Introduction
Background
Cockayne syndrome1 is a rare autosomal recessive, heterogeneous, multisystem disorder characterized by dwarfism, progressive pigmentary retinopathy, birdlike facies, and photosensitivity. The syndrome is divided into 2 subtypes. Cockayne syndrome I, or classic Cockayne syndrome, presents in childhood with characteristic facies and somatic features that occur late in the first decade of life. Cockayne syndrome II, or severe Cockayne syndrome, presents at birth with accelerated facial and somatic features. Individuals who are affected with Cockayne syndrome I typically have progressive neurologic degeneration with death occurring by the second or third decade of life, whereas patients with Cockayne syndrome II typically die by age 6-7 years.
Also see the eMedicine pediatrics article, Cockayne Syndrome.
Pathophysiology
Cockayne syndrome is an autosomal recessive disorder. A DNA repair defect is a prominent feature of Cockayne syndrome.
Cockayne syndrome, xeroderma pigmentosa, and trichothiodystrophy are 3 distinct syndromes with cellular sensitivity to ultraviolet (UV) irradiation. These syndromes arise from mutations of genes critical for nucleotide-excision repair and RNA transcription. At least 28 genes are involved in the nucleotide excision repair pathway, which is involved in protection against UV-induced DNA damage.2,3,4
Cockayne syndrome is not associated with skin cancer, despite the photosensitivity and DNA repair defect, unlike xeroderma pigmentosa. Trichothiodystrophy patients have sulfur-deficient brittle hair with a normal skin cancer risk. Progressive sensorineural deafness is an early feature of both Cockayne syndrome and xeroderma pigmentosa, but not trichothiodystrophy. Furthermore, the main neuropathology of xeroderma pigmentosa is a primary neuronal degeneration, while in Cockayne syndrome and trichothiodystrophy, myelination of the brain is reduced, suggesting that the neurological abnormalities may be caused by both developmental defects and faulty DNA repair of neuronal cells damaged by oxidative stress.2,3
Cockayne syndrome group A or B (CSA or CSB) genes are required for transcription-coupled repair, a subpathway of nucleotide-excision repair. At least 10 known CSA mutations have been characterized to date, primarily mutations in group 8 excision-repair cross-complementation gene (ERCC8) on band 5q12.5 CSB gene defects (ERCC6) result in altered expression of antiangiogenic and cell cycle genes and proteins, particularly p21, which can result in inhibition of cell cycle progression and growth. These may account for signs and symptoms not readily related to DNA repair deficiencies.6,7
See Causes.
Frequency
International
Cockayne syndrome is rare worldwide.
Mortality/Morbidity
Patients with Cockayne syndrome I have progressive, unremitting, neurologic deterioration usually leading to death by the second or third decade of life. Patients with Cockayne syndrome II typically have a worse prognosis, with death occurring earlier, typically by age 6 or 7 years.
Race
No racial predilection is reported for Cockayne syndrome.
Sex
No sexual predilection is described for Cockayne syndrome; the male-to-female ratio is equal.
Age
Cockayne syndrome I (CS-A) manifests in childhood. Cockayne syndrome II (CS-B) manifests at birth or in infancy, and it has a worse prognosis.
Clinical
History
- Patients with Cockayne syndrome usually appear normal at birth.
- Eventually, they present with a typical facial appearance of a pinched, narrow face and a beaked nose.
- Mental retardation, microcephaly, and growth failure become evident over time.
- Photosensitivity and progressive worsening neurologic signs and symptoms of ataxia and quick jerky movements are also noted.
- In Cockayne syndrome I, the phenotypic features of Cockayne syndrome may be subtle early in the disease course. The signs become evident later in the first decade of life.
- In CS-II, severe developmental delays are evident in the immediate postnatal period, and characteristic facies may be present by age 2 years.
Physical
- Appearance and habitus in Cockayne syndrome
- Microcephaly, a thin nose, and large ears give the patient a Mickey Mouse appearance.
- Patients may be cachectic.
- Skin findings in Cockayne syndrome
- Photosensitive eruption with erythema and scale may be observed.
- Affected areas show hyperpigmentation, telangiectasia, and atrophy.
- Subcutaneous lipoatrophy results in sunken eyes and an aged progeric appearance.
- Musculoskeletal findings in Cockayne syndrome: Microcephaly, short stature, long limbs with joint contractures, large hands and feet, kyphosis, thickened calvariae, sclerotic epiphyses of the fingers, and osteoporosis may be observed.
- Neurologic findings in Cockayne syndrome
- Intracranial calcifications and diffuse demyelination of the central nervous system and the peripheral nerves result in progressive neurologic deterioration, such as ataxia, tremors, and cog wheeling.
- Mental retardation may be noted.
- Progressive sensorineural deafness may occur.
- Ophthalmologic findings in Cockayne syndrome
- Salt and pepper retinal pigment, miotic pupils, cataracts, optic atrophy, corneal opacity, and nystagmus may be observed.
- Vision is preserved.
- Blepharokeratoconjunctivitis has been reported.8
- Dental findings in Cockayne syndrome: Caries may be present.
- Endocrinologic findings in Cockayne syndrome
- Hypogonadism occurs in 30% of males.
- Irregular menses occur in females.
Causes
- Cells with a defective DNA repair mechanism are sensitive to UV light.
- Decreased DNA and RNA synthesis, increased sister chromatid exchanges, and increased chromosomal breaks may occur.
- In Cockayne syndrome II, the defective CS group B protein, an SNF2-family DNA-dependent ATPase, is implicated in transcription elongation, transcription coupled repair, and DNA base excision repair.9
More on Cockayne Syndrome |
 Overview: Cockayne Syndrome |
| Differential Diagnoses & Workup: Cockayne Syndrome |
| Treatment & Medication: Cockayne Syndrome |
| Follow-up: Cockayne Syndrome |
| References |
| Next Page » |
References
Cockayne EA. Dwarfism with retinal atrophy and deafness. Arch Dis Child. 1936;11:1-8.
Chu G, Mayne L. Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy: do the genes explain the diseases?. Trends Genet. May 1996;12(5):187-92. [Medline].
Kraemer KH, Patronas NJ, Schiffmann R, Brooks BP, Tamura D, DiGiovanna JJ. Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship. Neuroscience. Apr 14 2007;145(4):1388-96. [Medline].
Ridley AJ, Colley J, Wynford-Thomas D, Jones CJ. Characterisation of novel mutations in Cockayne syndrome type A and xeroderma pigmentosum group C subjects. J Hum Genet. 2005;50(3):151-4. [Medline].
Henning KA, Li L, Iyer N, et al. The Cockayne syndrome group A gene encodes a WD repeat protein that interacts with CSB protein and a subunit of RNA polymerase II TFIIH. Cell. Aug 25 1995;82(4):555-64. [Medline].
Kleppa L, Kanavin OJ, Klungland A, Stromme P. A novel splice site mutation in the Cockayne syndrome group A gene in two siblings with Cockayne syndrome. Neuroscience. Apr 14 2007;145(4):1397-406. [Medline].
Cleaver JE, Hefner E, Laposa RR, Karentz D, Marti T. Cockayne syndrome exhibits dysregulation of p21 and other gene products that may be independent of transcription-coupled repair. Neuroscience. Apr 14 2007;145(4):1300-8. [Medline].
Bhojwani R, Lloyd IC, Alam S, Ashworth J. Blepharokeratoconjunctivitis in Cockayne syndrome. J Pediatr Ophthalmol Strabismus. May-Jun 2009;46(3):184-5. [Medline].
Christiansen M, Thorslund T, Jochimsen B, Bohr VA, Stevnsner T. The Cockayne syndrome group B protein is a functional dimer. FEBS J. Sep 2005;272(17):4306-14. [Medline].
Nardo T, Oneda R, Spivak G, et al. A UV-sensitive syndrome patient with a specific CSA mutation reveals separable roles for CSA in response to UV and oxidative DNA damage. Proc Natl Acad Sci U S A. Apr 14 2009;106(15):6209-14. [Medline].
Tan WH, Baris H, Robson CD, Kimonis VE. Cockayne syndrome: the developing phenotype. Am J Med Genet A. Jun 1 2005;135(2):214-6. [Medline].
Morris DP, Alian W, Maessen H, et al. Cochlear implantation in Cockayne syndrome: our experience of two cases with different outcomes. Laryngoscope. May 2007;117(5):939-43. [Medline].
Wooldridge WJ, Dearlove OR, Khan AA. Anaesthesia for Cockayne syndrome. Three case reports. Anaesthesia. May 1996;51(5):478-81. [Medline].
Yuen MK, Rodrigo MR, Law Min JC, Tong CK. Myocardial ischemia and delayed recovery after anesthesia in a patient with Cockayne syndrome: a case report. J Oral Maxillofac Surg. Dec 2001;59(12):1488-91. [Medline].
Raghavendran S, Brown KA, Buu N. Perioperative management of patients with Cockayne syndrome - recognition of accelerated aging with growth arrest. Paediatr Anaesth. Apr 2008;18(4):360-1. [Medline].
Hurwitz S. Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence. 2nd ed. Philadelphia, Pa: WB Saunders; 1993:96.
Nance MA, Berry SA. Cockayne syndrome: review of 140 cases. Am J Med Genet. Jan 1 1992;42(1):68-84. [Medline].
Ozdirim E, Topcu M, Ozon A, Cila A. Cockayne syndrome: review of 25 cases. Pediatr Neurol. Nov 1996;15(4):312-6. [Medline].
Spitz JL. Genodermatoses. Vol 1. Baltimore, Md: Williams & Wilkins; 1996:208-9.
Sybert VP. Genetic Skin Disorders. Vol 1. ed. New York, NY: Oxford University Press; 1997:559-61.
Further Reading
Keywords
CS-I, CS-II, classic Cockayne syndrome, severe Cockayne syndrome, dwarfism, progressive pigmentary retinopathy, birdlike facies, photosensitivity
