Genetics of Cockayne Syndrome Clinical Presentation
- Author: David Flannery, MD, FAAP, FACMG; Chief Editor: Maria Descartes, MD more...
Patients with Cockayne syndrome (CS) present with delayed psychomotor development, poor feeding, photosensitive rashes, and cataracts.
- Delayed psychomotor development: All patients with Cockayne syndrome type 1 (CKN1) have mental retardation. The delay becomes apparent around the age when walking and speech should be developing.
- 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 CKN1, which demonstrates a poorer prognosis and results in death at an earlier age.
In the first year, all patients with CKN1 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 CKN1 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.
See the list below:
- CKN1 is caused by a defect in the Cockayne syndrome type A gene (CSA or ERCC8) located on chromosome 5. Affected persons inherit 2 mutant genes, one from each parent. Cells carrying ERCC8 mutations are hypersensitive to 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 CS type 2 (MIM number 133540; CSB).[4, 5] This gene encodes helicase, a protein that is presumed to have DNA unwinding function. Mutations include a deletion of exon 4, an amino acid substitution at the 106th glutamine to proline (Q106P) in the WD-40 repeat motif of the CSA protein, and large deletion in the upstream region, including exon 1 of the CSA gene. The Q106P mutation could alter the propeller structure of the CSA protein, which is important for the formation of the CSA protein complex. Additionally, a missense mutation (A205P) and a nonsense (E13X) mutation have been identified, as well as a new common single nucleotide polymorphism in CKN1. No genotype-phenotype correlation is known.
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