Van Esch-O'driscoll Syndrome

A number sign (#) is used with this entry because of evidence that Van Esch-O'Driscoll syndrome (VEODS) is caused by hemizygous mutation in the POLA1 gene (312040) on chromosome Xp22.

Description

Van Esch-O'Driscoll syndrome (VEODS) is characterized by varying degrees of intellectual disability, moderate to severe short stature, microcephaly, hypogonadism, and variable congenital malformations (Van Esch et al., 2019).

Clinical Features

Van Esch et al. (2005) reported a 5-generation Belgian family in which 6 male family members had mental retardation, with low birth weights and subsequent growth retardation resulting in short stature and microcephaly. Three affected individuals also had hypergonadotropic hypogonadism, and 2 developed noninsulin-dependent diabetes mellitus in adulthood. Obligate carrier females were unaffected. Cognitive and psychosocial assessment of the 4 living patients showed mild to moderate mental retardation; the 2 better-functioning men showed significant discrepancy between verbal and performance IQ. All had good receptive language skills, but language expression was more delayed. All showed extremely poor social skills, with marked shyness and avoidance of social interactions. The youngest patient exhibited attention deficit/hyperactivity disorder (ADHD) that required medication.

Van Esch et al. (2019) studied 9 patients from 5 families with syndromic X-linked mental retardation, including the Belgian family (family A) originally reported by Van Esch et al. (2005). All affected individuals presented with different degrees of intellectual disability, moderate to severe proportionate short stature, microcephaly, and hypergonadotropic hypogonadism, as well as isolated congenital malformations.

Mapping

In a 5-generation Belgian family with syndromic X-linked mental retardation, Van Esch et al. (2005) performed 2-point linkage analysis using highly polymorphic microsatellite markers spanning the entire X chromosome and found linkage to a 6-cM interval at Xp22.1-p21.3, with a maximum lod score of 2.61 for markers DXS989 and DXS1061 (theta = 0.00).

Molecular Genetics

In 9 affected male patients from 5 unrelated families with syndromic X-linked mental retardation, Van Esch et al. (2019) identified 5 different mutations in the POLA1 gene (312040.0002-312040.0006). Carrier females were unaffected, and all showed significant to complete skewing of X inactivation.

Exclusion Studies

In a 5-generation Belgian family with syndromic X-linked mental retardation mapping to Xp22.1-p21.3, Van Esch et al. (2005) screened 2 MRX-associated genes mapping within the 6-cM interval, ARX (300382) and IL1RAPL1 (300206), but detected no mutations.