Chudley-McCullough syndrome

Last revised by Devpriyo Pal on 24 Jun 2022

Chudley-McCullough syndrome is an extremely rare autosomal recessive disorder characterized by early-onset sensorineural hearing loss and a distinctive combination of structural brain abnormalities, with relative preservation of psychomotor development.

Chudley-McCullough syndrome has an estimated prevalence of less than 1 in 1 million.

Asymmetrical ventricular enlargement and varying degrees of corpus callosum agenesis, together with macrocrania and sensorineural hearing loss may together be considered hallmarks of Chudley-McCullough syndrome 1.

Chudley-McCullough syndrome is characterized by early-onset sensorineural hearing loss and distinctive structural brain malformations with relatively preserved psychomotor development 2. The severity of hearing loss ranges from severe to profound and can present at birth or during infancy 3. Moderate intellectual disability and epilepsy have also been reported 4.

Factors which may be associated with increased risk of abnormal neurodevelopmental outcome include larger ventricle size, other brain abnormalities, other non-brain abnormalities and other genetic conditions known to cause neurodevelopmental disability 5.

Chudley-McCullough syndrome has been linked to homozygous inactivating mutations in the the gene encoding G-protein signaling modulator 2 (GPSM2) 6.  This protein is responsible for the polymerization of the cytoskeleton during stereocilia elongation, corpus callosum formation and neuronal growth in the brain 7. Mutated GPSM2 variants result in grey matter heterotopia, with cerebral and cerebellar hypoplasia.

GPSM2 is also present in abundance on the hair cells and supporting cells of the inner ear during early embryogenesis and pathogenic variants result in sensorineural hearing loss.

A constellation of brain malformations have been reported on both antenatal and post natal imaging 5.

  • ventriculomegaly with colpocephaly
  • absent cavum septum pellucidum
  • partial agenesis of corpus callosum
  • asymmetrical ventriculomegaly
  • colpocephaly with slit like frontal horns
  • varying degrees of corpus callosum agenesis
  • bilateral midline polymicrogyria
  • bilateral frontal subcortical heterotopia
  • cerebellar dysplasia
  • arachnoid cysts

The neurodevelopmental outcome of Chudley-McCullough syndrome is generally good, as long as there is early detection and management of the hearing loss 3.

Prenatal counseling is important if Chudley-McCullough syndrome is suspected on antenatal imaging, as the prognosis is good despite the prominent structural abnormalities. Confirmatory prenatal genetic testing therefore assists in appropriate maternal counseling.

Chudley-McCullough syndrome was first described by Chudley et al. in 1997, in a consanguineous Canadian-Mennonite dizygotic twin pair 8.

Syndromic forms of corpus callosum abnormalities are important differentials for consideration:


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