Chudley-Mccullough Syndrome

A number sign (#) is used with this entry because Chudley-McCullough syndrome (CMCS) is caused by homozygous or compound heterozygous mutation in the GPSM2 gene (609245) on chromosome 1p13.

Description

Chudley-McCullough syndrome is an autosomal recessive neurologic disorder characterized by early-onset sensorineural deafness and specific brain anomalies on MRI, including hypoplasia of the corpus callosum, enlarged cysterna magna with mild focal cerebellar dysplasia, and nodular heterotopia. Some patients have hydrocephalus. Psychomotor development is normal (summary by Alrashdi et al., 2011).

Clinical Features

Chudley et al. (1997) reported a Canadian Mennonite family in which a brother and sister had hydrocephalus due to obstruction at the foramen of Monro and profound bilateral sensorineural deafness. The parents were second cousins. Autosomal recessive inheritance was proposed on the basis of consanguinity, affected sibs of both sexes, and no evidence of intrauterine infections or other adverse perinatal events.

Hendriks et al. (1999) reported 2 sisters with congenital sensorineural hearing loss, partial agenesis of the corpus callosum, arachnoid cysts, and hydrocephalus. Both girls had normal psychomotor development and absence of any distinctive physical features. The parents had normal hearing and no abnormalities on brain MRI. They were nonconsanguineous but from the same small isolated village. The authors suggested that this combination probably represents a new autosomal recessive condition; however, the overlap with disorder in the families reported by Chudley et al. (1997) suggests otherwise.

Lemire and Stoeber (2000) presented 2 sisters of Mennonite descent with hydrocephalus and profound bilateral sensorineural deafness. The parents were nonconsanguineous. One sister had hydrocephalus due to obstruction of the foramen of Monro. This sister also had a full mutation in the FMR1 (309550) gene, presumed to be an incidental finding. The other sister had no evidence of a foramen of Monro obstruction but had other brain abnormalities, including callosal dysgenesis, gray matter heterotopia, cortical dysplasia, and cerebellar dysgenesis. The authors suggested the eponym Chudley-McCullough syndrome for this condition. They proposed that neuroimaging of the brain be considered in all individuals with profound sensorineural hearing loss, especially those of Mennonite background.

Welch et al. (2003) described a family in which 2 brothers and a sister had Chudley-McCullough syndrome. Each had profound sensorineural deafness that was either congenital or rapidly progressive in infancy, together with asymmetric dilatation of the lateral ventricle secondary to obstruction of the foramen of Monro. Other brain abnormalities included arachnoid cyst, partial agenesis of the corpus callosum, and abnormalities in the migration of cerebellar cells. Welch et al. (2003) recommended an audiologic assessment of all children with hydrocephalus, especially those with obstruction of the foramen of Monro.

Ostergaard et al. (2004) reported 2 Pakistani brothers, born of consanguineous parents, with Chudley-McCullough syndrome. They had partial agenesis of the corpus callosum, colpocephaly, dilatation of the lateral ventricles with macrocephaly, areas of cortical dysplasia, and sensorineural deafness. The older sib had mild mental retardation, whereas the younger sib was developmentally normal. A review of the literature showed that 6 reported patients had sensorineural hearing loss and colpocephaly. Mental retardation and facial dysmorphism were variable. Colpocephaly is characterized by enlargement of the occipital horns of the lateral ventricles with normal frontal horns, which may result from agenesis of the posterior corpus callosum. Ostergaard et al. (2004) concluded that the basic developmental defect in Chudley-McCullough syndrome is agenesis of the corpus callosum, not obstruction of the foramen of Monro.

Matteucci et al. (2006) reported 2 Italian sisters, born of nonconsanguineous parents, who had profound bilateral sensorineural hearing impairment, macrocephaly, minor dysmorphisms, and borderline psychomotor developmental delay, which the authors believed was related to the hearing defect. Brain MRI revealed all the anomalies variably described in previous reports, including hydrocephalus, partial agenesis of the corpus callosum, interhemispheric cyst, and cerebral and cerebellar cortex dysplasia. Matteucci et al. (2006) proposed that asymmetric enlargement of the ventricles and agenesis of the splenium, together with macrocephaly and deafness, be considered hallmarks of the syndrome.

Alrashdi et al. (2011) reported a 9-year-old girl, born of consanguineous Lebanese parents, with severe to profound sensorineural hearing loss since early infancy. Brain MRI showed hypoplasia of the corpus callosum, evidence of polymicrogyria in the frontal parasagittal region, foci of subcortical heterotopic gray matter, and hypoplasia of the inferior cerebellar vermis associated with enlargement of the cisterna magna. There were no apparent structural abnormalities of the inner ear structures or cranial nerve VIII. The patient did not have hydrocephalus or obstruction of the foramen of Monro, and she had normal psychomotor development.

Shahin et al. (2010) and Walsh et al. (2010) reported a large consanguineous Palestinian kindred in which 7 individuals had severe bilateral prelingual sensorineural deafness. Vision and vestibular function were normal. Yariz et al. (2012) reported a large consanguineous Turkish family in which 3 children presented with congenital severe to profound sensorineural hearing loss and no other abnormalities. The disorder was designated DFNB82. By brain imaging, Doherty et al. (2012) found that 1 of the patients from the Palestinian family described by Walsh et al. (2010) and all 3 Turkish patients reported by Yariz et al. (2012) had brain abnormalities consistent with a diagnosis of CMCS. All 4 patients had a short and thin corpus callosum, evidence of heterotopia and polymicrogyria, and arachnoid cysts; 3 had cerebellar dysplasia. However, none had ventriculomegaly.

Doherty et al. (2012) reported 12 patients from 8 families with Chudley-McCullough syndrome. Five of the families were Mennonite. All had severe to profound hearing loss and characteristic brain imaging findings, including ventriculomegaly, posterior agenesis of the corpus callosum, frontal polymicrogyria, frontal heterotopia, cerebellar dysplasia, and arachnoid cysts. Two patients had well-controlled seizures and 1 had mild to moderate intellectual disability.

Inheritance

The Chudley-McCullough syndrome is an autosomal recessive disorder (Chudley et al., 1997; Matteucci et al., 2006).

Mapping

In a consanguineous Palestinian family (family CG), originally thought to have nonsyndromic autosomal recessive deafness (DFNB82), Shahin et al. (2010) found linkage to a 3.1-Mb region on chromosome 1p13.3 (lod score of 5.16) between markers rs17542571 and rs1936942. The region overlapped the DFNB32 locus (608653) by 833 kb. Sequencing analysis excluded mutations in 2 candidate genes: VAV3 (605541) and SLC25A24 (608744).

Molecular Genetics

In affected members of a consanguineous Palestinian family with profound hearing loss, originally reported by Shahin et al. (2010), Walsh et al. (2010) identified a homozygous mutation in the GPSM2 gene (R127X; 609245.0001). All of the parents were unaffected and heterozygous for the mutation. By homozygosity mapping followed by candidate gene analysis, Yariz et al. (2012) identified a homozygous truncating mutation in the GPSM2 gene (Q562X; 609245.0002) in affected members of a consanguineous Turkish family with congenital hearing loss. All of the parents were unaffected and heterozygous for the mutation. Four patients originally reported to have nonsyndromic deafness by Walsh et al. (2010) and Yariz et al. (2012) were found by Doherty et al. (2012) to have neuroimaging abnormalities consistent with a diagnosis of Chudley-McCullough syndrome.

By homozygosity mapping and whole-exome sequencing of patients with Chudley-McCullough syndrome, Doherty et al. (2012) identified homozygous or compound heterozygous mutations in the GPSM2 gene (609245.0003-609245.0006). There were no apparent genotype/phenotype correlations. Doherty et al. (2012) postulated that the disorder results from asymmetric cell divisions in the brain during development.