DiagnosisClinical DiagnosisCockayne syndrome (CS) is characterized by growth failure and multisystemic degeneration, with a variable age of onset and rate of progression. The phenotypic spectrum of CS can be divided into three general clinical presentations: Cockayne syndrome type I. "Classic" CS in which the major features of the disease become apparent by age one to two yearsCockayne syndrome type II. A more severe form with abnormalities recognized at birth or in the early neonatal period Cockayne syndrome type III. Milder/later-onset forms that are still poorly defined Formal clinical diagnostic criteria have been proposed only for CS type I [Nance & Berry 1992]. Because of the progressive nature of CS, the clinical diagnosis of CS becomes more certain as additional signs and symptoms gradually manifest over time. At all stages of disease progression, molecular genetic testing can be useful for confirming the suspected clinical diagnosis. Classic Cockayne Syndrome (CS Type I) CS type I is suspected: In an older child when both major criteria are present and three minor criteria are present; In an infant or toddler when both major criteria are present, especially if there is increased cutaneous photosensitivity. Major criteriaPostnatal growth failure (height and weight <5th centile by age 2 years) Progressive microcephaly and neurologic dysfunction manifested as early developmental delay in most individuals, followed by progressive behavioral and intellectual deterioration in all individuals; brain MRI reveals leukodystrophy [Boltshauser et al 1989, Sugita et al 1992]. Intracranial calcifications are seen in some individuals. Minor criteriaCutaneous photosensitivity with or without thin or dry skin or hair (~75%) Demyelinating peripheral neuropathy diagnosed by electromyography, nerve conduction testing, and/or nerve biopsy Pigmentary retinopathy (~55%) and/or cataracts (~36%) Sensorineural hearing loss (~60%) Dental anomalies, including dental caries (~86%), enamel hypoplasia, anomalies of tooth number and anomalies of tooth size and shape A characteristic physical appearance of "cachectic dwarfism" with thinning of the skin and hair, sunken eyes, and a stooped standing posture Characteristic radiographic findings of thickening of the calvarium, sclerotic epiphyses, vertebral and pelvic abnormalities Family history. The presence of a similarly affected sib can be useful for diagnosis. Severe Cockayne Syndrome (CS Type II) CS type II is suspected: In infants with growth failure at birth and little postnatal increase in height, weight, or head circumference; When there is little or no postnatal neurologic development;When congenital cataracts as well as other structural defects of the eye (microphthalmos, microcornea, iris hypoplasia) are present. TestingAssay of cellular phenotype DNA repair assay. Assays of DNA repair are performed on skin fibroblasts. The most consistent findings in CS fibroblasts are: marked sensitivity to UV radiation; deficient recovery of RNA synthesis following UV damage; and impaired repair of actively transcribed genes, or "transcription-coupled repair" [Venema et al 1990, Troelstra et al 1992, van Gool et al 1997]. Complementation groups. Cells from individuals with CS can be divided into two complementation groups based on the protein that corrects the DNA repair defect: (1) the DNA excision repair protein ERCC-8 (formerly known as CS WD-repeat protein) in Cockayne syndrome-A (CSA) (25% of individuals) and (2) the DNA excision repair protein ERCC-6 in Cockayne syndrome-B (CSB) (75% of individuals) [Stefanini et al 1996]. Molecular Genetic TestingGenes. Mutations in two genesare known to cause Cockayne syndrome: ERCC6. Mutations in ERCC6 cause Cockayne syndrome complementation group type B (CSB), which accounts for 65% of cases [Troelstra et al 1992, Troelstra et al 1993]. ERCC8 (previously known as CKN1). Mutations in ERCC8 cause Cockayne syndrome complementation group type A (CSA), which accounts for 35% of cases [Henning et al 1995]. Most variants can be detected by DNA sequence analysis of the coding and flanking intronic regions of the genes. Deletion/duplication analysis and/or sequencing of the cDNA can detect additional variants in a minority of cases. Table 2 summarizes the type of mutations. Table 1. Summary of Molecular Genetic Testing Used in Cockayne SyndromeView in own windowGene Symbol% of CS Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilityERCC8~35% Sequence analysisSequence variants ^{1, 2, 3ClinicalDeletion / duplication analysis 4Exonic or whole-gene deletions 2, 5ERCC6~65% Sequence analysisSequence variants 1, 2, 3ClinicalDeletion / duplication analysis 4Exonic or whole-gene deletions 2, 51. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.2. Pathologic allelic variants reported in ERCC8 and ERCC6 are summarized in Table 2.3. A majority are nonsense or frameshift mutations that predict a truncated protein [Troelstra et al 1992, Mallery et al 1998, Colella et al 1999, Meira et al 2000, Horibata et al 2004].4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. Exonic or whole gene deletions of ERCC8 escape detection by sequence analysis when present in a heterozygous state or compound heterozygous state [Henning et al 1995, Ren et al 2003, Cao et al 2004].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To establish the diagnosis in a proband involves molecular genetic testing 1Sequence analysis of ERCC6, followed by deletion/duplication analysis. If no ERCC6 mutation is identified, sequence analysis of ERCC8, followed by deletion/duplication analysis
ORSequence analysis of ERCC6, followed by sequencing of ERCC8. If sequence analyses do not identify both mutations, deletion/duplication analysis of ERCC8 and ERCC6. 1. Testing algorithms vary by clinic and laboratory.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersERCC6. Mutations in ERCC6 have also been identified in individuals with: Cerebrooculofacioskeletal syndrome (COFS), now recognized to be part of the spectrum of Cockayne syndrome [Meira et al 2000]; DeSanctis-Cacchione variant of xeroderma pigmentosum (XP) [Colella et al 2000]; UV-sensitive syndrome (UVSS) [Horibata et al 2004]. ERCC8. No other phenotypes are associated with mutations in ERCC8.}

Natural HistoryBefore the molecular genetics of Cockayne syndrome was understood, it was thought to have a single, discrete phenotype: classic Cockayne syndrome. It is now recognized that Cockayne syndrome spans a phenotypic spectrum that includes the following [Nance & Berry 1992]: CS type I, the "classic" form [Lowry 1982] CS type II, a more severe form with symptoms present at birth (overlapping with cerebrooculofacioskeletal syndrome (COFS) and Pena-Shokeir type II syndrome)CS type III, a milder formXeroderma pigmentosum-Cockayne syndrome (XP-CS)CS Type IPrenatal growth is typically normal. Birth length, weight, and head circumference are normal. Within the first two years, however, growth and development fall below normal. By the time the disease has become fully manifest, height, weight, and head circumference are far below the fifth percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system function leads to severe disability. Severe dental caries occur in up to 86% of individuals. Photosensitivity can be severe, but individuals are not predisposed to skin cancers. Additional clinical abnormalities occurring in 10% or more of individuals include the following: Neurologic. Increased tone/spasticity, hyper- or hyporeflexia, abnormal gait or inability to walk, ataxia, incontinence, tremor, abnormal or absent speech, seizures, weak cry/poor feeding (as an infant), muscle atrophy, and behavioral abnormality Dermatologic. Anhidrosis and malar rash Ophthalmologic. Enophthalmos, pigmentary retinopathy (60%-100%), abnormal electroretinogram, cataracts of various types (15%-36%), optic atrophy, miotic pupils, farsightedness, decreased or absent tears, strabismus, nystagmus, photophobia, narrowed retinal arterioles, and microphthalmia Dental. Absent or hypoplastic teeth, delayed eruption of deciduous teeth, and malocclusion Renal. Abnormal renal function and pathologic abnormalities; noted in case reports, but usually not clinically significantEndocrine. Undescended testes, delayed/absent sexual maturation. No individuals with classic or severe CS (types I or II) have been known to reproduce. A successful (but very difficult) pregnancy has been reported in a young woman with mild CS (type III) [Lahiri & Davies 2003]. Gastrointestinal. Elevated liver function tests, enlargement of liver or spleen Death typically occurs in the first or second decade. The mean age of death is 12 years, but survival into the third decade has been reported. CS Type IIChildren with severe CS have evidence of growth failure at birth, with little or no postnatal neurologic development. Congenital cataracts or other structural anomalies of the eye are present in 30%. Affected individuals have arthrogryposis or early postnatal contractures of the spine (kyphosis, scoliosis) and joints. Affected children typically die by age seven years. CS type II overlaps clinically with the cerebrooculofacioskeletal syndrome (COFS), which is also referred to as Pena-Shokeir syndrome type II. CS Type IIIRecently, DNA sequencing has confirmed the diagnosis of CS type III in some individuals who have clinical features associated with CS but whose growth and/or cognition exceeds the expectations for CS type I [E Neilan, unpublished]. XP-CSSince the discovery of the genes in which mutations underlie CS, it has become evident that the distinctions between genotype, cellular phenotype, and clinical phenotype are not absolute. Xeroderma pigmentosum, a related DNA repair disorder, includes facial freckling and early skin cancers — features not found in CS. The DeSanctis-Cacchione variant of XP includes some features of CS (e.g., intellectual disability, spasticity, short stature, and hypogonadism) but does not include skeletal dysplasia, the facial phenotype of CS, or CNS dysmyelination and calcifications. Individuals with an XP clinical phenotype have been seen in association with a CS cellular phenotype and with a mutation in ERCC6 [Greenhaw et al 1992, Colella et al 2000]. Conversely, individuals with clinical features of CS but with XP-like skin cancers have been assigned to the XPB, XPD, and XPG complementation groups based on their biochemical characteristics (the ability to restore normal function to various DNA repair-deficient cell lines) [Okinaka et al 1997, Riou et al 1999, Van Hoffen et al 1999]. Individuals with other features of CS, but lacking sun sensitivity, have been reported. Mallery et al [1998] has reported a poor correlation between genotype and phenotype for this group of diseases. Neuropathology. A characteristic "tigroid" pattern of demyelination in the subcortical white matter of the brain and multifocal calcium deposition, with relative preservation of neurons and without senile plaques, amyloid, ubiquitin, or tau deposition, is observed [Itoh et al 1999].

Genotype-Phenotype CorrelationsThere is no correlation between the biochemical defect in UV-mediated DNA repair assays and the clinical severity of the syndrome. The ability to repair oxidative lesions may distinguish individuals with UVSS from those with CS [Nardo et al 2009]Early reports found no obvious genotype-phenotype correlations for mutations in either ERCC8 or ERCC6, suggesting that the clinical variability within the CS spectrum may not be accounted for by gene mutation alone.It has been reported that a null mutation of ERCC6 does not produce CS, but instead produces the mild UV-sensitive syndrome [Horibata et al 2004]. Thus, the presence of a truncated CSB protein or the presence of a chimeric protein consisting of the first five exons of ERCC6 and the PGBD3 transposon nested in intron 5 could have a specific deleterious effect [Newman et al 2008]. However this hypothesis does not currently account for all cases.

Differential DiagnosisThe differential diagnosis of CS depends on the presenting features of the particular individual. Abnormalities that suggest alternative diagnoses include congenital anomalies of the face, limbs, heart, or viscera; recurrent infections (other than otitis media or respiratory infections); metabolic or neurologic crises; hematologic abnormality (e.g., anemia, leukopenia); and cancer of any kind [Nance & Berry 1992].Growth failure is seen in chromosomal disorders and endocrine, metabolic, or gastrointestinal disorders, including malnutrition. Most leukodystrophies are not associated with growth failure, with the possible exception of the connatal form of Pelizaeus-Merzbacher disease. The presence of calcifications on brain imaging could suggest congenital infections such as rubella or toxoplasmosis, or disorders of calcium and phosphate metabolism. If photosensitivity or thinning of the skin and hair are prominent, the differential diagnosis includes xeroderma pigmentosum, Bloom syndrome, and the "premature aging" syndromes, including Hutchinson-Gilford progeria syndrome, Werner syndrome, and Rothmund-Thompson syndrome. The early presence of pigmentary retinopathy could suggest a mitochondrial disorder (see Mitochondrial Disorders Overview) or a peroxisomal biogenesis disorder (see Peroxisomal Biogenesis Disorder, Zellweger syndrome spectrum). Syndromes with profound growth failure (e.g., Cornelia de Lange syndrome, Dubowitz syndrome, Hallerman-Streiff syndrome, Rubinstein-Taybi syndrome, Russell-Silver syndrome, Seckel syndrome, and Wiedemann-Rautenstrauch syndrome) can usually be excluded on the basis of physical appearance. MICRO syndrome can resemble CS type II/COFS at birth, presenting with microcephaly, microcornea, and cataracts. It differs by the absence of rapidly progressive neurodegeneration and by the presence of normal DNA nucleotide excision repair [Graham et al 2004]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).CS type ICS type IIXP-CS

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Cockayne syndrome (CS), the following evaluations are recommended:Measurement of growth Developmental assessment Dental evaluation Dermatologic evaluations Ophthalmologic evaluations (possibly including electroretinogram) Audiologic evaluation (including audiogram) Brain MRI Laboratory studies to assess renal and hepatic function Testing for diabetes mellitus and disorders of calcium metabolism Skeletal x-rays to document the presence of skeletal dysplasia Nerve conduction studies to document the presence of a demyelinating neuropathy Treatment of ManifestationsThe following are appropriate:Individualized educational program for developmental delay Physical therapy and assistive devices to maintain ambulation in the presence of gait abnormalities Feeding gastrostomy tube placement for failure to thrive Medication for spasticity (baclofen) and tremor (carbidopa-levodopa) if needed Management of hearing loss Management of cataracts and other ophthalmologic complications Use of sunscreens for cutaneous photosensitivity Use of sunglasses for lens and retina protection Prevention of Secondary ComplicationsRecommended measures:Physical therapy to prevent joint contractures Aggressive dental care to minimize dental caries Home safety assessments to prevent falls SurveillanceYearly reassessment for known potential complications (e.g., hypertension; renal or hepatic dysfunction; declining vision and hearing) is appropriate.Agents/Circumstances to AvoidExcessive sun exposure should be avoided.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementIn pregnant women affected with CS, the limited size of the pelvis and abdomen is the major obstacle to the growth of the fetus and the major threat to the outcome of the pregnancy. Prevention of premature labor and caesarean section under spinal anesthesia are usually needed [Lahiri & Davies 2003, Rawlinson & Webster 2003].Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherGrowth hormone (GH) levels in individuals with Cockayne syndrome (CS) may be elevated or decreased [Park et al 1994, Hamamy et al 2005]. While individuals with CS do not appear to have an increased risk of malignancy (an effect which may be due to simultaneous transcription and cell proliferation deficiency), it is theoretically possible that GH treatment could reverse this compensatory effect and promote tumor growth. Therefore, in the absence of safety and efficacy data, GH treatment cannot be recommended in individuals with CS.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Cockayne Syndrome: Genes and DatabasesView in own windowComplementation GroupGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCockayne Syndrome-A (CSA)ERCC85q12​.1DNA excision repair protein ERCC-8ERCC8 homepage - Mendelian genesERCC8Cockayne Syndrome-B (CSB)ERCC610q11​.23DNA excision repair protein ERCC-6ERCC6 homepage - Mendelian genesERCC6Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Cockayne Syndrome (View All in OMIM) View in own window 133540COCKAYNE SYNDROME, TYPE B; CSB 216400COCKAYNE SYNDROME, TYPE A; CSA 609412EXCISION-REPAIR CROSS-COMPLEMENTING, GROUP 8; ERCC8 609413EXCISION-REPAIR CROSS-COMPLEMENTING, GROUP 6; ERCC6Molecular Genetic PathogenesisThe proteins encoded by ERCC6 and ERCC8 both play important roles in transcription-coupled nucleotide excision repair (TC-NER), a DNA repair process that preferentially removes UV-induced pyrimidine dimers and other transcription-blocking lesions from the transcribed strands of active genes. A deficiency of TC-NER is sufficient to explain the cutaneous photosensitivity of individuals with CS. It is unlikely, however, to explain the growth failure and neurodegeneration that typify CS. In contrast to CS, most individuals with xeroderma pigmentosum (XP) have normal growth and neurologic function, despite having combined deficiencies of both TC-NER and "global genome nucleotide excision repair" (GG-NER). To explain this apparent paradox, a critical role for the products of ERCC6 and ERCC8 outside of TC-NER has been suggested, such as an auxiliary function in transcription and/or in non-NER forms of DNA repair [de Waard et al 2004, van den Boom et al 2004].Table 2 summarizes the different types of mutations found in each gene according to the latest mutation review [Laugel et al 2010].Table 2. Summary of Types of Pathologic Mutations in Cockayne SyndromeView in own windowGene SymbolMutation TypeShort insertions or deletionsNonsenseMissenseSplicePartial- or whole-gene deletions or duplicationsERCC8~15%~10%~25%~30%~20%ERCC6~30%~30%~15%~20%~5%ERCC8 Normal allelic variants. ERCC8 has 12 exons (reference sequence NM_000082.3). Cao et al [2004] reported a normal allelic variant.Pathologic allelic variants. Several pathologic allelic variants in ERCC8 have been identified, including nonsense mutations, missense mutations, and large, partial-gene deletions [Henning et al 1995, Ren et al 2003, Cao et al 2004]. No single mutation type seems to predominate. Intriguingly, Komatsu et al [2004] recently reported finding multiple abnormal ERCC8 mRNA splice variants in an individual with CS, although they were unable to identify the DNA mutations responsible for these mRNA splicing abnormalities. The reported pathologic allelic variants in Cockayne syndrome have been summarized [Cleaver et al 1999, Laugel et al 2010]. See also Table A, HGMD.Normal gene product. ERCC8 encodes a 396-amino acid protein (reference sequence NP_000073.1 of 44 kd. It is a WD-repeat protein (tryptophan aspartate-repeats), which interacts with the excision repair protein ERCC-6 and the p44 protein. The p44 protein is a subunit of TFIIH, an RNA polymerase II transcription factor. The proteins encoded by ERCC8 and ERCC6 both appear to be involved in transcription-coupled DNA repair, and possibly in other processes [de Waard et al 2004]. Abnormal gene product. The pathogenic abnormalities thus far reported in ERCC8 vary from large, partial deletions of the gene that remove entire exons to missense mutations that alter a single amino acid [Henning et al 1995, Ren et al 2003, Cao et al 2004, Laugel et al 2010]. ERCC6 Normal allelic variants. ERCC6 has 21 exons (reference sequence NM_000124.2). Pathologic allelic variants. More than 60 different mutations have been reported in ERCC6. Most of these are nonsense or frameshift mutations [Troelstra et al 1992, Mallery et al 1998, Colella et al 1999, Meira et al 2000, Horibata et al 2004, Laugel et al 2010]. See Table A, HGMD.Normal gene product. ERCC6 encodes a 1493-amino acid protein (reference sequence NP_000115.1), containing at least seven domains that are conserved in DNA and RNA helicases. This protein appears to enhance the elongation of transcription products by RNA polymerase II, and possibly also RNA polymerases I and III. Both proteins encoded by ERCC8 and ERCC6 appear to be involved in transcription-coupled DNA repair [Licht et al 2003, van den Boom et al 2004]. Abnormal gene product. A large majority of the pathogenic mutations reported in ERCC6 are nonsense or frameshift mutations that encode a truncated protein or an unstable protein that decays. This somewhat unusual mutation spectrum suggests that the pathogenic mechanism may not be as simple as a loss of normal functions of the protein encoded by ERCC6. Indeed, Horibata et al [2004] report that in at least one case, a homozygous null mutation of ERCC6 failed to produce CS, causing instead only the much milder UV-sensitive syndrome.