopenia), thickening of the bones at the top of the skull (calvaria), deformations of the bones in the spine (vertebrae ), knock knees , and deterioration of the bones and joints. Affected individuals may also experience difficulty in coordinating movements (ataxia); muscle weakness (myopathy); delay in developing motor skills such as sitting and walking; speech impairments; increased risk of infections; enlargement of the liver and spleen (hepatosplenomegaly); a buildup of fluid in the brain (hydrocephalus); hearing loss; and a clouding of the lens of the eye (cataract ).

An inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual deficit. Epidemiology It occurs in approximately 1 in 500,000 live births. Clinical description Affected infants often appear normal at birth but their condition worsens progressively. However, some children are born with ankle equinus or develop hydrocephalus in the first year of life. Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life), skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum), hearing impairment (moderate-to-severe sensorineural hearing loss), gradual impairment of mental functions and speech, and often, periods of psychosis. Associated motor function disturbances include muscular weakness, joint abnormalities and ataxia.

Alpha mannosidosis is a lysosomal storage disorder , a form of inborn metabolic disease . It is characterized by intellectual disability, hearing loss, ataxia, skeletal abnormalities, and coarse facial features.Signs and symptoms vary, but often include mild to moderate intellectual disability, hearing loss, weakened immune system, distinctive facial features, and cerebellar disorders (e.g., ataxia). Symptoms slowly worsen over time. According to the severity of the symptoms it is classified in 3 sub-types: Type 1: A mild form recognized after age ten years with absence of skeletal abnormalities, muscle problems (myopathy), and slow progression Type 2: A moderate form recognized before age ten years with presence of skeletal abnormalities, myopathy, and slow progression. It is the most common form. Type 3: A severe form manifested as pregnancy loss or early death from progressive central nervous system involvement. Alpha mannosidosis is caused by a mutations in the MAN2B1 gene, which codifies a type of enzyme (lysosomal alpha-mannosidase), that degrade glycoproteins (proteins attached to sugar residues) into smaller fragments.

A rare genetic hepatic disease characterized by multiple segmental cystic dilatations of both central and smaller peripheral bile ducts associated with congenital hepatic fibrosis. Age of symptom onset is variable, as is disease progression. Patients present recurrent cholangitis, hepatolithiasis, and cholecystolithiasis. Portal hypertension may appear later in the disease course, and the risk of developing cholangiocarcinoma is increased significantly. The syndrome is often associated with autosomal recessive polycystic kidney disease.

Caroli disease (CD) is a rare congenital liver disease characterized by non-obstructive cystic dilatations of the intra-hepatic and rarely extra-hepatic bile ducts. Epidemiology Exact prevalence and annual incidence data are not available for CD, but the disease is known to be very rare. An estimated prevalence of 1/1,000,000 has been suggested. There is a slight female gender bias. Clinical description Caroli disease can present at any age. CD ranges from simple ectasias of the larger intra-hepatic bile ducts (in this less common form the name Caroli disease is used) to a syndromic form (Caroli syndrome) that is more common and includes congenital hepatic fibrosis. Some patients remain asymptomatic throughout the disease course. Some develop intra- or extra-hepatic calculi, leading to recurrent cholangitis (with bacteremia and sepsis), and acute pancreatitis.

48,XXYY syndrome is a chromosomal condition that causes infertility, developmental and behavioral disorders, and other health problems in males. 48,XXYY disrupts male sexual development. Adolescent and adult males with this condition typically have small testes that do not produce enough testosterone, which is the hormone that directs male sexual development. A shortage of testosterone during puberty can lead to reduced facial and body hair, poor muscle development, low energy levels, and an increased risk for breast enlargement (gynecomastia). Because their testes do not function normally, males with 48, XXYY syndrome have an inability to father children (infertility). 48,XXYY syndrome can affect other parts of the body as well. Males with 48,XXYY syndrome are often taller than other males their age with an average adult height of 6 feet 4 inches (193 cm).

A rare sex chromosome number anomaly disorder characterized, genetically, by the presence of an extra X and Y chromosome in males and, clinically, by tall stature, dysfunctional testes associated with infertility and insufficient testosterone production, cognitive, affective and social functioning impairments, global developmental delay, and an increased risk of congenital malformations. Epidemiology The estimated prevalence is between 1/18,000 to 1/50,000 male births. Clinical description Presentation is often in infancy or early childhood with hypotonia and global development delay, sometimes accompanied by mild dysmorphic facies, plagiocephaly, and flat feet. Testicular hypogonadism, starting in adolescence and persisting throughout adulthood, is nearly universal. Cryptorchidism, micropenis, and gynecomastia have been occasionally reported.

48,XXYY syndrome is a chromosomal condition, characterized by the presence of an extra X and Y chromosome in males, that causes medical and behavioral problems. 48,XXYY can be considered a variant of Klinefelter syndrome . Individuals with 48,XXYY are usually considerably tall with small testes that do not function normally leading to infertility . In addition, affected individuals have behavioral problems such as anxiety, aggressiveness, problems communicating, hyperactivity, depression, as well as general learning disabilities and intellectual impairment. Other medical probelms can include congenital heart defects, bone abnormalities, tremor, obesity, type 2 diabetes and/or respiratory problems. Patients have an essentially normal life expectancy but require regular medical follow-up.

Trisomy 13 is a type of chromosome disorder characterized by having 3 copies of chromosome 13 in cells of the body, instead of the usual 2 copies. In some people, only a portion of cells contains the extra chromosome 13 (called mosaic trisomy 13), whereas other cells contain the normal chromosome pair. Trisomy 13 causes severe intellectual disability and many physical abnormalities, such as congenital heart defects; brain or spinal cord abnormalities; very small or poorly developed eyes (microphthalmia); extra fingers or toes; cleft lip with or without cleft palate ; and weak muscle tone (hypotonia). Most cases are not inherited and result from a random error during the formation of eggs or sperm in healthy parents. Trisomy 13 is diagnosed based on the symptoms, clinical exam, and confirmed by the results of a chromosome test.

A rare T-cell non-Hodgkin lymphoma characterized by infiltration of lymph nodes by neoplastic cells of T follicular helper cell origin with a polymorphous inflammatory background including markedly increased follicular dendritic cells and EBV-positive B-cells, as well as prominent proliferation of high endothelial venules. The spleen, liver, skin, and bone marrow are also frequently involved. Patients typically present with generalized lymphadenopathy, hepatosplenomegaly, systemic symptoms, and polyclonal hypergammaglobulinemia. Pruritic skin rash, arthritis, pleural effusion, and ascites may also be observed. The condition is aggressive with generally poor prognosis.