A rare acquired immunodeficiency disorder characterized by the appearance of susceptibility to disseminated opportunistic infections (in particular, disseminated nontuberculous mycobacterial infection, salmonellosis, penicillosis, and varicella zoster virus infection) in previously healthy (HIV-negative) adults, associated with the presence of acquired autoantibodies to interferon gamma. Typical clinical manifestation includes lymphadenopathy (cervical or generalized), fever, weight loss and/or reactive skin lesions.

Adult-onset immunodeficiency with anti-interferon-gamma autoantibodies is an immunodeficiency disorder . It is associated with susceptibility to disseminated infections (dispersed throughout the body) caused by organisms that typically affect only people with weak immune systems (opportunistic pathogens). People with this disorder produce higher amounts of anti-interferon-gamma autoantibodies. These are specific immune system proteins that mistakenly target a person's own tissues. It is predominantly reported in Southeast Asians who were previously healthy.

Intraneural perineurioma is a rare tumor of cranial and spinal nerves arising from peripheral nerve sheet and composed exclusively or predominantly of cells showing perineurial differentiation. It presents as a localized, tubular or fusiform enlargement of a nerve or nerve segment, usually in the extremities or the trunk, associated with a motor-predominant mononeuropathy including slow, painless, gradual loss of motor function in the involved nerve trunk with muscle weakness and atrophy and, rarely, sensory dysfunction. Cranial nerve involvement is rare.

Description Familial hyperkalemic hypertension, also known as type II pseudohypoaldosteronism (PHAII) or Gordon syndrome, is a rare autosomal dominant disease in which a net positive sodium ion balance is associated with renal potassium ion retention, resulting in hypertension, hyperkalemia, and hyperchloremic metabolic acidosis (summary by Louis-Dit-Picard et al., 2012).

A number sign (#) is used with this entry because pseudohypoaldosteronism type IIB (PHA2B) is caused by heterozygous mutation in the WNK4 gene (601844) on chromosome 17q21. For a phenotypic description and a discussion of genetic heterogeneity of pseudohypoaldosteronism type II, see PHA2A (145260). Clinical Features Farfel et al. (1978, 1978) described an Ashkenazi Jewish family in which some members had hyperkalemia (6-7 mEq/L) evident in childhood and hypertension that developed later in life. The patients had mild acidosis of the proximal renal tubular acidosis type. Chlorothiazide administration promptly corrected all features. The syndrome affected 7 members of 3 generations with instances of male-to-male transmission, thus indicating autosomal dominant inheritance.

A rare genetic form of hypertension characterized by hyperkalemia, mild hyperchloremic metabolic acidosis, normal or elevated aldosterone, low renin, with normal renal glomerular filtration rate (GFR). Epidemiology The prevalence of the disorder is unknown. To date, more than 180 affected individuals and families have been reported. Clinical description Patients generally develop hypertension in adulthood. Hyperkalemia, mild hyperchloremic acidosis and low renin are present from a young age and are constant findings. Aldosterone levels may be normal to high. Hypervolemia is frequently observed.

Description Pseudohypoaldosteronism type II (PHA2), also known as Gordon hyperkalemia-hypertension syndrome, is characterized by hyperkalemia despite normal renal glomerular filtration, hypertension, and correction of physiologic abnormalities by thiazide diuretics. Mild hyperchloremia, metabolic acidosis, and suppressed plasma renin (179820) activity are variable associated findings (summary by Mansfield et al., 1997). Genetic Heterogeneity of Pseudohypoaldosteronism Type II PHA2A has been mapped to chromosome 1q31-q42. PHA2B (614491) is caused by mutations in the WNK4 gene on chromosome 17q21 (601844). PHA2C (614492) is caused by mutations in the WNK1 gene on chromosome 12p13 (605232).

Summary Clinical characteristics. Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia despite normal glomerular filtration rate (GFR) and frequently by hypertension. Other associated findings in both children and adults include hyperchloremia, metabolic acidosis, and suppressed plasma renin levels. Aldosterone levels are variable, but are relatively low given the degree of hyperkalemia (elevated serum potassium is a potent stimulus for aldosterone secretion). Hypercalciuria is well described. Diagnosis/testing. The diagnosis of PHAII is established in a proband: With hyperkalemia (in the setting of normal glomerular filtration), hypertension, metabolic acidosis, hyperchloremia, and suppressed plasma renin levels; AND/OR By the identification of a heterozygous pathogenic variant in CUL3 , WNK1 , or WNK4 or a heterozygous pathogenic variant or biallelic pathogenic variants in KLHL3 . Management. Treatment of manifestations: Electrolyte and blood pressure abnormalities of PHAII in children and adults are often corrected with thiazide diuretics.

Psuedohypoaldosteronism type 2 is an inborn error of metabolism. It is characterized by high blood pressure, high levels of potassium in the body, and metabolic acidosis . It is caused by mutations in the WNK1 or WNK4 gene. Treatment may involve dietary restriction of sodium and hydrochlorothiazide .

Sensorineural deafness with dilated cardiomyopathy is an extremely rare autosomal dominant syndrome described in two families to date and characterized by moderate to severe sensorineural hearing loss manifesting during childhood, and associated with late-onset dilated cardiomyopathy that generally progresses to heart failure.

15q13.3 microdeletion is a chromosomal change in which a small piece of chromosome 15 is deleted in each cell. The deletion occurs on the long (q) arm of the chromosome at a position designated q13.3. This chromosomal change increases the risk of intellectual disability, seizures, behavioral problems, and psychiatric disorders. However, some people with a 15q13.3 microdeletion do not appear to have any associated features. About half of all people with a 15q13.3 microdeletion have learning difficulties or intellectual disability, which is usually mild or moderate.

15q13.3 microdeletion syndrome is a genetic disorder caused by a deletion of several genes on chromosome 15 . When a syndrome is caused by the deletion of several genes, it is also known as a microdeletion syndrome or a contiguous gene deletion syndrome. Individuals with 15q13.3 microdeletion syndrome may have very different signs and symptoms from other affected individuals (even within the same family), or no symptoms at all. Features of the condition may include mild to moderate intellectual disabilities, learning delays, or normal intelligence; autism spectrum disorders; epilepsy (recurring seizures); and mental illness (such as schizophrenia or bipolar disorder). Various dysmorphic (abnormally formed) features have been reported, but there are no consistent physical features among individuals who have the condition. 15q13.3 microdeletion syndrome is caused by a deletion on the long arm of chromosome 15 that spans at least 7 genes and usually includes the CHRNA7 gene.It can be inherited in an autosomal dominant manner with reduced penetrance, or can occur as a new (de novo) deletion.

Pagnamenta et al. (2009) reported 3 male sibs with autism associated with an approximately 2.0-Mb deletion of chromosome 15q13.3 involving BP4-BP5 that was inherited from their unaffected mother.

15q13.3 microdeletion (microdel15q13.3) syndrome is characterized by a wide spectrum of neurodevelopmental disorders with no or subtle dysmorphic features. Epidemiology Its prevalence is unknown; nearly 150 cases have been reported, including a subset of healthy relatives of affected individuals. Males are more likely to be symptomatic. Clinical description The syndrome manifests in childhood or later in life. Patients present with developmental delay, mainly in speech acquisition, cognitive impairment in about half of the cases (usually mild, sometimes moderate to severe), idiopathic generalized epilepsy (IGE, including childhood or juvenile absence epilepsy, juvenile myoclonic epilepsy (see these terms) and epilepsies with generalized tonic-clonic seizures), neurobehavioral disorders of the autistic or psychotic spectrum (including impaired expressive language, poor eye contact, repetitive movements, hyperactivity, impulsive and/or aggressive behavior, and disturbed social interactions). Subtle dysmorphic features may be present (down-slanting palpebral fissures, prominent nasal tip, large ears, strabismus, clinodactyly of the 5th finger, pigmented naevi ).

Summary Clinical characteristics. Optic atrophy type 1 (OPA1, or Kjer type optic atrophy) is characterized by bilateral and symmetric optic nerve pallor associated with insidious decrease in visual acuity (usually between ages 4 and 6 years), visual field defects, and color vision defects. Visual impairment is usually moderate (6/10 to 2/10), but ranges from mild or even insignificant to severe (legal blindness with acuity <1/20). The visual field defect is typically centrocecal, central, or paracentral; it is often large in those with severe disease. The color vision defect is often described as acquired blue-yellow loss (tritanopia). Other findings can include auditory neuropathy resulting in sensorineural hearing loss that ranges from severe and congenital to subclinical (i.e., identified by specific audiologic testing only).

Optic atrophy 1 , also known as optic atrophy type 1 is a disease that affects the optic nerve . The optic nerve carries signals from the eye to the brain about what is seen. People with optic atrophy type 1 have an optic nerve that has lost some tissue ( atrophy ). This atrophy causes the optic nerve not to work as well as it should, which affects the vision. Signs and symptoms of optic atrophy type 1 include vision loss , difficulty distinguishing colors, and an abnormally pale appearance (pallor) of the optic nerve.

Dominant optic atrophy (DOA) is an inherited optic nerve disorder characterized by degeneration of the optic nerves. It typically starts during the first decade of life. Affected people usually develop moderate visual loss and color vision defects. The severity varies and visual acuity can range from normal to legal blindness. About 20% of people with DOA have non-ocular features, such as sensorineural hearing loss; myopathy ; peripheral neuropathy; multiple sclerosis-like illness; and spastic paraplegia (impaired function of the legs). These cases may be referred to as 'DOA plus.' DOA is inherited in an autosomal dominant manner and may be caused by a mutation in any of several genes, some of which have not been identified.

A number sign (#) is used with this entry because optic atrophy-1 (OPA1) is caused by heterozygous mutation in the gene encoding the human homolog of the S. pombe dynamin-related protein Msp1 (OPA1; 605290) on chromosome 3q29. Description Autosomal dominant optic atrophy is characterized by an insidious onset of visual impairment in early childhood with moderate to severe loss of visual acuity, temporal optic disc pallor, color vision deficits, and centrocecal scotoma of variable density (Votruba et al., 1998). Some patients with mutations in the OPA1 gene may also develop extraocular neurologic features, such as deafness, progressive external ophthalmoplegia, muscle cramps, hyperreflexia, and ataxia; see 125250. There appears to be a wide range of intermediate phenotypes (Yu-Wai-Man et al., 2010). Yu-Wai-Man et al. (2009) provided a detailed review of autosomal dominant optic atrophy and Leber hereditary optic neuropathy (LHON; 535000), with emphasis on the selective vulnerability of retinal ganglion cells to mitochondrial dysfunction in both disorders.

A number sign (#) is used with this entry because of evidence that optic atrophy-5 (OPA5) is caused by heterozygous mutation in the DNM1L gene (603850) on chromosome 12p11. Description OPA5 is an autosomal dominant form of nonsyndromic optic atrophy, manifest as slowly progressive visual loss with variable onset from the first to third decades. Additional ocular abnormalities may include central scotoma and color vision defects. The pathogenesis is related to defective mitochondrial fission (summary by Gerber et al., 2017). For a discussion of genetic heterogeneity of optic atrophy, see OPA1 (165500).

This article includes a list of general references , but it remains largely unverified because it lacks sufficient corresponding inline citations . Please help to improve this article by introducing more precise citations. ( October 2009 ) ( Learn how and when to remove this template message ) Kjer's optic neuropathy Other names Autosomal dominant optic atrophy, Kjer type; Kjer optic atrophy; or, Kjer's autosomal dominant optic atrophy. Specialty Neurology Dominant optic atrophy , or dominant optic atrophy, Kjer's type , is an autosomally inherited disease that affects the optic nerves , causing reduced visual acuity and blindness beginning in childhood. This condition is due to mitochondrial dysfunction mediating the death of optic nerve fibers. Dominant optic atrophy was first described clinically by Batten in 1896 and named Kjer’s optic neuropathy in 1959 after Danish ophthalmologist Poul Kjer, who studied 19 families with the disease. [1] Although dominant optic atrophy is the most common autosomally inherited optic neuropathy (i.e., disease of the optic nerves) aside from glaucoma , it is often misdiagnosed.

Optic atrophy type 1 is a condition that often causes slowly worsening vision, usually beginning in childhood. People with optic atrophy type 1 typically experience a narrowing of their field of vision (tunnel vision). Affected individuals gradually lose their sight as their field of vision becomes smaller. Both eyes are usually affected equally, but the severity of the vision loss varies widely, even among affected members of the same family, ranging from nearly normal vision to complete blindness. In addition to vision loss, people with optic atrophy type 1 frequently have problems with color vision (color vision deficiency) that make it difficult or impossible to distinguish between shades of blue and green.

A rare neuro-ophthalmological disease which is one of the most common forms of hereditary optic neuropathy characterized by progressive bilateral visual loss with an onset during the first decade of life, associated with optic disc pallor, visual acuity loss, visual field deficits and color vision defects. Epidemiology The prevalence of Autosomal dominant optic atrophy (ADOA) is variable, commonly varying between 1/10,000 in Denmark (due to a founder effect) to 1/35,000 in the UK and probably worldwide. Clinical description ADOA is usually detected during the first decade of life, often by vision screening in school but later onset is possible. Visual impairment is usually moderate (visual acuity ranges from 20/80 to 20/120) but may range from mild to severe. Visual field defect is typically centrocecal, central, or paracentral.

A rare maxillo-facial surgical disease characterized by an inflammatory, granulomatous lesion, most commonly of iatrogenic origin due to interaction of extravasated erythrocytes with exogenous lipids, in particular petrolatum-based antibiotic ointment used after surgical procedures. Most frequent locations are the paranasal sinuses and jaws, although the lesion can occur in any part of the body. It is typically found incidentally as an asymptomatic soft tissue swelling.

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-63 can be caused by mutation in the ACSL4 (300157) gene. Clinical Features Raynaud et al. (2000) reported a 4-generation family with nonspecific nonsyndromic X-linked mental retardation. Affected males showed nonprogressive mental retardation ranging from severe to moderate, without seizures, whereas carrier females showed highly variable cognitive capacities, ranging from moderate mental retardation to normal intelligence. Mapping Raynaud et al. (2000) reported a 4-generation family with nonspecific nonsyndromic X-linked mental retardation mapped between DXS990 and DXS1227 (Xq21.33-q27.1) with a maximum lod at theta = 0.0 of 2.14 at DXS1001. Molecular Genetics In the proband of the family reported by Raynaud et al. (2000) as MRX63, Meloni et al. (2002) identified a mutation in the ACSL4 gene (300157.0001).

Clinical Features Martinez et al. (2001) reported a 4-generation family in which 5 males had mild to moderate nonspecific mental retardation. Brain CT scan performed in 1 patient was normal. Inheritance The pedigree pattern in the family with mental retardation reported by Martinez et al. (2001) was consistent with X-linked inheritance. Mapping By typing of markers throughout the X chromosome in a 4-generation family with nonsyndromic mental retardation, Martinez et al. (2001) mapped the phenotype locus to a 2-cM interval between markers DXS8019 and DXS365 on chromosome Xp22.2. Molecular Genetics Exclusion Studies In a family with nonsyndromic mental retardation mapping to Xp22.2, Martinez et al. (2001) performed direct sequencing of the RSK2 gene (300075) but found no causal mutation. They concluded that another unidentified gene for X-linked mental retardation is located near RSK2.

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-104 (MRX104) is caused by mutation in the FRMPD4 gene (300838) on chromosome Xp22. Clinical Features Hu et al. (2016) reported a large family (P58) in which 5 males had mild to severe intellectual disability with variable seizures, poor or absent speech, and behavioral problems. They also reported an unrelated patient (L87) who presented at age 17 years with significant developmental delay, absence of speech, and autism spectrum disorder. Piard et al. (2018) reported follow-up of the patients reported by Hu et al. (2016) and identified 4 additional male patients from 2 additional unrelated families. Including the previous report, there were 10 affected males from 4 unrelated families with patients ranging from 4 to 66 years of age.

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-99 (MRX99) is caused by mutation in the USP9X gene (300072) on chromosome Xp11. Heterozygous mutation in the USP9X gene can also cause female-restricted X-linked syndromic mental retardation-99 (MRXS99F; 300968). Clinical Features Homan et al. (2014) reported 4 patients from 3 unrelated families with X-linked recessive mental retardation. The families were previously ascertained by Tarpey et al. (2009) in a large-scale study that resequenced coding exons of the X chromosome in patients with mental retardation. The patients showed developmental delay, hypotonia, and some behavioral abnormalities, such as aggression.

A number sign (#) is used with this entry because X-linked mental retardation-90 (MRX90) is caused by mutation in the DLG3 (300189) gene on chromosome Xq13. Clinical Features Tarpey et al. (2004) reported 4 families in each of which at least 2 males had moderate to severe nonsyndromic X-linked mental retardation. Philips et al. (2014) reported 2 unrelated Finnish families with MRX90. Three affected males in 1 family (D172) had delayed psychomotor development with speech delay, mild to moderate intellectual disability, narrow thorax, molar hypoplasia, short and upslanting palpebral fissures, high-arched palate, and hypotonia. Five males in the second family (D301) had delayed motor and language development with moderate to severe mental retardation.

A number sign (#) is used with this entry because this form of X-linked mental retardation, referred to as MRX41 or MRX48, is caused by mutation in the GDI1 gene (300104) on chromosome Xq28. Clinical Features Hamel et al. (1996) reported a family segregating mild to moderate mental retardation as an X-linked trait (MRX41). Des Portes et al. (1997) reported a large 3-generation family segregating nonspecific X-linked mental retardation (MRX48). The pedigree suggested X-linked semidominant inheritance: moderate to severe mental retardation was found in 7 males and milder intellectual impairment in 2 females, without any specific clinical, radiologic, or biologic features. Bienvenu et al. (1998) reported a large French family (family R) in which all affected males showed moderate to severe mental retardation.

A number sign (#) is used with this entry because X-linked mental retardation-21 (MRX21) is caused by mutation in the IL1RAPL1 gene (300206) on chromosome Xp21. Description This form of nonsyndromic X-linked mental retardation is characterized by a spectrum of cognitive neurologic impairments or disabilities ranging from moderate mental retardation to high-functioning autism. Males are typically severely affected, but some carrier females may manifest milder deficits (summary by Piton et al., 2008). Clinical Features Kozak et al. (1993) reported a 3-generation Italian family in which 4 male patients had moderate mental retardation without any specific or consistent phenotypic abnormalities. One obligate female carrier had mild retardation and another 2 had normal intelligence, suggesting incomplete penetrance in females.

Clinical Features Golla et al. (2002) reported a family in which 4 males had mild to moderate nonspecific X-linked mental retardation, with no intellectual impairment in their obligate carrier mothers. Mapping By linkage analysis in a family in which 4 affected males had nonsyndromic mental retardation, Golla et al. (2002) obtained the same multipoint lod score of 2.08 for 2 intervals on the X chromosome: one in the pericentromeric region and the other at Xq26. Since the responsible gene was not characterized, haplotyping was the only means available for carrier and prenatal testing for this form of MRX, which they designated MRX42. Carrier risk estimation using pedigree and haplotype data for 5 females at risk was presented, and the difficulties of prenatal diagnosis given linkage to 2 different regions was discussed.

., MRX1, MRX2) if a minimal lod score of 2.0 was demonstrated between the MR locus and one or more X chromosome markers.

., MRX1, MRX2) if a minimal lod score of 2.0 was demonstrated between the MR locus and 1 or more X chromosome markers.

A number sign (#) is used with this entry because this form of nonspecific X-linked mental retardation is caused by mutation in the FTSJ1 gene (300499). Clinical Features Nonspecific X-linked mental retardation (MRX) includes several distinct entities with mental retardation but without additional distinguishing features. Hamel et al. (1999) described a 4-generation family segregating X-linked mental retardation. Affected members had nonprogressive mental retardation noted during childhood, and several demonstrated aggressive behavior. The mental retardation in tested members of the family was moderate to severe; none of the patients was able to read, write, or solve simple arithmetic problems.

A number sign (#) is used with this entry because of evidence that Tonne-Kalscheuer syndrome (TOKAS) is caused by hemizygous mutation in the RLIM gene (300379) on chromosome Xq13. Description Tonne-Kalscheuer syndrome (TOKAS) is an X-linked recessive multiple congenital anomaly disorder with 2 main presentations. Most patients exhibit global developmental delay apparent from early infancy, impaired intellectual development, speech delay, behavioral abnormalities, and abnormal gait. Affected individuals also have dysmorphic facial features that evolve with age, anomalies of the hands, feet, and nails, and urogenital abnormalities with hypogenitalism. A subset of more severely affected males develop congenital diaphragmatic hernia in utero, which may result in perinatal or premature death.

A number sign (#) is used with this entry because this form of nonsyndromic X-linked mental retardation is caused by mutation in the gene encoding p21-activated kinase-3 (PAK3; 300142). Clinical Features Des Portes et al. (1997) reported a French family in which 6 males in 2 generations had nonsyndromic X-linked mental retardation. All affected males had moderate to severe mental retardation without seizures, statural growth deficiencies, or other physical abnormalities. Gedeon et al. (2003) reported an Australian family with nonsyndromic MRX affecting 19 males in 5 generations. Some of the patients had relatively long ears, but no other physical abnormalities.

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-105 (MRX105) is caused by mutation in the USP27X gene (300975) on chromosome Xp11. Clinical Features Hu et al. (2016) reported 2 unrelated families (D177 and L75) in which a total of 7 males had borderline to moderate intellectual disability, variable poor or absent speech, and behavioral problems. No additional clinical details were provided. Inheritance The transmission pattern of MRX105 in the families reported by Hu et al. (2016) was consistent with X-linked recessive inheritance. Molecular Genetics In 3 affected males from a family (D177) with MRX105, Hu et al. (2016) identified a hemizygous truncating mutation in the USP27X gene (300975.0001). An unrelated male patient (family L75) with MRX105 was found to carry a hemizygous missense mutation in the USP27X gene (Y381H; 300975.0002); 3 others males in this family were affected, but genetic studies were not performed.

Clinical Features Vervoort et al. (2002) reported 9 male patients with a mutation in the AGTR2 gene who had moderate to severe mental retardation. Five of the patients had seizures and, with the exception of 1 patient, they were not hypertensive. Two patients also showed autistic behavior. Cytogenetics Vervoort et al. (2002) analyzed a de novo balanced translocation 46,X,t(X;7)(q24;q22) in a female patient with moderate mental retardation. This patient had completely skewed X inactivation. They mapped the X-chromosome breakpoint and demonstrated by RT-PCR that the AGTR2 gene was silenced in this patient. History Vervoort et al. (2002) screened affected males from 33 families with possible X-linked MR but no definitive linkage data, and a large cohort of 552 unrelated male patients with MR of unknown cause but negative for the FMR1 expansion.

A number sign (#) is used with this entry because this form of X-linked mental retardation (MRX19) is caused by mutation in the RPS6KA3 gene (300075). Description X-linked mental retardation-19 (MRX19) is a nonsyndromic form of mild to moderate mental retardation. Carrier females may be mildly affected. Mutation in the RPS6KA3 gene also causes Coffin-Lowry syndrome (CLS; 303600), a mental retardation syndrome with dysmorphic facial features and skeletal anomalies. Some patients with RPS6KA3 mutations have an intermediate phenotype with mental retardation and only mild anomalies reminiscent of CLS. These individuals have mutations resulting in some residual protein function, which likely explains the milder phenotype (summary by Field et al., 2006).

Clinical Features Shoichet et al. (2003) reported a 7-year-old girl with severe developmental delay who had a de novo balanced chromosome rearrangement, t(X;7)(p11.3;q11.21). At age 2 years, she did not yet walk or speak, and she exhibited clearly delayed psychomotor development. At age 3 years 9 months, occasional convulsions, predominantly localized to the shoulders and upper back, were reported, which led to the diagnosis of myoclonic epilepsy. At age 5 years 6 months, her physical development was in the normal range. She had no dysmorphic features. Screening for inborn errors of metabolism resulted in no indication of amino acidopathies or organic acidurias.

Clinical Features Molinari et al. (2008) reported an Australian family with nonsyndromic X-linked mental retardation. Of 5 sibs, there was 1 healthy girl, 2 girls with mild mental retardation, and 2 boys with severe mental retardation. The 2 affected males had a similar phenotype with the same degree of handicap. Both were in educational classes for the moderately handicapped and were able to hold a limited conversation; however, neither learned to read or write. Both were on disability pensions as adults. Their mother was described as slow and was found to carry the mutation.

Clinical Features Annunziata et al. (2003) reported an Italian family in which 9 males in 2 generations had nonspecific moderate to severe mental retardation. Mapping In an Italian family in which 9 males in 2 generations had nonspecific mental retardation, Annunziata et al. (2003) found linkage of the disorder to the pericentromeric region of the X chromosome. Haplotype construction delineated an 8-cM critical region for the locus, which they designated MRX81, at Xp11.2-q12 between DXS1039 and DXS1216. Molecular Genetics Exclusion Studies Annunziata et al. (2003) excluded 2 candidate genes for MRX81: oligophrenin-1 (300127) and ephrin-B1 (300035). INHERITANCE - X-linked recessive NEUROLOGIC Central Nervous System - Mental retardation, moderate to severe MISCELLANEOUS - Based on a report of 9 affected males from one Italian family - No consistent features other than mental retardation - Obligate carrier females have normal intelligence ▲ Close

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-96 (MRX96) is caused by mutation in the SYP gene (313475). Clinical Features Tarpey et al. (2009) identified 4 families with X-linked mental retardation who had mutations in the SYP gene. In 3 families, all with truncating mutations, mental retardation was mild to moderate and there were no consistent additional features, although epilepsy was noted in some individuals. Female carriers had no manifestations. Molecular Genetics The SYP mutations found by Tarpey et al. (2009) in 4 unrelated families with mental retardation included 3 truncating mutations and a missense mutation (313475.0001-313475.0002). INHERITANCE - X-linked recessive NEUROLOGIC Central Nervous System - Mental retardation, mild to moderate - Epilepsy (in some patients) MOLECULAR BASIS - Caused by mutation in the synaptophysin gene (SYP, 313475.0001 ) ▲ Close

A number sign (#) is used with this entry because of evidence that the phenotype is caused by microduplications within a region of chromosome Xp11.22 (chrX:53.0-54.3 Mb) that involve the HSD17B10 (300256) and HUWE1 (300697) genes. Increased dosage of HUWE1 is believed to be responsible for the phenotype (Froyen et al., 2012). Point mutations in the HSD17B10 and HUWE1 genes have been found to cause syndromic forms of mental retardation, MRXS10 (see 300438) and MRXST (309590), respectively. Clinical Features Gedeon et al. (1994) reported a family in which 6 males spanning 3 generations had moderate mental retardation with slow speech development inherited in an X-linked pattern. No significant common dysmorphic features were noted. Donnelly et al. (1996) reported a 4-generation family with multiple males affected with global retardation that became apparent between ages 2 and 4 years.

Clinical Features Hamel et al. (1999) described a 6-generation family segregating X-linked mental retardation. Affected members demonstrated nonprogressive mental retardation during childhood and had large, simple ears, relatively large hands, and normal behavior. The propositus also had clinodactyly of the fifth fingers and flat feet; findings in other affected individuals included short stature, high-arched palate, high nasal bridge, full lips, and large testes. The mental retardation in family MRX45 ranged from mild to severe: most affected members showed higher adaptive than intellectual functioning, and most could read, write, and solve simple arithmetic problems. Cytogenetics In a female patient with severe mental retardation and a de novo translocation t(X;9)(p11.23;q34.3), Kleefstra et al. (2004) characterized the breakpoints and found that the translocation disrupted the ZNF81 gene.

Clinical Features Sismani et al. (2003) reported a Greek family with apparently nonsyndromic X-linked mental retardation. The affected males had moderate to severe mental retardation, severe speech problems, and aggressive behavior. Mapping Sismani et al. (2003) performed linkage analysis on a Greek family with apparently nonsyndromic X-linked mental retardation. Two-point linkage analysis with 26 polymorphic markers spanning the entire X chromosome allowed assignment of the causative gene to a 27-Mb interval in Xq12-q21.3. Molecular Genetics Exclusion Studies In affected members of a family segregating X-linked mental retardation, Sismani et al. (2003) performed DNA analysis of 3 known or candidate MRX genes from the Xq12-q21 region, OPHN1 (300127), ATRX (300032), and RSK4 (300303), and found no mutations.

Clinical Features Yntema et al. (1998) reported a large Dutch family in which 12 males in 3 generations were affected with nonspecific X-linked mental retardation. Of 9 examined patients, 6 showed moderate mental retardation, and 1 each showed mild, severe, and profound mental retardation. Obligate female carriers were all normal. Mapping Linkage analysis of the family reported by Yntema et al. (1998) yielded a maximum lod score of 5.12 at HPRT between DXS8072 and DXS294 at Xq25-q26. Cytogenetics Kutsche et al. (2000) studied a male patient with severe mental retardation, mildly dysmorphic features, and sensorineural hearing loss who carried an apparently balanced X;21 translocation with breakpoints in Xq26 and 21p11. His unaffected mother carried the same translocation (von Ballestrem et al., 1996).

Clinical Features Lehrke (1974) described a nonspecific form of X-linked mental retardation in a large kindred designated family 1. The pedigree was updated by Howard-Peebles and Roberts (1984). Affected males had lower verbal IQs than performance IQs. Several of the affected males had performance IQs above 80; however, because of the lower (12.3 points on average) verbal IQs, they were considered retarded. Mapping Gregg et al. (1996) mapped the gene for this form of X-linked mental retardation, designated MRX23, to Xq23-q24 by linkage studies in the large kindred (family 1) of Lehrke (1974). Multipoint linkage analysis gave a maximum lod score of 6.7 between markers DXS1220 and DXS424.

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-72 (MRX72) is caused by hemizygous mutation in the RAB39B gene (300774) on chromosome Xq28. Mutation in the RAB39B gene can also cause X-linked recessive mental retardation with early-onset Parkinson disease, known as Waisman syndrome (WSMN; 311510). Clinical Features Russo et al. (2000) reported a 3-generation Sardinian family segregating X-linked mental retardation. Three affected individuals had seizures and 1 had features of autism (see 209850). Giannandrea et al. (2010) reported a large family with X-linked mental retardation spanning 2 generations.

A number sign (#) is used with this entry because nonsyndromic X-linked mental retardation-58 is caused by mutation in the TM4SF2 gene (TSPAN7; 300096) on chromosome Xp11. Clinical Features Holinski-Feder et al. (1999) described an Austrian family with nonsyndromic X-linked mental retardation. The 5 affected males in the family had mild to moderate mental retardation and no consistent dysmorphic features, while obligatory carrier females were normal. Mapping By linkage analysis in an Austrian family with nonsyndromic X-linked mental retardation, Holinski-Feder et al. (1999) mapped the disorder locus to an X pericentromeric location, with flanking markers DXS989 and DXS1111, with a maximum multipoint lod score of 2.09. Molecular Genetics In the affected family reported by Holinski-Feder et al. (1999), Abidi et al. (2002) identified a 2-bp deletion (300096.0003) in the TM4SF2 gene, resulting in a premature stop codon and truncated protein.

Clinical Features Gendrot et al. (1994) reported a French family in which 9 persons had moderate mental deficiency and poor speech in 3 generations. Some of the patients had facial dysmorphism, epilepsy, and macroorchidism. Mapping By linkage analysis in a family segregating mental retardation, Gendrot et al. (1994) found no recombination between the disease locus, designated MRX14, and 2 loci: DXS255 at Xp11.22 (maximum lod = 3.31 at theta = 0) and PGKP1 at Xq11.2-q12 (maximum lod = 3.08 at theta = 0). In a note added in proof, Gendrot et al. (1994) stated that they had found a recombination with MAOB (309860) at Xp11.3, reducing the linkage interval to Xp11.3-q13.3. GU - Macroorchidism Neuro - Moderate mental deficiency - Poor speech - Epilepsy Facies - Facial dysmorphism Inheritance - X-linked ▲ Close

IQSEC2 is a genetic condition that causes intellectual disability and sometimes other physical, neurological, or psychiatric symptoms. People with this condition can have seizures that are often difficult to control with medications. Other symptoms may include motor and language development delay, regression of learning abilities, autistic-like behavior, characteristic hand movements, and behavioral problems. Physical features may include abnormal head shape (plagiocephaly), very small head (microcephaly), reduced muscle tone (hypotonia), and crossed eyes (strabismus). This condition is caused by mutations in the IQSEC2 gene, which is located on chromosome X .

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-101 (MRX101) is caused by mutation in the MID2 gene (300204) on chromosome Xq22. One such family has been reported. Clinical Features Geetha et al. (2014) reported a large family from northern India in which 11 males spanning 3 generations had mental retardation. All 6 patients evaluated had global developmental delay. Facial dysmorphism was not prominent, but several patients had long face, prominent ears, and squint or strabismus. Two had seizures. Most also had hyperactivity, often with aggressive outbursts. Inheritance The transmission pattern in the family with MRX101 reported by Geetha et al. (2014) was consistent with X-linked recessive inheritance.

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-107 (MRX107) is caused by hemi- or heterozygous mutation in the CXORF56 gene (301012) on chromosome Xq24. One such family has been reported. Clinical Features Verkerk et al. (2018) reported a large 3-generation Dutch family in which 5 males and 1 female had mild to moderate intellectual disability. The patients had delayed development but were able to attend special schools, and some were able to work in a sheltered environment. Two males had significant behavioral problems, such as pervasive developmental disorder, attention disorder, hyperactivity, and transgressive behavior. The patients had variable dysmorphic facial features, including long, narrow face, prominent chin, upward slanting palpebral fissures, flat philtrum, narrow upper lip, and large ears with prominent cruxes.

Clinical Features Lugtenberg et al. (2006) studied a family in which 6 males in 3 generations had moderate to severe nonsyndromic mental retardation in an X-linked pattern of inheritance (XLMR). The 17-year-old proband had an IQ of 45. His mother had normal intelligence. He was the second son of unrelated parents and had 1 affected brother, 3 healthy sisters, and 1 carrier sister with borderline intelligence. Mapping The family reported by Lugtenberg et al. (2006) segregating X-linked mental retardation had previously been studied (family T40) by Raynaud et al. (2000), who found evidence of linkage of mental retardation to Xp11.3. History In a family in which 6 males in 3 generations had moderate to severe nonsyndromic mental retardation in a pattern consistent with X-linked recessive inheritance, Lugtenberg et al. (2006) identified a 352G-T transversion in exon 6 of ZNF674 cDNA, predicted to result in a glu118-to-ter (E118X; 300573.0001) truncated protein containing the Kruppel-associated box domains but lacking the zinc finger domains, which are crucial for DNA binding.

A number sign (#) is used with this entry because of evidence that this form of nonsyndromic X-linked mental retardation (MRX97) is caused by hemizygous mutation in the ZNF711 gene (314990) on chromosome Xq21. Clinical Features Yntema et al. (1999) reported a family (MRX65) in which 6 males in 3 generations had mild to moderate intellectual disability with speech delay. Four patients were obese. Van der Werf et al. (2017) provided follow-up of this family, noting that dysmorphic features included a broad face and prominent forehead. Van der Werf et al. (2017) reported another 4-generation family in which 5 males had mild to moderate intellectual disability, most often with motor delay and poor speech. Two had autistic features. Variable dysmorphic features included long face, synophrys, and relatively large ears.

Clinical Features Martinez et al. (2004) described a Basque family in which 5 males in 4 sibships in 2 generations had nonsyndromic mental retardation. Mapping In a Basque family with nonsyndromic mental retardation, Martinez et al. (2004) found linkage to Xq24-q25 with a maximum lod score of 2.4. Haplotype studies and multipoint linkage analysis suggested a localization of the MRX82 locus to an interval of 7.6 Mb defined by markers DXS6805 and DXS7346, in Xq24 and Xq25, respectively. The linked interval contained the gene encoding glutamate receptor-3 (GRIA3; 305915), but mutation analysis showed no pathologic changes. INHERITANCE - X-linked recessive SKELETAL Spine - Kyphosis - Scoliosis NEUROLOGIC Central Nervous System - Mental retardation, mild to profound - Seizures (patient A) - Abnormal EEG (patient B) - Postnatal hypotonia (patient A) - Normal cerebral CT scan (patient A) Behavioral Psychiatric Manifestations - Autistic behavior (patient A) MISCELLANEOUS - Based on a report of an extended ethnically Basque family ▲ Close

Clinical Features Zhang et al. (2004) reported a Chinese family in which 3 males in 3 generations had nonspecific X-linked mental retardation. The obligate carrier females were not affected. Mapping By 2-point linkage analysis, Zhang et al. (2004) demonstrated linkage of nonspecific mental retardation in a Chinese family to several markers located at Xq22.2, with a maximum lod score of 2.41 at theta = 0.0 for 2 adjacent markers (DXS1191 and DXS1230). Recombination events were observed with flanking markers DXS8080 and DXS456, located at Xp11.3 and Xq22.3, respectively, and a region of approximately 22.3 cM was defined. The localized region observed in this family overlapped with 29 other MRX loci previously reported in Xp11.3-q22.3. INHERITANCE - X-linked recessive GROWTH Height - Short stature HEAD & NECK Face - Broad forehead NEUROLOGIC Central Nervous System - Mental retardation, mild to moderate MISCELLANEOUS - No characteristic pattern of anomalies ▲ Close

Clinical Features Proops et al. (1983) reported a Japanese family (family F) living in Hawaii with mental retardation in 3 generations. Affected males were mildly or moderately retarded, while a number of heterozygous females were mildly retarded. The affected males were relatively short with a large head, highly arched palate, square face, prominent ears, and large testicular volumes. Their speech was limited and characterized by repetitive phrases or inflections. Affected males and females were described as having a pleasant demeanor.

A number sign (#) is used with this entry because this form of nonspecific X-linked mental retardation is caused by mutation in the ARX gene (300382) on chromosome Xp21. Description ARX-related mental retardation is a form of nonsyndromic X-linked mental retardation. It is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from lissencephaly (LISX2; 300215) to Proud syndrome (300004) to infantile spasms without brain malformations (EIEE1; 308350) to Partington syndrome (309510) (Kato et al., 2004; Wallerstein et al., 2008). Clinical Features Hamel et al. (1999) described a two 4-generation families (MRX43 and MRX52) segregating X-linked mental retardation. Affected members in family MRX43 had moderate to profound nonprogressive mental retardation recognized in early childhood.

Clinical Features Ahmad et al. (2001) described a large Pakistani family with X-linked nonspecific mental retardation. Mapping By linkage analysis in a Pakistani family segregating nonsyndromic mental retardation, Ahmad et al. (2001) identified a novel disease locus, MRX53, located in a critical region spanning approximately 15 cM between DXS1210 and DXS1047 on Xq22.2-q26. A lod score of 3.34 at no recombination was obtained with markers DXS1072 and DXS8081. INHERITANCE - X-linked recessive NEUROLOGIC Central Nervous System - Mental retardation (IQ between 45-50) - Normal gross motor development MISCELLANEOUS - Based on a report of 8 affected males in one Pakistani family ▲ Close

Clinical Features Claes et al. (1997) added 2 families to the growing list of nonspecific X-linked mental retardation (XLMR) families in which the disease gene could be mapped to a specific site on the X chromosome. The first family reported was designated MRX49 (300114). The second of these families, designated MRX50, contained 4 males in 2 generations showing moderate mental retardation. Mapping Linkage analysis in the MRX50 family by Claes et al. (1997) showed location of the locus at Xp11.3-p11.21 in the pericentromeric part of the short arm of the X chromosome, overlapping with a large number of other MRX gene regions: MRX1 (309530), MRX5, MRX7, MRX8, MRX9 (309549), MRX10, MRX11, MRX12 (300957), MRX13, MRX14 (300062), MRX15, MRX18, MRX22, MRX26, MRX31, and MRX38 (see 300419). Gedeon et al. (1996) hypothesized that all of the MRX assignments clustered on the pericentromeric part of Xp could be accounted for by 2 gene locations, namely the MRX1 and the MRX10 locations. Some of these families with pericentromeric gene locations show additional characteristic abnormalities and some of them show manifestations of disease in heterozygous carriers.

Splenic marginal zone lymphoma Specialty Hematology , oncology Splenic marginal zone lymphoma ( SMZL ) is a type of cancer (specifically a lymphoma ) made up of B-cells that replace the normal architecture of the white pulp of the spleen . The neoplastic cells are both small lymphocytes and larger, transformed lymphoblasts , and they invade the mantle zone of splenic follicles and erode the marginal zone , ultimately invading the red pulp of the spleen. Frequently, the bone marrow and splenic hilar lymph nodes are involved along with the peripheral blood . The neoplastic cells circulating in the peripheral blood are termed villous lymphocytes due to their characteristic appearance. [1] Contents 1 Cause 2 Diagnosis 3 Prognosis 4 Molecular findings 4.1 Immunophenotype 4.2 Genetics 5 Epidemiology 6 Synonyms 7 See also 8 References 9 External links Cause [ edit ] The cell of origin is postulated to be a post-germinal center B-cell with an unknown degree of differentiation. [1] SMZL is a form of cancer known to be associated with Hepatitis C virus infection. [ citation needed ] Diagnosis [ edit ] Enlargement of the spleen is a requirement for the diagnosis of SMZL and is seen in nearly all people affected by SMZL (often without lymphadenopathy). [1] Aside from the uniform involvement of the spleen , the bone marrow is frequently positive in patients with SMZL. Nodal and extranodal involvement are rare. [1] Circulating lymphoma cells are sometimes present in peripheral blood , and they occasionally show short villi at the poles of cells and plasmacytoid differentiation. [2] Autoimmune thrombocytopenia and anemia sometimes seen in patients with SMZL.

Splenic marginal zone lymphoma is a rare, indolent B-cell non-Hodgkin lymphoma characterized by abnormal clonal proliferation of mature B-lymphocytes with involvement in the spleen, bone marrow and, frequently, the blood. It usually presents with splenomegaly, lymphocytosis, anemia and/or thrombocytopenia. Hepatitis C virus and autoimmune manifestations, such as autoimmune hemolytic anemia and autoimmune thrombocytopenia, could be associated.