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Cockayne syndrome

Authors: Dr Claudia Hadlow, Medical Officer, John Hunter Hospital, Newcastle, NSW, Australia; Dr Matthew James Verheyden, Medical Officer, Royal North Shore Hospital, Sydney, NSW, Australia; Dr Paul Chee, Consultant Dermatologist and Director of Dermatology at the John Hunter Hospital and the Royal Newcastle Centre, NSW, Australia. DermNet NZ Editor in Chief: Adjunct A/Prof Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. July 2020.


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What is Cockayne syndrome?

Cockayne syndrome is a genetic degenerative disorder first described by E. Cockayne in 1936 [1,2]. It is classified into three clinical subtypes based on the severity of disease and the age of presentation:

  • Cockayne syndrome Type 1 (CS-1) — the classical form that presents in the first two years of life.
  • Cockayne syndrome Type 2 (CS-2) — a congenital form which is more severe than CS-1. Symptoms are present from birth.
  • Cockayne syndrome Type 3 (CS-3) — this presents later in life and has a milder course. Growth and/or cognitive function are less impaired than in CS-1.

Who gets Cockayne syndrome?

Cockayne syndrome is rare, with a prevalence of 2.5 per million with only around 180 cases reported in the literature worldwide. It has been described in both sexes and in people from varied racial backgrounds [3].

A sibling of a child with Cockayne syndrome has a 25% chance of having the disease [4].

What causes Cockayne syndrome?

Cockayne syndrome is an inherited autosomal recessive disorder. For an individual to express the phenotype, their genotype must comprise of two recessive alleles, one from each parent [1].

Mutations occur in excision repair cross complementation genes (ERCC) and may arise in the ERCC6 or ERCC8 genes, which code for proteins involved in DNA repair. Mutations to these genes result in defective DNA repair, such as transcription-coupled nucleotide excision repair affecting ribonucleic acid (RNA) synthesis that repairs damage resulting from UV radiation. The result is cell malfunction and apoptosis (bodily-directed cell death).

What are the clinical features of Cockayne syndrome?

Cockayne syndrome is a multisystem disorder with variable severity.

The cutaneous features of Cockayne syndrome are:

Other features of Cockayne syndrome include:

  • Growth retardation, dwarfism, and cachexia (height and weight are < 5th centile before the age of 2) [3]
  • Microcephaly and neurological dysfunction resulting in early developmental delay followed by a progressive deterioration in behaviour and intellect [3]
  • Cognitive deficits [1]
  • Typical pinched ‘bird-like’ facial appearance with a beaked nose, deep sunken eyes, and progeria-like features [5]
  • Disproportionately large extremities
  • Prognathism [7]
  • Pigmentary retinopathy [1]
  • Cataracts [1]
  • Dental decay [5]
  • Sensorineural deafness [1]
  • Hypertension
  • Gastroesophageal reflux resulting in feeding difficulties [1]
  • Difficulties in walking and other movements.

What are the complications of Cockayne syndrome?

The ERCC6 and ERCC8 gene mutations of Cockayne syndrome cause progressive cellular dysfunction and apoptosis across multiple organ systems.

People with Cockayne syndrome experience severe liver failure and may die if exposed to the drug metronidazole [7].

Cockayne syndrome is not associated with an increased risk of cancer [8].

How is Cockayne syndrome diagnosed?

Cockayne syndrome is diagnosed with the presence of clinical features, which become more obvious over time due to the progressive nature of the disease.

The diagnosis is confirmed by genetic testing. Targeted single gene sequencing and extended genetic panels are available to identify whether the patient has both pathogenic allele variants in ERCC6 or ERCC8.

Prenatal diagnosis of Cockayne syndrome involves gene sequencing from chorionic villous sampling (sampling of the placental tissue) and amniotic fluid cultures [4].

Prospective parents can also undergo molecular genetic testing for carrier status prior to conception [3].

What is the differential diagnosis for Cockayne syndrome?

The differential diagnoses for Cockayne syndrome will vary according to the presenting features of the individual patient [4].

Xeroderma pigmentosum

Xeroderma pigmentosum is due to defective global genomic nucleotide excision repair. It presents with sun sensitivity, sunlight-induced ocular complications, and an increased risk of cutaneous neoplasms. It does not cause growth retardation. Pigmentary changes are more prominent in xeroderma pigmentosum than in Cockayne syndrome. One in four people with xeroderma pigmentosum has neurological symptoms [6].

Progeria

Progeria is characterised by dwarfism and a premature-aged appearance without photosensitivity, ocular symptoms, or disproportionately large extremities.

Rothmund-Thomson syndrome

Rothmund-Thomson syndrome is characterised by poikiloderma on the face, extremities, and buttocks. It also causes photosensitivity.

Bloom syndrome

Bloom syndrome causes growth retardation and erythema of the hands and feet. Neurological and cognitive development is normal.

Trichothiodystrophy

The photosensitive form of trichothiodystrophy is also due to mutations in excision repair genes. It results in ichthyosis and tiger-tail hairs, unlike Cockayne syndrome [8].

What is the treatment for Cockayne syndrome?

There is no cure for Cockayne syndrome. Treatment involves supportive measures, including photoprotection, optimisation of nutrition, physiotherapy, and occupational therapy.

Children with Cockayne syndrome should undergo at least annual surveillance with the following considerations.

  • Oral motor and dietary assessment, as the children are at risk of inadequate calorie consumption due to muscle weakness and neurological deficit. Some children are fed via a nasogastric tube.
  • Neurological assessment of the cranial nerves, and upper and lower limbs.
  • Hearing assessment; some children require hearing aids.
  • Blood glucose
  • Liver enzymes
  • Kidney function.
  • Blood pressure.
  • Dental assessment and dental care.

Genetic counselling should be considered by parents of a child with Cockayne syndrome due to the risk for future pregnancies [4].

What is the outcome for Cockayne syndrome?

Individuals with Cockayne syndrome rarely live past the second to third decade of life due to ambulatory and feeding difficulties associated with neurological degeneration [1].

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References

  1. Karikkineth AC, Scheibye-Knudsen M, Fivenson E, Croteau DL, Bohr VA. Cockayne syndrome: clinical features, model systems and pathways. Ageing research reviews 2017; 33: 3–17. DOI: 10.1016/j.arr.2016.08.002. PubMed
  2. Cockayne EA. Dwarfism with retinal atrophy and deafness. Arch Dis Child 1936; 11: 1. DOI: 10.1136/adc.11.61.1. PubMed
  3. Laugel V. Cockayne syndrome. InGeneReviews® [Internet] 2019 Aug 29. University of Washington, Seattle. PubMed
  4. Kumar AS, Aruna C, Swapna K, Ramamurthy DV. Neonatal onset Cockayne syndrome: A rare photogenodermatosis. Ind J Paediatr Dermatol 2016; 17: 297. Journal
  5. Stern-Delfils A, Spitz MA, Durand M, et al. Renal disease in Cockayne syndrome. Eur J Med Genet 2020; 63: 103612. DOI: 10.1016/j.ejmg.2019.01.002. PubMed
  6. DiGiovanna JJ, Patronas N, Katz D, Abangan D, Kraemer KH. Xeroderma pigmentosum: spinal cord astrocytoma with 9-year survival after radiation and isotretinoin therapy. J Cutan Med Surg 1998; 2: 153–8. DOI: 10.1177/120347549800200308. PubMed
  7. Ataee P, Karimi A, Eftekhari K. Hepatic Failure following Metronidazole in Children with Cockayne Syndrome. Case Rep Pediatr 2020; 2020: 9634196. DOI: 10.1155/2020/9634196. PubMed Central
  8. Bolognia J, Schaffer J, Cerroni L. (2017). Dermatology Volume 2 (4th ed).

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