What is Cohen syndrome?

Cohen Syndrome: A Rare Genetic Disorder

Cohen syndrome is a rare autosomal recessive disorder caused by mutations in the VPS13B gene (also called COH1) on chromosome 8q22, characterized by developmental delay, intellectual disability, microcephaly, distinctive facial features, progressive retinopathy, myopia, and intermittent neutropenia. 1, 2, 3

Genetic Basis

• Cohen syndrome results from biallelic mutations in VPS13B, with extensive allelic heterogeneity explaining the significant clinical variability observed between patients 2, 4
• Most mutations result in premature termination codons, though intronic splice site variants and large deletions have also been identified 2, 4
• The disorder follows autosomal recessive inheritance, meaning both parents must be carriers for a child to be affected 3, 5
• Molecular diagnosis can be achieved through trio whole exome sequencing (WES), MLPA analysis for large deletions, and cDNA sequencing to confirm splice variants 2, 5, 6

Core Clinical Features

Neurological and Developmental

• Developmental delay of varying degree is present in all patients, representing the most consistent feature of the syndrome 4
• Intellectual disability ranges from mild to severe across affected individuals 3, 4
• Early-onset hypotonia is characteristic, particularly in infancy 5
• Postnatal microcephaly develops in most but not all patients 2, 3, 4

Craniofacial Features

• Distinctive facial dysmorphism is present in all patients and includes characteristic features that aid in clinical recognition 4
• Typical facial features include prominent nasal bridge, high-arched eyebrows, downslanting palpebral fissures, and wave-shaped eyelids 3
• Low-set and posteriorly-rotated ears may be present 1

Ophthalmologic Manifestations

• Early-onset myopia (severe) is present in all affected individuals and represents a cardinal diagnostic feature 4
• Progressive pigmentary retinopathy develops by school age in most patients, though it is not universally present 3, 4
• Retinal dystrophy can lead to progressive vision loss over time 3

Hematologic Features

• Intermittent neutropenia occurs in many but not all patients 3, 4
• The neutropenia pattern is variable and may not be consistently detected on routine screening 1, 4

Musculoskeletal Features

• Joint laxity (hypermobile joints) is present in all patients and represents another consistent diagnostic feature 5, 4
• Truncal obesity with abnormal fat distribution develops in many affected individuals 2, 3
• Short stature is commonly observed 3

Behavioral Characteristics

• An overly friendly, sociable behavior pattern is characteristic of Cohen syndrome 6

Clinical Variability and Diagnostic Considerations

• The clinical presentation is highly variable, with only five features consistently present across all patients: developmental delay, early-onset myopia, joint laxity, facial dysmorphism, and intellectual disability 4
• Retinopathy at school age, microcephaly, and neutropenia are common but not requisite for diagnosis 4
• The syndrome is considered underdiagnosed, particularly in children presenting with developmental delay and intellectual disability without the full constellation of features 2

Diagnostic Strategy

• Genetic testing should include trio-WES as the primary diagnostic modality, as it can identify both coding variants and guide further testing for structural variants 2, 5, 6
• MLPA analysis should be performed when WES is negative or shows only a single heterozygous variant, as large deletions may be missed by standard sequencing 2
• Intronic regions should be analyzed when clinical suspicion is high but standard exome sequencing is negative, as pathogenic splice site variants outside coding regions have been identified 2
• cDNA sequencing and expression analysis can confirm the functional impact of suspected splice variants 2

Prognosis and Management

• Treatment is primarily supportive and addresses individual manifestations 3
• Prognosis varies depending on the severity of intellectual disability and associated complications 3
• Regular ophthalmologic monitoring is essential given the progressive nature of retinal disease 3
• Monitoring for neutropenia may be warranted, though the clinical significance of intermittent neutropenia in Cohen syndrome remains unclear 1, 4