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| COCKAYNE SYNDROME, TYPE A; CSA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| CKN1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because Cockayne syndrome type A (CSA) is caused by homozygous or compound heterozygous mutation in the gene encoding the group 8 excision-repair cross-complementing protein (ERCC8; 609412) on chromosome 5q11. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cockayne syndrome is characterized by abnormal and slow growth and development that becomes evident within the first few years after birth. 'Cachectic dwarfism' describes the outward appearance of afflicted individuals. Other features include cutaneous photosensitivity, thin, dry hair, a progeroid appearance, progressive pigmentary retinopathy, sensorineural hearing loss, dental caries, and a characteristic stance in the ambulatory patient. Patients often show disproportionately long limbs with large hands and feet, and flexion contractures of joints are usual skeletal features. Knee contractures result in a 'horse-riding stance.' There is delayed neural development and severe progressive neurologic degeneration resulting in mental retardation. The mean age at death in reported cases is 12.5 years, although a few affected individuals have lived into their late teens or twenties. Remarkably, in striking contrast with xeroderma pigmentosum, patients with CS have no significant increase in skin cancer or infection (Nance and Berry, 1992). Lowry (1982) noted that there is an early-onset form of Cockayne syndrome in which patients may show abnormalities at birth and have a shorter survival. Lowry (1982) thus suggested that CS could be divided clinically into the more common type I, with classic CS symptoms that manifest within the first few years or life, and the less common type II, with more severe symptoms that manifest prenatally. Mallery et al. (1998) found no correlation between genotype and phenotype among 16 patients with CS of varying severities, and concluded that clinical differences were based on other genetic backgrounds or the intrauterine environment. Cockayne syndrome shows some overlap with certain forms of xeroderma pigmentosum (XP), another disorder caused by defective DNA repair. See XP complementation group B (ERCC3; 133510), which maps to chromosome 2q21; XP complementation group D (ERCC2; 126340), which maps to chromosome 19q; and XP complementation group G (ERCC5; 133530), which maps to chromosome 13. Rapin et al. (2000) reviewed the clinical, pathologic, and molecular features of Cockayne syndrome, xeroderma pigmentosum, and the XP-CS complex. They presented a case of XP-CS with neuropathologic findings. Genetic Heterogeneity of Cockayne Syndrome Cockayne syndrome type B (CSB; 133540) is caused by mutation in the ERCC6 gene (609413) on chromosome 10q11. The 2 forms of Cockayne syndrome were originally distinguished as complementation groups in cell studies. Approximately 20% of patients have been assigned to the CSA complementation group (Mallery et al., 1998). See 216411 for a possible third form of Cockayne syndrome. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 sibs of nonconsanguineous parents, Neill and Dingwall (1950) described a progeria-like syndrome characterized by dwarfism, microcephaly, severe mental retardation, 'pepper-and-salt' chorioretinitis, and intracranial calcification. The diagnosis may have been Cockayne syndrome. Death from early atherosclerosis occurred in these sibs, as in progeria (Neill, 1966). Examination of the brain of the 2 sibs showed massive pericapillary calcification in the putamina, thalami and cerebellar white matter superficial to the dentate nuclei. In the larger vessels the calcification was mainly in the adventitial coat (Norman, 1963). Paddison et al. (1963) reported a striking pedigree with Cockayne syndrome. In 4 patients with Cockayne syndrome, Brumback et al. (1978) noted development of the triad of normal pressure hydrocephalus: dementia, gait disturbance, and incontinence. Higginbottom et al. (1979) noted that hypertension and renal disease are frequent complications of Cockayne syndrome. Bensman et al. (1982) found decreased or undetectable thyroid hormone in the serum of 7 cases of CS. Sato et al. (1988) reviewed renal lesions. Early onset was described by Houston et al. (1982) and by Moyer et al. (1982). In studies of 3 sibs with Cockayne syndrome, Smits et al. (1982) found segmental de- and remyelination with onion-bulb formation in sural nerve biopsies and disturbed visual and brainstem auditory evoked responses indicative of CNS demyelination. They suggested that this finding supports the theory that Cockayne syndrome is a leukodystrophy, as first proposed by Moosa and Dubowitz (1970). Patton et al. (1989) described 2 cases of early-onset Cockayne syndrome in unrelated infants. In both, striking failure of growth and developmental deterioration began around 6 months of age. Studies of cultured fibroblasts showed the characteristics typical of Cockayne syndrome, and examination of the brain in 1 patient who died at the age of 34 months showed leukodystrophy with 'tigroid' demyelinization similar to that reported in later-onset cases of Cockayne syndrome. Although the disorder resembled cerebrooculofacioskeletal syndrome (COFS; 214150), the pathologic and fibroblast studies seemed to indicate that it was the same as Cockayne syndrome. Traboulsi et al. (1992) described the ocular findings in 8 patients varying in age from 1 to 25 years. Strabismus was present in 4 patients and cataracts in 2, while 3 had nystagmus. Visual acuity was relatively well preserved in 6 patients, including a 25-year-old man with a visual acuity of 20/60 in each eye despite advanced retinal pigmentary changes. In an exhaustive review, Nance and Berry (1992) commented that in contrast to other disorders of DNA repair, cancer has not been reported as a feature of classic CS. Furthermore, there appears to be no predisposition to infectious complications. The authors emphasized probable heterogeneity. Mahmoud et al. (2002) reported 3 sisters showing clinical features and investigational findings of CS. The 12-year-old proband had typical features of CS. She had no apparent problems until the end of the first year when growth and developmental delay prompted medical evaluation. Brain CT, bone x-rays, and auditory and ophthalmologic evaluation confirmed the clinical impression of CS. Her 2 sisters were later found to have CS. The sisters varied in clinical severity as 2 of them, including the proband, had cataracts and early global delay and died early of inanition and infection. The third had a normal course until the age of 2 years when she started to show deceleration in growth and delay in development. She exhibited mental retardation but did not have cataract and was still ambulatory at the age of 10 years. The parents were not related and the father was married to 2 other wives with 11 unaffected children. Upon analysis of cerebrospinal fluid neurotransmitters in a 16-year-old Sri Lankan male with Cockayne syndrome, Ellaway et al. (2000) found a decreased level of 5-hydroxyindole acetic acid and a normal level of homovanillic acid, with a consequent low 5-hydroxyindole acetic acid:homovanillic acid ratio. Peripheral serotonin levels, platelet serotonin, and urinary 5-hydroxyindole acetic acid levels, plasma phenylalanine levels, and dihydropteridine reductase activity were all normal. In view of these findings, the primary disorder of central serotonin metabolism was considered and the proband was treated with 5-hydroxytryptophan. There was no clinical improvement over a period of 2 years, but his cognitive function, tremor, and gait did not deteriorate. Ellaway et al. (2000) also measured resting energy expenditure and found this to be 75% of the predicted value; they suggested that this situation in Cockayne syndrome might be similar to that of anorexia nervosa, where resting energy expenditure is reduced but normalizes upon refeeding, with concomitant increases in body weight. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Biochemical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Schmickel et al. (1977) showed that fibroblasts from 2 unrelated children with Cockayne syndrome exhibited increased sensitivity to UV irradiation, but not to X-irradiation, as measured by colony-forming ability. In addition, both cell lines showed normal rates of removal of thymidine dimers. Andrews et al. (1978) found that CS fibroblasts had markedly decreased post-UV light colony-forming ability compared to controls. However, the patients' fibroblasts had normal rates of UV-induced unscheduled DNA synthesis, indicating that the defect in these cells was not due to abnormal DNA excision repair. The findings differentiated CS from xeroderma pigmentosum, in which DNA excision repair is deficient. Hoar and Waghorne (1978) found normal UV-induced unscheduled DNA synthesis and normal post-replication repair in CS cells. Mayne and Lehmann (1982) showed that cells from patients with Cockayne syndrome failed to recover RNA synthesis after UV irradiation despite normal excision and daughter-strand repair pathways. The findings indicated that recovery of RNA synthesis is an important early response to UV irradiation. Schweiger et al. (1987) suggested that the defect in DNA repair in Cockayne syndrome is located beyond incision, exonuclease reaction, and DNA synthesis, and that it may involve a defect in DNA ligase. Venema et al. (1990) demonstrated a defect in preferential DNA repair of transcriptionally active DNA in Cockayne syndrome. Cells from normal controls repaired UV-induced pyrimidine dimers at a faster rate in transcriptionally active DNA when compared to a nontranscribed locus or to the genome overall. In contrast, cells from CS patients were unable to repair transcriptionally active DNA as rapidly and efficiently as normal cells, although repair occurred at a slower rate similar to that of untranscribed DNA. Venema et al. (1990) concluded that CS fibroblasts have lost the preferential repair of active genes but are proficient in overall genome repair. Venema et al. (1990) suggested that the results help to elucidate the pleiotropic clinical effects associated with disorders having defects in the repair of DNA damage. In particular, neurodegeneration appeared to be associated with the loss of preferential repair of active genes and not simply correlated with reduced levels of overall repair. Lehmann et al. (1993) found failure of RNA synthesis to recover to normal rates after UV irradiation in cells from 29 of 52 patients for whom the clinical diagnosis of Cockayne syndrome was considered a possibility; the other 23 had a normal response. From review of the clinical details, they concluded that, apart from the cardinal features of dwarfism and mental retardation, sun sensitivity correlated best with a positive cellular diagnosis. Pigmentary retinopathy, gait defects, and dental caries were also good indicators, although several patients with a positive cellular diagnosis did not have these features. Van Oosterwijk et al. (1996) examined the sensitivity of CSA and CSB fibroblast cells to the DNA damaging agent N-acetoxy-2-acetylaminofluorene (NA-AAF), which mimics UV irradiation. They found that although CS cells are 3-fold more sensitive to NA-AAF than are normal cells and are unable to recover the ability to synthesize RNA, this sensitivity is not due to defective transcription-coupled repair of active genes. They concluded that a transcription defect is the underlying cause of the hypersensitivity and prolonged repressed RNA synthesis. Complementation Groups A and B Tanaka et al. (1981) used cell fusion techniques to demonstrate that there are at least 2 complementation groups in Cockayne syndrome. Fusion between certain cell lines allowed recovery of a nearly normal rate of semiconservative DNA synthesis after UV irradiation. Lehmann (1982) performed cell fusion studies on cultured cells from 11 patients with Cockayne syndrome. The 11 cell lines were assigned to 3 complementation groups: 2 to group A, 8 to group B, and 1 to group C. The group C patient was thought to have xeroderma pigmentosum also and was the sole known representative of the XP complementation group B (133510). The patient had clinical as well as biologic features of both disorders. See 610651. Jaeken et al. (1989) studied 3 patients with unusually severe CS. Unlike classic CS, the disorder had its onset in the first weeks of life and led to unusually early death. Fibroblasts from 2 of the patients showed a complete defect in the repair of UV-induced thymine dimer lesions; the fibroblasts were unable to remove thymine dimer lesions from their DNA, had a severe reduction of RNA synthesis rates after UV irradiation, and showed no reactivation of a UV-inactivated indicator gene and no DNA recondensation after UV irradiation. DNA repair investigated in these 2 strains resembled that of xeroderma pigmentosum cells of complementation group A (278700). In contrast, fibroblasts from the third patient showed the same in vitro repair characteristics as classic CS cells. The findings in the 2 patients with a complete defect of thymine dimer removal supported the suggestion of Marshall et al. (1980) that there are transitional forms between CS and XP, since in the various forms of the latter condition (with the exception of XP variant), removal of pyrimidine dimer lesions is the underlying defect. Preliminary complementation experiments indicated that the 3 patients belonged to CS complementation group A. Stefanini et al. (1996) analyzed cell cultures from 22 Cockayne syndrome donors from different countries and different racial groups. In particular, they tested the cultures for complementation, which they defined as the restoration of normal RNA synthesis rates in UV-irradiated heterokaryons. Cultures from 5 patients were assigned to complementation group A and the remaining 17 were assigned to complementation group B. The authors detected no distinctions (racial, clinical, or cellular) between the 2 complementation groups. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Diagnosis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prenatal Diagnosis Sugita et al. (1982) made the prenatal diagnosis of Cockayne syndrome on the basis of sensitivity of amniocytes to ultraviolet light. Colony-forming ability of the cells from the affected fetus was reduced after UV exposure as compared with normals. Lehmann et al. (1985) demonstrated the feasibility of prenatal diagnosis by study of RNA synthesis in cultured amniotic cells after irradiation with ultraviolet light. Not only are cultured cells from CS patients hypersensitive to the lethal effects of UV and some chemical carcinogens, but also the normal recovery in DNA and RNA synthesis after UV exposure does not occur (Mayne and Lehmann, 1982). A prenatal test based on this observation is simple and rapid and its outcome is unambiguous. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Management | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neilan et al. (2008) reported 3 adolescent patients with Cockayne syndrome who showed a clear reduction in tremors and improvement in fine hand movements, including handwriting, following treatment with carbidopa-levodopa. The findings implicated the dopaminergic pathway in the pathogenesis of this disorder. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Henning et al. (1995) identified mutations in the ERCC8 gene in CSA cDNAs of all CSA cell lines examined, including an identical mutation in 2 CSA sibs (609412.0001). In a cell line from an 11-year-old girl with photophobia, dwarfism, mental retardation, cataracts, retinopathy, and optic atrophy, Cao et al. (2004) identified compound heterozygosity for a nonsense mutation (E13X; 609412.0003) and a missense mutation (A205P; 609412.0005) in the ERCC8 gene. In a cell line from a patient with CSA, Ridley et al. (2005) identified compound heterozygosity for an E13X mutation and a novel missense mutation (A160V; 609412.0004) in the ERCC8 gene. Bertola et al. (2006) analyzed the ERCC8 gene in 8 patients from 6 Brazilian families with typical CSA and identified homozygosity or compound heterozygosity for ERCC8 mutations in all of them. The authors stated that there was no obvious genotype/phenotype correlation across the mutation spectrum. Khayat et al. (2010) analyzed the Y322X ERCC8 mutation (609412.0002) in the Arab Christian population of northern Israel and found a carrier frequency of 6.79. Haplotype analysis as well as the high carrier frequency suggested that Y322X is an ancient founder mutation that may have originated in the Christian Lebanese community. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| History | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Edward Alfred Cockayne (1880-1956) was a London physician who concentrated on diseases of children, particularly hereditary diseases. His 'Inherited Abnormalities of the Skin and its Appendages,' published in 1933, was an extensive collation of pedigrees from the literature. Forty years later, McKusick (1973) reviewed the subject of 'genetics and dermatology' under the subtitle 'If I were to rewrite Cockayne's Inherited Abnormalities of the Skin.' McKusick (1973) also provided biographic information on Cockayne, including his important contributions to entomology. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bregman et al. (1996); Cleaver et al. (1999); Cockayne (1933); Cotton et al. (1970); Cunningham et al. (1978); Deschavanne et al. (1981); Fujimoto et al. (1969); Gandolfi et al. (1984); Lanning and Simila (1970); Macdonald et al. (1960); Mayne et al. (1984); Neer et al. (1994); Nishio et al. (1988); Norman and Tingey (1966); Pearce (1972); Pfeiffer and Bachmann (1973); Proops et al. (1981); Rowlatt (1969); Sugarman et al. (1977); Tanaka et al. (1985) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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