Corpus Callosum, Agenesis Of, With Abnormal Genitalia

A number sign (#) is used with this entry because agenesis of the corpus callosum with abnormal genitalia and mental retardation, also known as Proud syndrome, is caused by mutation in the ARX gene (300382).

Description

Proud syndrome is an X-linked developmental disorder characterized by agenesis of the corpus callosum, severe mental retardation, seizures, and spasticity. Males are severely affected, whereas females may be unaffected or have a milder phenotype (Proud et al., 1992). Proud syndrome 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 to infantile spasms without brain malformations (EIEE1; 308350) to syndromic (309510) and nonsyndromic (300419) mental retardation (Kato et al., 2004; Wallerstein et al., 2008).

Clinical Features

Proud et al. (1992) reported on 4 generations in a family in which 3 living males, 3 males who died in infancy, and 3 females had neurologic impairment and agenesis of the corpus callosum. Manifestations in the surviving males included severe acquired micrencephaly, mental retardation, limb contractures, scoliosis, tapered fingers with hyperconvex nails, a characteristic face with large eyes, prominent supraorbital ridges, synophrys, optic atrophy, broad alveolar ridges, and seizures. Urologic anomalies included renal dysplasia, cryptorchidism, and hypospadias. Two affected females were less severely impaired and continued to be socially active, but had spastic quadriplegia and seizures. One obligate carrier was retarded with emotional problems, whereas another obligate carrier and her daughter were clinically normal. The authors noted that these findings are consistent with X-linked inheritance with variable expression in females.

Carrier Females

Marsh et al. (2009) reviewed 25 heterozygous female carriers of known ARX mutations and found that 8 (35%) had significant developmental abnormalities. Twenty-three of the 25 were relatives of a male with an ARX mutation, including 14 mothers and 9 other female relatives. Six of the females had been reported by Bonneau et al. (2002) and 4 had been reported by Proud et al. (1992), ascertained based on the identification of a male relative with XLAG (300215) or Proud syndrome, respectively. Clinical features of the affected females were variable, but included agenesis of the corpus callosum, delayed motor development, attention-deficit hyperactivity disorder, learning disabilities, and seizures. None had infantile spasms. Only 3 (33%) of the 9 female relatives other than mothers had completely normal development. Marsh et al. (2009) noted an ascertainment bias: the first reports of human ARX mutations described asymptomatic mothers as healthy carrier of the mutations, which fits well with their having lived to adulthood and having high reproductive fitness. In contrast, other female relatives tended to be more severely affected. The data of Marsh et al. (2009) did not show clear evidence for skewing of X inactivation in either symptomatic or asymptomatic females, but the number of females tested was too low to draw firm conclusions. Marsh et al. (2009) also found that about half of female mice with targeted disruption of the Arx gene developed seizures, further indicating that some female carriers may be affected.

Mapping

By DNA analysis using a series of X-linked probes in a family with corpus callosum agenesis and abnormal genitalia, Proud et al. (1992) found linkage to a region between Xp21.3 and Xp11.3 with a lod score of 1.26 at theta = 0.

Molecular Genetics

Kato et al. (2004) identified mutations in the ARX gene in 20 patients with brain and genital malformations, including the 3 males reported by Proud et al. (1992), who had a thr333-to-asn mutation (T33N; 300382.0015). Two of the other patients had hydranencephaly and abnormal genitalia (see, e.g., 300382.0016) and the rest had X-linked lissencephaly and ambiguous genitalia (XLAG; 300215).

Genotype/Phenotype Correlations

In a review of 29 males with ARX mutations, Kato et al. (2004) found that those with premature termination or nonsense mutations had brain malformation syndromes, including XLAG and Proud syndrome, whereas those with expansion of the polyalanine tract (300382.0001 and 300382.0002) had epileptic encephalopathy (308350) or mental retardation without brain malformations (309510). Missense mutations were equally divided between the 2 groups, but the more severe phenotypes correlated with mutations in highly conserved regions.