What is Cockayne syndrome?

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Cockayne syndrome (CS) is a rare, heterogeneous, multisystem disease that is typically apparent at birth or during childhood. The disorder is characterized by cachetic dwarfism, neurological deficits, sensitivity to sunlight (photosensitivity), and premature aging (progeria).
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Risk Factors

The incidence of CS has been estimated at about 1 in 560,000 live births in Western Europe; a similar incidence is likely in other parts of the world. In 2014 the US National Library of Medicine's Genetics Home Reference website reports about two incidents per million newborns in the United States and Europe. Individuals with a family history of CS or whose parents carry known mutations in the ERCC6 (also known as CSB, ARMD5, or RAD26) or ERCC8 (also known as CSA) gene are at increased risk. No predispositions based upon sex or ethnicity have been noted.

Etiology and Genetics

CS is caused by mutations in the ERCC6 gene on chromosome 10q11 or in the ERCC8 gene on chromosome 5q12.1. Roughly 75 percent of cases are attributable to mutations in the ERCC6 gene, with the remaining 25 percent due to mutations in the ERCC8 gene. CS is an autosomal recessive disorder, meaning that the affected individual carries two copies of the defective gene in each cell. The parents are heterozygous, each carrying one copy of the defective gene. Heterozygous individuals do not typically show any symptoms of the disease.

The CSB and CSA proteins are believed to play a role in the repair of transcriptionally active genes (transcription-coupled DNA repair). The defect in DNA repair is thought to result in the accumulation of DNA damage and cell death. There is currently no clear association between type of mutation and the severity of symptoms observed.

CS is a heterogeneous disease. Three distinct major subtypes have been identified that vary in severity and prognosis. CS type I (Type A) is the classic form of the disease in which growth and developmental abnormalities are noted in the first few years of life. CS type II (Type B) is the most severe form of the disease, with growth failure present at birth and little postnatal neurological development. CS type III (Type C) is a less common, milder form of the disease that typically is seen later in life. A fourth subtype called xeroderma pigmentosum–Cockayne syndrome (XP-CS) has been recognized that combines features of both diseases but is caused by mutations in genes other than ERCC6 or ERCC8.

Symptoms

Individuals with CS display physical features of cachectic dwarfism, with thinning of the skin and hair, sunken eyes, and a stooped standing posture. Symptoms may also include disproportionately long arms and legs, large low-set ears, bird-like facies (facial expressions), microcephaly (small head), joint contractures, gait disturbances, and sensitivity to sunlight. Neurodevelopmental delays, which vary in severity, are characteristic of the disease. Hearing loss (deafness), eye problems (retinal atrophy and cataracts), and dental caries are also common and become progressively worse with age. Other observed symptoms, including hypertension, early atherosclerosis, intracranial calcification, and glomerulosclerosis, appear to be related to premature aging.

Screening and Diagnosis

Clinical diagnosis of CS is usually made when an infant or child fails to grow properly (postnatal growth failure) and has signs of neurologic dysfunction. In addition, affected children often have a characteristic appearance, are sensitive to sunlight, and show signs of premature aging (progeria). Diagnosis of CS may be delayed or missed due to heterogeneity in symptoms among patients as well as to the rarity and progressive nature of the disease. Diagnosis can be confirmed by sequencing of the ERCC8 and ERCC6 genes in the affected individual.

Treatment and Therapy

No specific treatment for CS currently exists. Patients are treated based on their individual symptoms. Infants with the most severe form of CS may require tube feeding to prevent malnutrition. Physical therapy may be performed to minimize effects of joint contractures and to maintain mobility. Speech, vision, hearing, and occupational therapy may also be provided.

Prevention and Outcomes

For individuals with a family history of CS, genetic counseling is recommended. Genetic testing can be performed on the unborn child to determine if he or she carries a mutation in the ERCC8 or ERCC6 gene. Parents who are heterozygous for the causative mutation (carriers) have a 25 percent chance of having a child who does not have CS and who does not carry the mutation, a 50 percent chance of having a heterozygous (carrier) child, and a 25 percent chance of having a child with CS.

Typical life expectancy is dependent on the subtype of the disease but is generally shorter than normal. Individuals with CS type I usually live one or two decades. Individuals with CS type II usually die before age seven. Individuals with CS type III can survive into their thirties or forties. Individuals who do survive longer do not have an increased incidence of skin cancer despite their photosensitivity.

Bibliography

Cleaver, James E., et al. "Conceptual Developments in the Causes of Cockayne Syndrome." Mechanisms of Ageing and Development 134.5–6 (2013): 284–290. Print.

De Boer, J., and J. H. Hoeijmakers. “Nucleotide Excision Repair and Human Syndromes.” Carcinogenesis 21 (2000): 453–460. Print.

Friedberg, E. C., G. C. Walker, and W. Siede. DNA Repair and Mutagenesis. 2d ed. Washington, DC: ASMP, 2006. Print.

Genetics Home Reference. "Cockayne Syndrome." Genetics Home Reference. NIH/NLM, 14 July 2014. Web. 18 July 2014.

Laugel, Vincent. "Cockayne Syndrome: The Expanding Clinical and Mutational Spectrum." Mechanisms of Ageing and Development 134.5–6 (2013): 161–170. Print.

Nance, M. A., and S. A. Berry. “Cockayne Syndrome: Review of 140 Cases.” American Journal of Medical Genetics 42 (1992): 68–84. Print.

Tan, W. H., H. Baris, C. D. Robson, and V. E. Kimonis. “Cockayne Syndrome: The Developing Phenotype.” American Journal of Medical Genetics A 135 (2005): 214–216. Print.

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