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, ... 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. - Genetic Heterogeneity of Cockayne Syndrome Cockayne syndrome is a genetically heterogeneous disorder, and certain types show some overlap with certain forms of xeroderma pigmentosum (XP), another disorder caused by defective DNA repair. See also Cockayne syndrome B (133540), caused by mutation in the ERCC6 gene (609413) on chromosome 10q11; XPG/CS (see 278780), caused by mutation in the ERCC5 gene (133530) on chromosome 13q33; XPB/CS (see 610651), caused by mutation in the ERCC3 gene (133510) on chromosome 2q21; and XPF/CS (see 278760), caused by mutation in the ERCC4 gene (133520) on chromosome 16p13. Rapin et al. (2000) reviewed the clinical, pathologic, and molecular features of Cockayne syndrome, xeroderma pigmentosum, and the XP-CS complex.
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 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.
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 ... 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.