Cockayne Syndrome

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Background

Cockayne syndrome[1] is a rare autosomal recessive (see diagram below), heterogeneous, multisystem disorder characterized by dwarfism, progressive pigmentary retinopathy, birdlike facies, and photosensitivity. The syndrome is divided into two 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.[2, 3]



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Autosomal recessive inheritance pattern.

Also see the 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.[4, 5, 6]

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.[4, 5, 7, 8]

Cockayne syndrome group A or B (CSA or CSB) genes are required for transcription-coupled repair, a subpathway of nucleotide-excision repair.[9] At least 30 known CSA mutations have been characterized to date, primarily mutations in group 8 excision-repair cross-complementation gene (ERCC8) on band 5q12.[10] CSB gene defects (ERCC6) (at least 78 different mutations) 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.[11, 12] These may account for signs and symptoms not readily related to DNA repair deficiencies.[13, 14]

See Causes.

Etiology

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.[15]

Epidemiology

Frequency

Cockayne syndrome is rare worldwide.

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.

Prognosis

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.

Patient Education

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

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 Examination

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.

Cyanotic acral edema of the extremities[16]

Nail dystrophies and hair anomalies[16]

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 [17]

Salt and pepper retinal pigment, miotic pupils, cataracts, optic atrophy, corneal opacity, and nystagmus may be observed.

Vision is preserved.

Blepharokeratoconjunctivitis has been reported.[18]

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.

Complications

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

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.[20]

Other Tests

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

Medical Care

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

Studies showing hepatic toxicity associated with metronidazole use suggests that metronidazole is contraindicated in patients with Cockayne syndrome.[21]

Surgical Care

Cochlear implantation can help minimize the effects of auditory impairment.[22, 23]

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.[24] Depending on the severity of the Cockayne syndrome, it may not be uncommon to encounter adult diseases, such as myocardial ischemia,[25] renal impairment, and diabetes mellitus, even in early childhood.[26]

Consultations

Consult the following specialists for Cockayne syndrome patients:

Author

Suguru Imaeda, MD, Chief of Dermatology, Yale University Health Services; Chief of Dermatology, Veterans Affairs Connecticut Healthcare System; Assistant Professor, Department of Dermatology, Yale University School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

David F Butler, MD, Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.

Additional Contributors

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: Received consulting fee from Orfagen for consulting; Received consulting fee from Maruho for consulting; Received consulting fee from Astellas for consulting; Received consulting fee from Abbott for consulting; Received consulting fee from Leo Pharma for consulting; Received consulting fee from Biogenoma for consulting; Received honoraria from Janssen for speaking and teaching; Received honoraria from Medac for speaking and teaching; Received consulting fee from Dignity Sciences for consulting; .

References

  1. Cockayne EA. Dwarfism with retinal atrophy and deafness. Arch Dis Child. 1936. 11:1-8.
  2. Natale V. A comprehensive description of the severity groups in Cockayne syndrome. Am J Med Genet A. 2011 May. 155A(5):1081-95. [View Abstract]
  3. Wilson BT, Stark Z, Sutton RE, Danda S, Ekbote AV, Elsayed SM, et al. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet Med. 2016 May. 18 (5):483-93. [View Abstract]
  4. Chu G, Mayne L. Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy: do the genes explain the diseases?. Trends Genet. 1996 May. 12(5):187-92. [View Abstract]
  5. Kraemer KH, Patronas NJ, Schiffmann R, Brooks BP, Tamura D, DiGiovanna JJ. Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship. Neuroscience. 2007 Apr 14. 145(4):1388-96. [View Abstract]
  6. 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. [View Abstract]
  7. Hayashi M, Miwa-Saito N, Tanuma N, Kubota M. Brain vascular changes in Cockayne syndrome. Neuropathology. 2011 Jul 12. [View Abstract]
  8. Zhang WR, Garrett GL, Cleaver JE, Arron ST. Absence of skin cancer in the DNA repair-deficient disease Cockayne Syndrome (CS): A survey study. J Am Acad Dermatol. 2016 Jun. 74 (6):1270-2. [View Abstract]
  9. Scheibye-Knudsen M, Tseng A, Borch Jensen M, Scheibye-Alsing K, Fang EF, Iyama T, et al. Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA. Proc Natl Acad Sci U S A. 2016 Nov 1. 113 (44):12502-12507. [View Abstract]
  10. 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. 1995 Aug 25. 82(4):555-64. [View Abstract]
  11. Laugel V. Cockayne syndrome: the expanding clinical and mutational spectrum. Mech Ageing Dev. 2013 May-Jun. 134(5-6):161-70. [View Abstract]
  12. Calmels N, Botta E, Jia N, Fawcett H, Nardo T, Nakazawa Y, et al. Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome. J Med Genet. 2018 Mar 23. [View Abstract]
  13. 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. 2007 Apr 14. 145(4):1397-406. [View Abstract]
  14. 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. 2007 Apr 14. 145(4):1300-8. [View Abstract]
  15. Christiansen M, Thorslund T, Jochimsen B, Bohr VA, Stevnsner T. The Cockayne syndrome group B protein is a functional dimer. FEBS J. 2005 Sep. 272(17):4306-14. [View Abstract]
  16. Frouin E, Laugel V, Durand M, Dollfus H, Lipsker D. Dermatologic findings in 16 patients with Cockayne syndrome and cerebro-oculo-facial-skeletal syndrome. JAMA Dermatol. 2013 Dec. 149(12):1414-8. [View Abstract]
  17. Wu Y, Zheng Y, Yan X, Huang Y, Jiang Y, Li H. Ocular findings in a patient with Cockayne syndrome with two mutations in the ERCC6 gene. Ophthalmic Genet. 2016 May 17. 1-3. [View Abstract]
  18. Bhojwani R, Lloyd IC, Alam S, Ashworth J. Blepharokeratoconjunctivitis in Cockayne syndrome. J Pediatr Ophthalmol Strabismus. 2009 May-Jun. 46(3):184-5. [View Abstract]
  19. 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. 2009 Apr 14. 106(15):6209-14. [View Abstract]
  20. Tan WH, Baris H, Robson CD, Kimonis VE. Cockayne syndrome: the developing phenotype. Am J Med Genet A. 2005 Jun 1. 135(2):214-6. [View Abstract]
  21. Wilson BT, Strong A, O'Kelly S, Munkley J, Stark Z. Metronidazole Toxicity in Cockayne Syndrome: A Case Series. Pediatrics. 2015 Sep. 136 (3):e706-8. [View Abstract]
  22. Morris DP, Alian W, Maessen H, et al. Cochlear implantation in Cockayne syndrome: our experience of two cases with different outcomes. Laryngoscope. 2007 May. 117(5):939-43. [View Abstract]
  23. Van Wyhe RD, Emery CV, Williamson RA. Cochlear implantation in pediatric patients with Cockayne Syndrome. Int J Pediatr Otorhinolaryngol. 2018 Mar. 106:64-67. [View Abstract]
  24. Wooldridge WJ, Dearlove OR, Khan AA. Anaesthesia for Cockayne syndrome. Three case reports. Anaesthesia. 1996 May. 51(5):478-81. [View Abstract]
  25. 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. 2001 Dec. 59(12):1488-91. [View Abstract]
  26. Raghavendran S, Brown KA, Buu N. Perioperative management of patients with Cockayne syndrome - recognition of accelerated aging with growth arrest. Paediatr Anaesth. 2008 Apr. 18(4):360-1. [View Abstract]
  27. Hurwitz S. Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence. 2nd ed. Philadelphia, Pa: WB Saunders; 1993. 96.
  28. Spitz JL. Genodermatoses. Baltimore, Md: Williams & Wilkins; 1996. Vol 1: 208-9.
  29. Sybert VP. Genetic Skin Disorders. 1st ed. New York, NY: Oxford University Press; 1997. Vol 1: 559-61.

Autosomal recessive inheritance pattern.

Autosomal recessive inheritance pattern.