New X‐linked syndrome with seizures, acquired micrencephaly, and agenesis of the corpus callosum

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Abstract
We report on 4 generations in a family with 3 living males, 3 males who died in infancy, and 3 females with neurologic impairment and agenesis of the corpus callosum (ACC). Manifestations in the surviving males include severe acquired micrencephaly, mental retardation, limb contractures, scoliosis, tapered digits with hyperconvex nails, a characteristic face with large eyes, prominent supraorbital ridges, synophris, optic atrophy, broad alveolar ridges and seizures. Urologic anomalies include renal dysplasia, cryptorchidism, and hypospadias. Two affected females were less severely impaired and continued to be socially responsive as adults, but had spastic quadriplegia and seizures. One obligate heterozygote was retarded with emotional problems while another obligate carrier female and her daughter were clinically normal. Pedigree analysis suggested X‐linked inheritance with variable expression in females. These findings are inconsistent with the well‐described X‐linked conditions with ACC including FG syndrome and Aicairdi syndrome. ACC has not been described in Coffin‐Lowry syndrome, a condition with similar clinical findings, which also demonstrates marked variability of expression in carrier females.In order to assist in carrier determination, brain imaging studies and DNA linkage analysis of the affected relatives was performed. We found a spectrum of agenesis of the corpus callosum with the most severe manifestations in the most severely affected males. DNA analysis using a series of X‐linked probes suggests linkage with a LOD score of 1.26 at θ=0 to a region between p 11.3 and p 21.3.