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Chudley McCullough syndrome — Clinical Guidelines

Overview

Chudley-McCullough syndrome (CMS) is an autosomal recessive disorder characterized by profound congenital sensorineural hearing loss and distinctive brain malformations, including partial agenesis of the corpus callosum, frontal polymicrogyria, gray matter heterotopia, cerebellar dysplasia, ventriculomegaly, and arachnoid cysts 1 3. Despite these severe brain anomalies, individuals typically do not exhibit significant neurodevelopmental deficits beyond those related to hearing loss. The syndrome underscores the importance of comprehensive genetic and neuroimaging evaluations in patients presenting with sensorineural hearing loss and atypical brain imaging findings. Early recognition and intervention, particularly in hearing management, are crucial for optimizing developmental outcomes in affected individuals 1 6.

Pathophysiology

The pathophysiology of Chudley-McCullough syndrome is rooted in mutations within the G protein-signaling modulator 2 gene (GPSM2). GPSM2 plays a critical role in planar cell polarity and spindle orientation during asymmetric cell divisions, processes essential for proper brain development 1 4. Mutations in GPSM2, including deletions, nonsense mutations, and splice-site alterations, disrupt these cellular mechanisms, leading to the characteristic brain malformations observed in CMS. Specifically, impaired planar polarity and disrupted spindle orientation contribute to the formation of frontal polymicrogyria and gray matter heterotopia, while defects in neuronal migration and proliferation underlie partial agenesis of the corpus callosum and cerebellar dysplasia 1 4. These molecular disruptions translate into the clinical presentation of profound sensorineural hearing loss and complex cerebral anomalies without overt neurodevelopmental delay, highlighting the gene's pivotal role in both auditory and cerebral development 1 4.

Epidemiology

The exact incidence and prevalence of Chudley-McCullough syndrome remain uncertain due to its rarity and variability in reporting across different populations. However, it appears to affect individuals globally, with notable cases reported from diverse geographic regions including Europe, North America, and Yemen 4 5. The syndrome predominantly affects newborns and young children, with no significant sex predilection noted in the literature. Genetic counseling and prenatal screening are increasingly recognized as important strategies given the autosomal recessive inheritance pattern, particularly in families with a history of similar conditions or consanguinity 3 5. Trends over time suggest an increasing awareness and diagnostic capability due to advancements in genetic sequencing technologies, leading to more frequent identification of GPSM2 mutations 1 5.

Clinical Presentation

Chudley-McCullough syndrome manifests primarily with profound congenital sensorineural hearing loss, often detected at birth or shortly thereafter. Neurological examination typically reveals no significant cognitive or motor delays beyond those expected from hearing impairment. However, red-flag features include macrocrania, colpocephaly (asymmetric enlargement of the frontal horns of the lateral ventricles), and characteristic brain imaging findings such as agenesis of the splenium of the corpus callosum, frontal subcortical heterotopia, and cerebellar dysplasia 3 6. These imaging anomalies are crucial for clinical suspicion and subsequent diagnostic confirmation. Early identification of these features is essential for timely intervention and management 3 6.

Diagnosis

The diagnosis of Chudley-McCullough syndrome involves a combination of clinical evaluation and advanced diagnostic techniques. Initial suspicion arises from the presence of profound sensorineural hearing loss coupled with characteristic brain malformations identified through neuroimaging (MRI). Key diagnostic criteria include:

Clinical Criteria:

- Profound congenital sensorineural hearing loss confirmed by audiometry 1 3. - Presence of brain malformations on MRI, specifically: - Partial agenesis of the corpus callosum - Frontal polymicrogyria - Gray matter heterotopia - Cerebellar dysplasia - Ventricular dilatation (ventriculomegaly) - Arachnoid cysts 3 6.

Genetic Testing:

- Whole-exome sequencing or targeted sequencing of GPSM2 to identify pathogenic variants 1 4 5. - Specific mutations to look for include: - c.1473delG (frameshift mutation) 5 - c.1055C>A (nonsense mutation leading to p.Ser352*) 4 - Other reported GPSM2 variants causing canonical splice-site mutations or deletions 1.

Differential Diagnosis:

- Agenesis of the Corpus Callosum (ACC) Syndromes: Distinguished by absence of hearing loss and variability in brain malformations 3. - Polymicrogyria Syndromes: Often associated with additional neurological deficits beyond hearing loss 6. - Other Sensorineural Hearing Loss Syndromes: Exclude genetic causes like Pendred syndrome or connexin 26 mutations by genetic testing 1.

Management

Initial Management

Hearing Rehabilitation:

- Early fitting of hearing aids to mitigate language and cognitive delays 6. - Consider cochlear implants if hearing aids are insufficient 6.

Neurological Monitoring:

- Regular MRI follow-ups to monitor brain development and detect any complications such as progressive ventriculomegaly 3.

Specialist Referral and Advanced Management

Audiological and Speech Therapy:

- Intensive speech and language therapy to support developmental milestones 6. - Regular audiological assessments to adjust hearing aids or cochlear implants as needed 6.

Neurological Interventions:

- Avoid unnecessary neurosurgical interventions such as shunting for ventriculomegaly, as these are generally not indicated in CMS 6.

Specific Considerations

Monitoring and Follow-Up:

- Annual MRI scans to assess brain development and detect any new abnormalities 3. - Regular developmental assessments to track cognitive and motor progress 6.

Complications

Progressive Neurological Issues:

- Potential for progressive ventriculomegaly, though typically managed conservatively without surgical intervention 3 6.

Developmental Delays:

- Primarily related to untreated hearing loss; early intervention can mitigate these risks 6.

When to Refer:

- To pediatric neurologists for complex neuroimaging findings or developmental concerns 3. - To genetic counselors for family planning and genetic counseling 5.

Prognosis & Follow-up

The prognosis for individuals with Chudley-McCullough syndrome is generally favorable regarding cognitive development, provided there is early intervention for hearing loss. Key prognostic indicators include:

Timeliness and effectiveness of hearing rehabilitation 6.

Absence of progressive neurological complications detected through regular MRI monitoring 3.

Recommended follow-up intervals include:

Initial: Immediate audiological and genetic evaluations post-diagnosis 1 3.

Short-term (6-12 months): MRI to confirm initial findings and assess brain development 3.

Long-term (annually): Audiological assessments, developmental evaluations, and MRI scans to monitor progress and detect any new issues 6.

Special Populations

Pediatrics: Early intervention is critical for optimal developmental outcomes, focusing on hearing aids or cochlear implants and speech therapy 6.

Genetic Counseling: Essential for families with a history of CMS or consanguinity, to assess carrier status and recurrence risk 5.

Geographic Variations: Awareness of specific founder mutations, such as the Dutch c.1473delG variant, can guide targeted genetic screening in certain populations 5.

Key Recommendations

Genetic Testing for GPSM2 Mutations: Perform whole-exome sequencing or targeted GPSM2 sequencing in patients with profound sensorineural hearing loss and characteristic brain malformations (Evidence: Strong 1 4 5).

Early Hearing Rehabilitation: Initiate hearing aids or cochlear implants promptly to support language development (Evidence: Moderate 6).

Regular Neuroimaging: Conduct annual MRI scans to monitor brain development and detect complications (Evidence: Moderate 3 6).

Developmental Assessments: Schedule regular developmental evaluations to track cognitive and motor progress (Evidence: Moderate 6).

Avoid Unnecessary Neurosurgery: Refrain from shunting procedures for ventriculomegaly unless clinically indicated (Evidence: Expert opinion 6).

Genetic Counseling: Offer genetic counseling to families for risk assessment and family planning (Evidence: Moderate 5).

Multidisciplinary Care: Engage pediatric neurologists, audiologists, and speech therapists in the management plan (Evidence: Expert opinion).

Prenatal Screening: Consider prenatal genetic testing in high-risk pregnancies (Evidence: Moderate 3).

Long-term Monitoring: Maintain consistent follow-up intervals to address evolving needs and detect late-onset complications (Evidence: Expert opinion).

Support Services: Provide access to support services for families to manage the long-term care requirements (Evidence: Expert opinion).

References

1 Doherty D, Chudley AE, Coghlan G, Ishak GE, Innes AM, Lemire EG et al.. GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome. American journal of human genetics 2012. link 2 Blauen A, Stutterd CA, Stouffs K, Dumitriu D, Deggouj N, Lockhart PJ et al.. Chudley-McCullough Syndrome: A Recognizable Clinical Entity Characterized by Deafness and Typical Brain Malformations. Journal of child neurology 2021. link 3 Chapman T, Perez FA, Ishak GE, Doherty D. Prenatal diagnosis of Chudley-McCullough syndrome. American journal of medical genetics. Part A 2016. link 4 Hamzeh AR, Nair P, Mohamed M, Saif F, Tawfiq N, Al-Ali MT et al.. A novel nonsense GPSM2 mutation in a Yemeni family underlying Chudley-McCullough syndrome. European journal of medical genetics 2016. link 5 Almomani R, Sun Y, Aten E, Hilhorst-Hofstee Y, Peeters-Scholte CM, van Haeringen A et al.. GPSM2 and Chudley-McCullough syndrome: a Dutch founder variant brought to North America. American journal of medical genetics. Part A 2013. link 6 Kau T, Veraguth D, Schiegl H, Scheer I, Boltshauser E. Chudley-McCullough syndrome: case report and review of the neuroimaging spectrum. Neuropediatrics 2012. link

Chudley McCullough syndrome