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Cockayne Syndrome

Updated: Nov 6, 2009

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

Differential Diagnoses

Bloom Syndrome (Congenital Telangiectatic Erythema)
Hartnup Disease
Rothmund-Thomson Syndrome
UV-sensitive syndrome
Werner Syndrome
Xeroderma Pigmentosum

Workup

Laboratory Studies

In Cockayne syndrome patients, UV-irradiated cells show decreased DNA and RNA synthesis.
Laboratory studies are mainly useful to eliminate other disorders. For example, skeletal radiography, endocrinologic tests, and chromosomal breakage studies can help in excluding disorders included in the differential diagnosis.

Imaging Studies

Brain CT scanning in Cockayne syndrome patients may reveal calcifications and cortical atrophy.¹¹

Other Tests

Amniotic fluid cell culturing is used to demonstrate that fetal cells are deficient in RNA synthesis after UV irradiation.

Treatment

Medical Care

Medical care for Cockayne syndrome patients includes photoprotection with sunscreens and clothing.

Surgical Care

Cochlear implantation can help minimize the effects of auditory impairment.¹²

Consultations

Consult the following specialists for Cockayne syndrome patients:

Neurologist for neurologic deterioration, ataxia, and deafness
Ear, nose, and throat specialist for sensorineural deafness
Ophthalmologist for optic atrophy and cataracts
Dentist for caries
Geneticist for prenatal evaluation and genetic counseling

Follow-up

Complications

In Cockayne syndrome, death by the second or third decade of life occurs as a result of progressive neurologic degeneration.

Prognosis

The prognosis for Cockayne syndrome is poor, with death occurring in the second or third decade of life.

Patient Education

A genetic counselor should educate the parents of the Cockayne syndrome patient.

Miscellaneous

Medicolegal Pitfalls

Parents need genetic counseling so that amniocentesis can be performed with future pregnancies.

Special Concerns

Prenatal evaluation is possible. Amniotic fluid cell culturing is used to demonstrate that fetal cells are deficient in RNA synthesis after UV irradiation.

Perioperative management of Cockayne syndrome patients requires special consideration of the characteristic growth arrest, with failure to grow coupled with accelerated aging. Weight-appropriate rather than age-appropriate airway equipment is necessary for airway management.¹³ Depending on the severity of the Cockayne syndrome, it may not be uncommon to encounter adult diseases, such as myocardial ischemia,¹⁴ renal impairment, and diabetes mellitus, even in early childhood.¹⁵

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. 2^nd 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.

Keywords

CS-I, CS-II, classic Cockayne syndrome, severe Cockayne syndrome, dwarfism, progressive pigmentary retinopathy, birdlike facies, photosensitivity

Contributor Information and Disclosures

Author

Suguru Imaeda, MD, Chief of Dermatology, Yale University Health Services; Chief of Dermatology, West Haven Veterans Affairs Medical Center; Assistant Professor, Department of Dermatology, Yale University School of Medicine
Suguru Imaeda, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Connecticut State Medical Society, Sigma Xi, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Medical Editor

Jacek C Szepietowski, MD, PhD, Professor, Vice-Head, Department of Dermatology, Venereology and Allergology, Wroclaw Medical University; Director of the Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Poland
Disclosure: Stiefel Salary Employment; Orfagen Consulting fee Consulting; Maruho Consulting fee Consulting; Astellas Consulting fee Consulting

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

CME Editor

Catherine M Quirk, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania
Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Acknowledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous Chief Editor, William D. James, MD, to the development and writing of this article.

Further Reading