| Patient Education |
|
Click here for patient education.
|
|
You are in: eMedicine Specialties >
Dermatology > PEDIATRIC DISEASES
Cockayne Syndrome
Article Last Updated: Nov 1, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 9  
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 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
Editors: Jacek C Szepietowski, MD, PhD, Professor and Vice-Head, Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Poland; David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic; Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
Author and Editor Disclosure
Synonyms and related keywords:
CS-I, CS-II, classic Cockayne syndrome, severe Cockayne syndrome, dwarfism, progressive pigmentary retinopathy, birdlike facies, photosensitivity
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 (CS-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 (CS-II), or severe Cockayne syndrome, presents at birth with accelerated facial and somatic features. Individuals who are affected with CS-I typically have progressive neurologic degeneration with death occurring by the second or third decade of life, whereas patients with CS-II typically die by age 6 or 7 years.
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
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. CSB gene defects 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.4, 5
See Causes.
Frequency
International
This condition is rare worldwide.
Mortality/Morbidity
Patients with CS-I have progressive, unremitting, neurologic deterioration usually leading to death by the second or third decade of life. Patients with CS-II typically have a worse prognosis, with death occurring earlier, typically by age 6 or 7 years.
Race
No racial predilection is reported.
Sex
No sexual predilection is described; the male-to-female ratio is equal.
Age
CS-I (CS-A) manifests in childhood. CS-II (CS-B) manifests at birth or in infancy, and it has a worse prognosis.
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 CS-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
- Microcephaly, a thin nose, and large ears give the patient a Mickey Mouse appearance.
- Patients may be cachectic.
- Skin findings
- 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: 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
- 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
- Salt and pepper retinal pigment, miotic pupils, cataracts, optic atrophy, corneal opacity, and nystagmus may be observed.
- Vision is preserved.
- Dental findings: Caries may be present.
- Endocrinologic findings
- 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 CS-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.6
Bloom Syndrome (Congenital Telangiectatic Erythema)
Hartnup Disease
Rothmund-Thomson Syndrome
Werner Syndrome
Xeroderma Pigmentosum
Other Problems to be Considered
Seckel syndrome (bird-headed dwarfism)
Lab Studies
- 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 scan may reveal calcifications and cortical atrophy.
Other Tests
- Amniotic fluid cell culturing is used to demonstrate that fetal cells are deficient in RNA synthesis after UV irradiation.
Medical Care
Medical care includes photoprotection with sunscreens and clothing.
Surgical Care
Cochlear implantation can help minimize the effects of auditory impairment.7
Consultations
Consult the following specialists:
- 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
Complications
Death by the second or third decade of life occurs as a result of progressive neurologic degeneration.
Prognosis
The prognosis is poor, with death occurring in the second or third decade of life.
Patient Education
A genetic counselor should educate the parents of the patient.
Medical/Legal 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.
- 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].
- Kleppa L, Kanavin ØJ, Klungland A, Strømme 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].
- 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].
- Morris DP, Alian W, Maessen H, Creaser C, Demmons-O'Brien S, Van Wijhe R, et al. Cochlear implantation in Cockayne syndrome: our experience of two cases with different outcomes. Laryngoscope. May 2007;117(5):939-43. [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, Topçu M, Ozön A, Cila A. Cockayne syndrome: review of 25 cases. Pediatr Neurol. Nov 1996;15(4):312-6. [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].
- 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.
- 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].
Cockayne Syndrome excerpt Article Last Updated: Nov 1, 2007
|
