ABSTRACT
Ch apter 8 Molecular Basis and Molecular Diagnosis of Cockayne Syndrome Edward G. Neilan and W. Clark Lam bert3*1 IntroductionAs has been pointed out in the “Preface” o f this book, and in references 1-5, Cockayne syndrome (CS) spans a wide spectrum o f phenotypes that include: CS Type I, the “classic” form; CS Type II, a more severe form w ith symptoms present at b irth [also known as cerebro-oculo-facio syndrome (COFS) and Pena-Shokeir syndrome Type II]; CS Type III, a milder form; and xeroderma pigmentosum-Cockayne overlap syndrome (XP-CS).CS Type I is characterized by norm al prenatal grow th bu t w ith the onset o f growth and developmental abnormalities in the first two years o f life. The disease then is hilly manifested, w ith the height, weight and head circumference all far below the fifth percentile. Progressive impairm ent o f vision, hearing and both central and peripheral nervous system function leads to severe disability. Affected individuals typically die in the first or second decade o f life. The more severe CS Type II, also known as “connatal” CS, is characterized by growth failure in utero which is manifested at birth, with litde or no postnatal neurological development. Congenital cataracts and/or other structural abnormalities o f the eye may be present. Early postnatal contractures o f the spine (kyphosis, scoliosis) and joints are observed. Affected children usually die by age seven years. CS Type III is characterized essentially by norm al growth and cognitive development followed by late onset o f signs o f the disease. XP-CS includes, in addition to features typical o f CS, facial freckling and xerosis (dry skin) followed by early skin cancers characteristic o f XP. Features typical o f CS include m ental retardation, spasticity, short stature, and hypogonadism. However, XP-CS does no t include the facial phenotype o f CS, skeletal involvement or CN S demyelination and calcifications. We w ith others have reviewed these overlap syndromes in chapter 7.Classic CS is diagnosed by major clinical findings (postnatal growth failure and progressive neurological dysfunction) accompanied by other m inor criteria. Some cases are atypical and may require molecular genetic testing. Two genes known to be responsible for most cases o f CS: E R C C 6 or CSB (approximately 75% o f affected individuals) and ERC C 8, CKN1, or CSA (approximately 25% o f affected individuals). Sequence analyses for bo th genes are available.1 CS is inherited as an autosomal recessive trait. N o individual w ith CS has been reported to reproduce. Once the m utation has been identified in the proband, carrier detection in at-risk family members is available on a clinical basis. Prenatal and pre-implantation testing is no t routinely available, but may be available through laboratories offering custom prenatal testing. Formal clinical diagnostic criteria have been proposed only for CS Type I.6 Because o f the progressive nature o f the disease, the clinical diagnosis o f CS becomes more certain as additional signs and symptoms gradually become manifested as the patient grow up. Laboratory testing can be useful for confirming the suspected clinical diagnosis at any stage o f disease progression.
