eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics
Cockayne Syndrome
Updated: May 4, 2007
Introduction
Background
Cockayne syndrome (CS) spans a spectrum that includes CS type 1, the classic form; CS type 2, a more severe form with symptoms present at birth (ie, cerebrooculofacial-skeletal [COFS] syndrome, Pena-Shokeir type 2 syndrome); CS type 3, a milder form; and xeroderma pigmentosa–Cockayne syndrome (XP-CS). The discussion in this article is limited to CS types 1 and 2, also termed CS types A and B, respectively.
CS type 1 (CKN1; Online Mendelian Inheritance in Man [OMIM] number 216400) and CS type 2 (CSB; OMIM number 133540) are rare autosomal recessive disorders that feature growth deficiency, premature aging, and pigmentary retinal degeneration along with a complement of other clinical findings. CS type 1 presents at birth, whereas CS type 2 appears during early childhood. CKN1 was first reported in 1936. Fatality usually occurs in early adolescence, but some patients survive until early adulthood.
Pathophysiology
Premature aging is the cardinal feature of both types; however, within the first 2 years of life, growth and development become abnormal. By the time the disease has fully manifested, height, weight, and head circumference are far below the fifth percentile. The characteristic physical appearance of cachectic dwarfism with thinning of the skin and hair, sunken eyes, and a stooped standing posture illustrates the aging process. Pathologic studies reveal diffuse and extensive demyelination in the central and peripheral nervous systems. Patients demonstrate pericapillary calcifications in the cortex and basal ganglia at an early age; severe neuronal loss in the cerebral cortex and cerebellum also occurs. These changes correlate with the physiologic changes of aging.
Frequency
United States
Incidence is less than 1 case per 250,000 live births.
Mortality/Morbidity
Patients are at risk for postnatal growth failure, pigmentary retinal degeneration, and premature death before adulthood.
- Postnatal growth failure: Profound growth failure begins within the first year of life. Weight is affected more than length, and cachectic dwarfism results. A rare subset of patients, classified as having severe CKN1, have low birth weight with almost no postnatal growth.
- Pigmentary retinal degeneration: This diagnostic criterion for CKN1 (salt-and-pepper appearance in the retinas) develops later in life. Cataracts are the second most common eye finding.
- Premature death: The characteristic appearance of aging in children with Cockayne syndrome is striking. The mean and median age of death is 12 years, and most patients die as a result of pneumonia or other respiratory infections.
Race
CNK1 is panethnic.
Sex
Male-to-female ratio is 1:1, which is consistent with an autosomal recessive disorder.
Age
As a progressive congenital disorder, clinical symptoms may not be manifested until late infancy or early childhood.
Clinical
History
Patients 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.
Physical
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.
Causes
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 ribonucleic acid (RNA) after exposure to UV light. In addition, the cells cannot remove and degrade deoxyribonucleic acid (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). 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 exists.
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| References |
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References
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Further Reading
Keywords
Cockayne syndrome, Cockayne syndrome type A, CS, CAS, excision-repair cross-complementing group 8, ERC8, ERCC8, CKN1, cachectic dwarfism, premature aging, growth failure, pigmentary retinal degeneration, Cockayne syndrome type B, ERCC6, CS type 1, CS type 2
