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Conditions

Cohen syndrome

Cohen syndrome is a rare autosomal recessive cause of syndromic intellectual disability. Features are variable but typically include characteristic facial features, microcephaly and progressive visual impairment.

Overview

Cohen syndrome is typically associated with characteristic facial differences, truncal obesity, acquired microcephaly, moderate to profound neurodevelopmental delay and progressive visual impairment.

Clinical features

The cardinal features of Cohen syndrome are:

  • global developmental delay;
  • early-onset myopia (age is five standard deviations above the mean) with progressive pigmentary retinopathy;
  • truncal obesity from mid childhood, with relatively short stature;
  • joint hypermobility;
  • facial dysmorphism: thick hair, eyebrows and eyelashes, down-slanting palpebral fissures, short, upturned philtrum, hypotonic facial expression with open mouth and prominent upper central incisors;
  • acquired microcephaly;
  • neutropenia (sometimes associated with aphthous ulcers); and
  • friendly disposition.

Other features include:

  • significant feeding difficulties in the neonatal period, requiring artificial feeding techniques;
  • failure to thrive;
  • neonatal hypotonia;
  • small or narrow hands or feet; and
  • increased risk of autoimmunity (diabetes mellitus, coeliac disease, thyroid conditions).

A clinical diagnosis of Cohen syndrome can be made in a proband with six of the eight cardinal features listed above.

Genomics

Cohen syndrome is caused by biallelic pathogenic variants (gene changes on both copies) in the VPS13B gene (previously referred to as COH1). VPS13B is involved in glycosylation, whereby glycans (sugars) are attached to lipids or proteins. Glycoproteins and glycolipids have important functions in all tissues and organs. When errors in glycosylation occur, therefore, multiple organs can be affected, and there will nearly always be neurological features.

Pathogenic variants are typically those that cause loss of function of the gene, including whole gene deletions of VPS13. Common founder pathogenic variants in VPS13 have been identified in the Finnish and Amish populations.

Diagnosis

While a clinical diagnosis of Cohen syndrome can be made if a patient has six of the eight cardinal features, it is good practice to seek a molecular diagnosis. Many of the features of Cohen syndrome overlap with other causes of syndromic intellectual disability and accurate diagnosis is important.

In many cases, molecular diagnosis will precede clinical suspicion as Cohen syndrome is rare and there are many conditions that can present similarly.

The VPS13B gene test is included in the following clinical indication codes: R29 Intellectual disability, R27 Paediatric disorders, R149 Severe early onset obesity and R32 Retinal disorders.

The choice of test will depend on presenting features. For those in whom developmental delay/intellectual disability are key features please see Presentation: Child with developmental delay or intellectual disability. If obesity is the predominant feature, see Presentation: Patient with possible monogenic obesity. Where necessary, more than one code can be selected at the same time. If you have a clinical suspicion of the condition, detail it on the test request.

If the diagnosis is suspected due to an affected sibling, the laboratory will analyse the familial variant. It is therefore important that this is clearly communicated on the request form, including the affected sibling’s name and date of birth.

Inheritance and genomic counselling

Cohen syndrome is an autosomal recessive condition. The parents of most affected individuals are carriers of the condition and therefore have a 25% (one in four) chance of having another affected child. Prenatal counselling is important as testing in early pregnancy and preimplantation genetic testing are available.

Affected individuals and close blood relatives can also benefit from prenatal counselling. Carrier status can be determined in unaffected relatives.

Management

Management of children with Cohen syndrome is complex and should be delivered via a multidisciplinary team, including an ophthalmology and haematology assessment. Management approach guidelines have been published by several authors – see ‘Resources’. Treatment is directed toward the clinical manifestation of the individual patient. Medications known to decrease the neutrophil count should be used with caution.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 25/02/2025
  • Next review due: 25/02/2027
  • Authors: Dr Lianne Gompertz
  • Reviewers: Dr Ellie Hay, Dr Joanna Kennedy