Genetics of Cockayne Syndrome Clinical Presentation

  • Author: David Flannery, MD, FAAP, FACMG; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 12, 2012
 

History

Patients with Cockayne syndrome (CS) present with delayed psychomotor development, poor feeding, photosensitive rashes, and cataracts.

  • Delayed psychomotor development: All patients with Cockayne syndrome type 1 (CKN1) have mental retardation. The delay becomes apparent around the age when walking and speech should be developing.
  • Poor feeding: Some patients present during infancy with weak or poor feeding; however, the diagnosis is usually not made at this time.
  • Photosensitive rashes: More than 75% of patients have photosensitivity. Other skin findings include decreased amounts of subcutaneous tissue, dry scaly skin, and thin dry hair.
  • Cataracts: The presence of cataracts in children younger than 3 years is associated with the severe form of CKN1, which demonstrates a poorer prognosis and results in death at an earlier age.
Next

Physical

In the first year, all patients with CKN1 demonstrate growth failure, which includes progressive microcephaly in most patients.

  • Neurologic examination shows increased or decreased muscle tone and reflexes. Ambulant patients present with an unusual gait resulting from leg spasticity, ataxia, and contractures of the hips, knees, and ankles.
  • Pigmentary degeneration of the retina is one hallmark of this disorder, with cataracts and optic atrophy or optic disk pallor as frequent findings.
  • Ophthalmologic changes are progressive.
  • More than one half of patients with CKN1 have mild-to-severe sensorineural hearing loss.
  • Many patients have moderate-to-severe dental caries; permanent teeth have short roots.
  • Most patients have photodermatitis that leads to dry scaly skin. Patients develop an aged appearance as a result of the disease process.
  • Major structural anomalies of the renal system rarely occur. Some patients develop decreased creatinine clearance but usually do not require medical treatment.
  • Cryptorchidism or testicular hypoplasia affects approximately one third of males. Females have menses, although cycles are irregular. Puberty may be delayed in both sexes.
Previous
Next

Causes

  • CKN1 is caused by a defect in the Cockayne syndrome type A gene (CSA or ERCC8) located on chromosome 5.[1] Affected persons inherit 2 mutant genes, one from each parent. Cells carrying ERCC8 mutations are hypersensitive to UV light. They do not recover the ability to synthesize RNA after exposure to UV light. In addition, the cells cannot remove and degrade DNA lesions from strands that have active transcription.
  • Mutations in the DNA excision repair gene ERCC6 located on band 10q11 cause CS type 2 (MIM number 133540; CSB).[2, 3] This gene encodes helicase, a protein that is presumed to have DNA unwinding function. Mutations include a deletion of exon 4, an amino acid substitution at the 106th glutamine to proline (Q106P) in the WD-40 repeat motif of the CSA protein, and large deletion in the upstream region, including exon 1 of the CSA gene. The Q106P mutation could alter the propeller structure of the CSA protein, which is important for the formation of the CSA protein complex. Additionally, a missense mutation (A205P) and a nonsense (E13X) mutation have been identified, as well as a new common single nucleotide polymorphism in CKN1. No genotype-phenotype correlation is known.
Previous
Proceed to Workup
 
 
Contributor Information and Disclosures
Author

David Flannery, MD, FAAP, FACMG  Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia

David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics and American College of Medical Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Elaine H Zackai, MD  Professor of Pediatrics, Professor of Obstetrics and Gynecology, Professor of Pediatrics in Human Genetics, University of Pennsylvania School of Medicine; Director, Clinical Genetics Center, University of Pennsylvania; Senior Physician and Director of Clinical Genetics, The Children's Hospital of Philadelphia

Elaine H Zackai, MD is a member of the following medical societies: American Cleft Palate/Craniofacial Association, American College of Medical Genetics, and American Society of Human Genetics

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David Flannery, MD, FAAP, FACMG  Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia

David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics and American College of Medical Genetics

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

  1. Khayat M, Hardouf H, Zlotogora J, Shalev SA. High carriers frequency of an apparently ancient founder mutation p.Tyr322X in the ERCC8 gene responsible for Cockayne syndrome among Christian Arabs in Northern Israel. Am J Med Genet A. Dec 2010;152A(12):3091-4. [Medline].

  2. Laugel V, Dalloz C, Durand M, et al. Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome. Hum Mutat. Nov 5 2009;[Medline].

  3. Zhang H, Gao J, Ye J, Gong Z, Gu X. Maternal origin of a de novo microdeletion spanning the ERCC6 gene in a classic form of the Cockayne syndrome. Eur J Med Genet. Jul-Aug 2011;54(4):e389-93. [Medline].

  4. [Guideline] Cunniff C. Prenatal screening and diagnosis for pediatricians. Pediatrics. Sep 2004;114(3):889-94. [Medline].

  5. Cao H, Williams C, Carter M, Hegele RA. CKN1 (MIM 216400): mutations in Cockayne syndrome type A and a new common polymorphism. J Hum Genet. 2004;49(1):61-3. [Medline].

  6. Chien YH, Chou HC, Hwu WL. Cockayne syndrome in a family. Acta Paediatr Taiwan. Jan-Feb 2002;43(1):46-9. [Medline].

  7. Cleaver JE, Thompson LH, Richardson AS, States JC. A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. Hum Mutat. 1999;14(1):9-22. [Medline].

  8. Greenhaw GA, Hebert A, Duke-Woodside ME, et al. Xeroderma pigmentosum and Cockayne syndrome: overlapping clinical and biochemical phenotypes. Am J Hum Genet. Apr 1992;50(4):677-89. [Medline].

  9. Higginbottom MC, Griswold WR, Jones KL, et al. The Cockayne syndrome: an evaluation of hypertension and studies of renal pathology. Pediatrics. Dec 1979;64(6):929-34. [Medline].

  10. Kleijer WJ, van der Sterre ML, Garritsen VH. Prenatal diagnosis of the Cockayne syndrome: survey of 15 years experience. Prenat Diagn. Oct 2006;26(10):980-4. [Medline].

  11. Lehmann AR, Francis AJ, Giannelli F. Prenatal diagnosis of Cockayne's syndrome. Lancet. Mar 2 1985;1(8427):486-8. [Medline].

  12. Mathur R, Chowdhury MR, Singh G. Recent advances in chromosome breakage syndromes and their diagnosis. Indian Pediatr. Jun 2000;37(6):615-25. [Medline].

  13. Moyer DB, Marquis P, Shertzer ME, Burton BK. Cockayne syndrome with early onset of manifestations. Am J Med Genet. Oct 1982;13(2):225-30. [Medline].

  14. Nance MA, Berry SA. Cockayne syndrome: review of 140 cases. Am J Med Genet. Jan 1 1992;42(1):68-84. [Medline].

  15. Proops R, Taylor AM, Insley J. A clinical study of a family with Cockayne's syndrome. J Med Genet. Aug 1981;18(4):288-93. [Medline].

  16. Rapin I, Weidenheim K, Lindenbaum Y. Cockayne syndrome in adults: review with clinical and pathologic study of a new case. J Child Neurol. Nov 2006;21(11):991-1006. [Medline].

  17. Ren Y, Saijo M, Nakatsu Y, et al. Three novel mutations responsible for Cockayne syndrome group A. Genes Genet Syst. Feb 2003;78(1):93-102. [Medline].

  18. Sugita T, Ikenaga M, Suehara N, et al. Prenatal diagnosis of Cockayne syndrome using assay of colony-forming ability in ultraviolet light irradiated cells. Clin Genet. Sep 1982;22(3):137-42. [Medline].

  19. 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].

  20. Traboulsi EI, De Becker I, Maumenee IH. Ocular findings in Cockayne syndrome. Am J Ophthalmol. Nov 15 1992;114(5):579-83. [Medline].

  21. Venema J, Mullenders LH, Natarajan AT, et al. The genetic defect in Cockayne syndrome is associated with a defect in repair of UV-induced DNA damage in transcriptionally active DNA. Proc Natl Acad Sci U S A. Jun 1990;87(12):4707-11. [Medline].

 
Previous
Next
 
Autosomal recessive inheritance pattern.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.