Sign Up for a Free Account
  • Updated 03.22.2024
  • Released 04.07.1995
  • Expires For CME 03.22.2027

Cockayne syndrome



Cockayne syndrome is a rare, autosomal recessive, multisystem, progressive degenerative brain disease caused by pathogenic variations in the excision repair cross complementation group 8 (ERCC8; OMIM# 609412) and excision repair cross complementation group 6 (ERCC6; OMIM# 609413) leading to Cockayne syndrome type A (OMIM# 216400) and type B (OMIM# 133540), respectively. The features of Cockayne syndrome include cachectic dwarfism, cataracts, optic atrophy, intellectual disability, unusual facies and body habitus, hearing loss, a peculiar form of fine pigmentary retinitis without the typical spicules of retinitis pigmentosa, and some similarities to the condition progeria. The neurologic abnormalities observed in patients with Cockayne syndrome are often collectively referred to as Cockayne syndrome neurologic disease. The phenotypic spectrum of Cockayne syndrome has been divided into three clinical presentations.

Cockayne syndrome type I (“classic” form) is a moderate form that presents with growth and developmental abnormalities in the first 2 years of life. The prenatal period of growth is normal, and death occurs by the first or second decade of life.

Cockayne syndrome type II is more severe form in which major abnormalities are recognized at birth or in the early neonatal period, with little or no postnatal development. Death occurs by 5 years of age.

The term cerebro-oculo-facio-skeletal (COFS) syndrome and its synonym, Pena-Shokeir syndrome type II, have been used to refer to a heterogeneous group of disorders characterized by congenital neurogenic arthrogryposis (multiple joint contractures), microcephaly, microphthalmia, and cataracts. The original cases of COFS syndrome described by Pena and Shokeir in 1974 among native Canadian families from Manitoba harbor homozygous pathogenic variants in ERCC6. COFS syndrome is now regarded as an allelic and prenatal form of Cockayne syndrome, partly overlapping with Cockayne syndrome type II, and includes the most severe cases of the Cockayne syndrome phenotypic spectrum (61).

Cockayne syndrome type III is a milder or late-onset form that presents after 2 years of age, and growth and cognition are relatively better as compared to other forms. Some very mild patients even reach a normal height and weight and a normal intellectual level but show late-onset cerebellar ataxia and secondary cognitive decline. This adult-onset subgroup of Cockayne syndrome is sometimes named Cockayne syndrome type IV and often represents a very difficult diagnostic challenge (35). Both Cockayne syndrome type III and type IV show purely neurodegenerative symptoms of the Cockayne syndrome spectrum.

A subset of patients presenting with mutations in one of several xeroderma pigmentosum genes, including ERCC3 (encodes XPB), ERCC2 (encodes XPD), ERCC4 (encodes XPF), ERCC5 (encodes XPG), and ERCC1 (DNA excision repair protein that works with ERCC4), also experience neurologic disease that is characteristic of Cockayne syndrome, along with the elevated risk of skin cancer observed in xeroderma pigmentosum. Such patients are classified as having xeroderma pigmentosum–Cockayne syndrome and belong to complementation group Cockayne syndrome type C.

Cockayne syndrome is extremely rare, with approximately 200 cases in the literature. In Europe, its annual incidence is estimated at 1 case per 200,000 births (84; 87). In a nationwide survey of Cockayne syndrome in Japan, the incidence was estimated to be 2.77 per million births (95% CI: 2.19–3.11), and the prevalence was approximately 1 in 2,500,000 (58). No race or sex predilection is reported for Cockayne syndrome; the male-to-female ratio is equal. Cockayne syndrome type 1 manifests in childhood, whereas type 2 has a worse prognosis and manifests at birth or in infancy. Death generally occurs by the age of 30 years, secondary to inanition or infection. Current management focuses on symptomatic therapy, although the possibility of gene therapy is under investigation.

Key points

• Cockayne syndrome is an autosomal recessive multisystem disorder, predominantly characterized by neurologic and sensory impairment, cachectic dwarfism, and photosensitivity.

• Based on the complementation groups, Cockayne syndrome is divided into types A, B, and C. The clinical features represent a spectrum of severity, and Cockayne syndrome is divided into clinical types I to III based on the features.

• Clinically, the most typical form is known as Cockayne syndrome type I. A severe form seen at birth is known as Cockayne syndrome type II (also includes COFS). A much milder form is known as Cockayne syndrome type III, including the anecdotal adult-onset type IV). In addition, an entity known as xeroderma pigmentosum–Cockayne syndrome is recognized.

• Diagnosis is made on clinical grounds and confirmed by molecular genetic testing. Molecular prenatal diagnosis of Cockayne syndrome has been successful. Carrier detection (50% chance of being an asymptomatic carrier) is available once the mutations have been identified in the proband.

• Treatment consists of purely supportive care.

• Cockayne syndrome is characterized by a deficiency in the transcription-couple DNA repair pathway caused by mutations mainly in the Cockayne syndrome group B gene (ERCC6 or CSB).

Historical note and terminology

Cockayne syndrome, or Cockayne-Neill-Dingwall syndrome, was first reported by English physician Edward Alfred Cockayne (1880–1956) in 1936 and re-described in 1946 in a brother and sister with dwarfism and retinal atrophy (18). He made a follow-up report in 1946, at which time he reported that the children were markedly different than at the first presentation (19). The features of the condition included the postnatal onset of dwarfism, cataracts, optic atrophy, mental retardation, unusual facies and body habitus, hearing loss, and a peculiar form of fine pigmentary retinitis without the typical spicules seen in retinitis pigmentosa. Neill and Dingwall later reported on another child and commented on some similarities to the condition of progeria (80), hence, the other name of the syndrome, “Neill-Dingwall syndrome.” Macdonald and colleagues reported three additional patients in a family (67). They saw a clear and sharp distinction between Cockayne syndrome and progeria, a point that has been clearly borne out by the discovery of the underlying pathogenesis in Cockayne syndrome.

The first step towards the development of experimental models of Cockayne syndrome was the in vitro culture of skin fibroblasts derived from patients with Cockayne syndrome in the 1970s. These fibroblasts were shown to be extremely sensitive to UV light (98; 03) and displayed a marked defect in the recovery of RNA synthesis after UV irradiation (62) due to a failure in the repair of transcriptionally active genes (116; 114). Subsequently, evaluation of post-UV RNA synthesis recovery in multinucleated cells obtained by the fusion of cells from different Cockayne syndrome donors led to the identification of three complementation groups (A, B, and C) (106; 62). In the 1990s, the genes corresponding to A and B were characterized and termed CSA and CSB, respectively. Group C identified by Lehmann corresponded to the xeroderma pigmentosum–Cockayne syndrome spectrum. CSB was originally termed ERCC6 (excision repair cross-complementation group 6) because it was found to complement the nucleotide excision repair (NER) defect in the complementation group 6 of rodent cell lines defective in excision repair (111). Subsequently, Troelstra demonstrated that ERCC6 gene expression could reverse UV sensitivity and rescue post-UV RNA synthesis in CSB but not in CSA (112). In 1995, the second gene ERCC8 encoding CSA protein was identified, which reversed the UV sensitivity of Cockayne syndrome cells from group A (42). Subsequently, it became clear that both genes interacted with each other and played critical roles in the transcription-coupled nucleotide excision repair (TC-NER) of damaged DNA (47).

This is an article preview.
Start a Free Account
to access the full version.

  • Nearly 3,000 illustrations, including video clips of neurologic disorders.

  • Every article is reviewed by our esteemed Editorial Board for accuracy and currency.

  • Full spectrum of neurology in 1,200 comprehensive articles.

  • Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660



ISSN: 2831-9125