Genetics of Cockayne Syndrome Clinical Presentation

Patients with Cockayne syndrome (CS) present with delayed psychomotor development, growth failure, poor feeding, photosensitive rashes, and cataracts.

• Delayed psychomotor development - All patients with Cockayne syndrome type I have intellectual disability and developmental delays. The delay becomes apparent early when motor milestones are not met on time.  

• Growth failure - This is notable within the first 2 years of life in Cockayne syndrome type I and at birth in the type II syndrome; height, weight, and head circumference fall below normal and eventually end up below the fifth percentile. 

• Poor feeding - Some patients present during infancy with weak or poor feeding; however, the diagnosis is usually not made at this time.

• Photosensitive rashes - More than 75% of patients have photosensitivity. Other skin findings include decreased amounts of subcutaneous tissue, dry scaly skin, and thin dry hair.

• Cataracts - The presence of cataracts in children younger than 3 years is associated with the severe form of Cockayne syndrome type I, which demonstrates a poorer prognosis and results in death at an earlier age. ^[2]

In the first year, all patients with Cockayne syndrome type 1 demonstrate growth failure, which includes progressive microcephaly in most patients.

• Neurologic examination shows increased or decreased muscle tone and reflexes. Ambulant patients present with an unusual gait resulting from leg spasticity, ataxia, and contractures of the hips, knees, and ankles.

• Pigmentary degeneration of the retina is one hallmark of this disorder, with cataracts and optic atrophy or optic disk pallor as frequent findings.

• Ophthalmologic changes are progressive.

• More than one half of patients with Cockayne syndrome type I have mild-to-severe sensorineural hearing loss.

• Many patients have moderate-to-severe dental caries; permanent teeth have short roots.

• Most patients have photodermatitis that leads to dry scaly skin. Patients develop an aged appearance as a result of the disease process.

• Major structural anomalies of the renal system rarely occur. Some patients develop decreased creatinine clearance but usually do not require medical treatment.

• Cryptorchidism or testicular hypoplasia affects approximately one third of males. Females have menses, although cycles are irregular. Puberty may be delayed in both sexes.

Cockayne syndrome type I is caused by a defect in the Cockayne syndrome type A gene (CSA or ERCC8), located on chromosome 5. ^[5] Affected persons inherit two mutant genes, one from each parent, with ERCC8 mutations accounting for about 35% of Cockayne syndrome cases. ^[4]  Cells carrying ERCC8 mutations are hypersensitive to ultraviolet (UV) light. They do not recover the ability to synthesize RNA after exposure to UV light. In addition, the cells cannot remove and degrade DNA lesions from strands that have active transcription.

Mutations in the DNA excision repair gene ERCC6 located on band 10q11 cause Cockayne syndrome type II (MIM number 133540; CSB). ^{[6, 7]} These mutations account for about 65% of Cockayne syndrome cases. ^[4]  This gene encodes helicase, a protein that is presumed to have DNA unwinding function. ^[1]

No genotype-phenotype correlation is known. ^[4]  ERCC8 and ERCC6 are believed to code for DNA excision repair proteins.