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Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

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Cockayne Syndrome

, MD, PhD.

Author Information and Affiliations

Initial Posting: ; Last Update: August 29, 2024.

Estimated reading time: 30 minutes

Summary

Clinical characteristics.

Cockayne syndrome (referred to as CS in this GeneReview) spans a continuous phenotypic spectrum that includes CS type I, the "classic" or "moderate" form; CS type II, a more severe form with symptoms present at birth (this form overlaps with cerebrooculofacioskeletal [COFS] syndrome); CS type III, a milder and later-onset form; and COFS syndrome, a fetal form of CS.

CS type I is characterized by normal prenatal growth with the onset of growth and developmental abnormalities in the first two years. 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; death typically occurs in the first or second decade.

CS type II is characterized by growth failure at birth, with little or no postnatal neurologic development. Congenital cataracts or other structural anomalies of the eye may be present. Affected children have early postnatal contractures of the spine (kyphosis, scoliosis) and joints. Death usually occurs by age five years.

CS type III is a phenotype in which major clinical features associated with CS only become apparent after age two years; growth and/or cognition exceeds the expectations for CS type I.

COFS syndrome is characterized by very severe prenatal developmental anomalies (arthrogryposis and microphthalmia).

Diagnosis/testing.

The diagnosis of Cockayne syndrome is established in a proband with biallelic pathogenic variants in ERCC6 or ERCC8 identified by molecular genetic testing.

Management.

Treatment of manifestations: Feeding gastrostomy tube placement as needed; individualized educational programs for developmental delay; medications for tremor and spasticity as needed; physical therapy to prevent contractures; use of sunglasses for lens/retina protection; treatment of cataracts and other ophthalmologic complications, hearing loss, hypertension, and gastroesophageal reflux as in the general population; aggressive dental care to minimize dental caries; use of sunscreens and limitation of sun exposure for cutaneous photosensitivity.

Surveillance: Biannual assessment of diet, nervous system, and ophthalmologic status; yearly assessment for complications such as hearing loss, hepatic or renal dysfunction, and hypertension.

Agents/circumstances to avoid: Excessive sun exposure and use of metronidazole. Extra vigilance is needed for opioid and sedative use. Use of growth hormone treatment is not recommended in those with CS.

Genetic counseling.

Cockayne syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the CS-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

GeneReview Scope

Cockayne Syndrome (CS): Phenotypic Spectrum
  • CS type I
  • CS type II
  • CS type III
  • Cerebrooculofacioskeletal (COFS) syndrome

For synonyms and outdated names see Nomenclature.

Diagnosis

Formal clinical diagnostic criteria originally proposed for Cockayne syndrome (CS) type I [Nance & Berry 1992] were revised and subsequently expanded [Natale 2011, Laugel 2013]. A diagnostic scoring system has been recently proposed based on both clinical and imaging criteria [Spitz et al 2021].

Cockayne syndrome is characterized by growth failure and multisystemic involvement, with a variable age of onset and rate of progression. Due to the progressive nature of CS, the clinical diagnosis becomes more certain as additional clinical manifestations gradually evolve over time.

To facilitate clinical recognition and follow up, the phenotypic spectrum of CS can be divided into different clinical presentations. Note, however, that among all individuals with CS there is a continuous spectrum of clinical severities and that intermediate phenotypes may arise.

  • Cockayne syndrome (CS) type I, "classic" CS, in which the major features of the disease become apparent during early childhood
  • Cockayne syndrome (CS) type II, a more severe form with abnormalities recognized at birth or during the neonatal period with early lethality
  • Cockayne syndrome (CS) type III, a milder, later-onset form in which major features become apparent during late childhood
  • Cerebrooculofacioskeletal (COFS) syndrome, a very severe fetal phenotype with arthrogryposis, prenatal growth failure, congenital microcephaly, and congenital cataracts or microphthalmia

Suggestive Findings

Cockayne syndrome should be suspected in individuals with the following findings.

Major criteria

  • Postnatal 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 white matter dysmyelination and cerebral and cerebellar atrophy [Koob et al 2010, Koob et al 2016]. Intracranial calcifications (mainly located in the basal ganglia) are seen in some individuals.
    Note: White matter dysmyelination is usually present at disease onset. Cerebral and cerebellar atrophy appear during the course of the disease and worsen over time. Intracranial calcifications may be absent in some individuals, especially during the early stages, but when present typically become more prominent with time.

Minor criteria

  • Cutaneous photosensitivity
  • Demyelinating peripheral neuropathy diagnosed by nerve conduction testing
  • Pigmentary retinopathy and/or cataracts
  • Sensorineural hearing loss
  • Dental anomalies including dental caries, enamel hypoplasia, and anomalies of tooth number, size, and shape
  • A characteristic physical appearance of "cachectic dwarfism" with sunken eyes

CS type I (classic) is suspected:

  • In an older child when both major criteria are present and at least three minor criteria are present;
  • In an infant or toddler when both major criteria are present, especially if there is increased cutaneous photosensitivity.

CS type II (severe) 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 are present.

CS type III (mild) is suspected:

  • In children or teenagers with short stature, mild neurologic impairment, and progressive ataxia;
  • Especially but not exclusively when there is cutaneous photosensitivity.

COFS syndrome is suspected when prenatal growth failure and congenital microcephaly are associated with arthrogryposis and congenital cataracts as well as other structural defects of the eye (microphthalmia, microcornea, iris hypoplasia).

Establishing the Diagnosis

Clinical diagnosis. The clinical diagnosis of Cockayne syndrome can be established in a proband based on the diagnostic scoring system established by Spitz et al [2021], which helps define the likelihood of CS and provides guidance on appropriate molecular confirmation.

Molecular diagnosis. The molecular diagnosis of Cockayne syndrome is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in one of the genes listed in Table 1 identified by molecular genetic testing.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance) in one of the genes listed in Table 1 does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When the phenotypic and neuroimaging findings suggest the diagnosis of Cockayne syndrome, molecular genetic testing approaches include use of a multigene panel.

A multigene panel that includes some or all of the genes listed in Table 1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of Cockayne syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. Note: Several pathogenic variants have been detected in the noncoding region of ERCC8 that may be detectable by genome sequencing [Laugel et al 2010, Schalk et al 2018].

Note: If exome sequencing is not diagnostic, an exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Cockayne Syndrome

Gene 1, 2Proportion of Cockayne Syndrome Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 3 Identified by Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
ERCC6 ~65%90% 610% 6
ERCC8 ~35%88% 612% 6
1.

Genes are listed in alphabetic order.

2.

See Table A. Genes and Databases for chromosome locus and protein.

3.

See Molecular Genetics for information on variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.

6.

Laugel et al [2010], Calmels et al [2018], and data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

DNA repair assay. If the diagnosis of Cockayne syndrome is strongly suspected but molecular genetic testing does not identify pathogenic variants in one of the associated genes, an assay of the cellular phenotype can be considered.

Assays of DNA repair are performed on skin fibroblasts. The most consistent findings in CS fibroblasts are marked sensitivity to UV radiation and deficient recovery of RNA synthesis following UV damage (i.e., impaired repair of actively transcribed genes, or "transcription-coupled repair") [Nakazawa et al 2010].

Clinical Characteristics

Clinical Description

Cockayne syndrome is characterized by growth failure, microcephaly, neurodevelopmental delays, cutaneous photosensitivity, sensorial impairment, and dental anomalies [Laugel 2013].

Before the molecular genetics of Cockayne syndrome was understood, it was thought to have a single, discrete phenotype: classic Cockayne syndrome. Importantly, it is now recognized that Cockayne syndrome spans a continuous phenotypic spectrum without clear thresholds and includes the following but somewhat arbitrary subtypes [Nance & Berry 1992]. A quantitative severity scoring system has been designed to account for this continuous spectrum and to help clinicians follow the course of the disease in affected individuals [Spitz et al 2021].

  • CS type I, the "classic" form
  • CS type II, a more severe form with symptoms present at birth (overlapping with cerebrooculofacioskeletal syndrome [COFS])
  • CS type III, a milder form
  • Cerebrooculofacioskeletal (COFS) syndrome, the most severe end of the phenotypic spectrum of CS, with findings identifiable during fetal life

To date, hundreds of individuals have been identified with Cockayne syndrome and biallelic pathogenic variants in ERCC6 or ERCC8. The following description of the phenotypic features associated with this condition is based on these reports.

Table 2.

Cockayne Syndrome: Comparison of Phenotypes by Select Features

FeatureCS Type ICS Type IICS Type IIICOFS Syndrome
Typical age of onset Early childhood (age <2 years)At birth (severe)Late childhood (age >2 years)During fetal life
Growth failure Prenatal growth normal; onset of growth failure age <2 yearsOnset at birthLate childhood (age >2 years)Onset during fetal life
Photosensitivity Clinically variableClinically variableClinically variableClinically variable
Vision issues Cataracts, pigmentary retinopathy, optic atrophyCongenital cataracts , pigmentary retinopathy, optic atrophyCataracts, pigmentary retinopathy, optic atrophyCongenital cataracts, pigmentary retinopathy, optic atrophy
Hearing issues Progressive neurosensorial hearing lossProgressive neurosensorial hearing lossProgressive neurosensorial hearing lossProgressive neurosensorial hearing loss
Neurologic abnormalities Developmental delay, intellectual disability, cerebellar ataxia, spasticity, peripheral neuropathySevere developmental delay, severe intellectual disability, cerebellar ataxia, spasticity, peripheral neuropathyIntellectual disability, dementia, cerebellar ataxia, spasticity, peripheral neuropathyArthrogryposis, severe developmental delay, cerebellar ataxia, spasticity, peripheral neuropathy
Skin cancer predisposition NoneNoneNoneNone
Progression Progresses throughout childhoodAlmost no psychomotor developmentProgresses throughout childhood & adulthoodAlmost no psychomotor development
Prognosis Death during 1st or 2nd decade (mean age 16 years)Death usually in 1st decade but prolonged survival possible in a few casesLong-term survival into adulthoodDeath usually in 1st decade but prolonged survival possible in a few cases
Typical facial appearance ("cachectic dwarfism" w/sunken eyes) Present in early lifePresent in early lifeMay appear progressively in late stagesDistinct morphologic features w/prominent nasal root & prominent metopic suture; no clear cachectic appearance in most cases

COFS = cerebrooculofacioskeletal syndrome; CS = Cockayne syndrome

CS Type I

Presentation. Prenatal 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 centile.

Progression. Progressive impairment of vision, hearing, and central and peripheral nervous system function leads to severe disability. Brain MRI reveals white matter dysmyelination and progressive cerebral and cerebellar atrophy. Photosensitivity is variable, 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, stooped standing posture, abnormal gait or inability to walk, ataxia, incontinence, tremor, abnormal or absent speech, seizures, weak cry / poor feeding (as an infant), muscle atrophy, and behavior abnormalities
  • Dermatologic. Anhidrosis, malar rash, thin dry hair [Frouin et al 2013]
  • Ophthalmologic. Enophthalmos, pigmentary retinopathy (60%-100%), abnormal electroretinogram, cataracts of various types (15%-36%), optic atrophy, miotic pupils, decreased or absent tears, strabismus, nystagmus, photophobia, narrowed retinal arterioles
  • Hearing. Sensorineural hearing loss
  • Dental. Absent or hypoplastic teeth, enamel hypoplasia, delayed eruption of deciduous teeth, and malocclusion. Enamel anomalies frequently lead to severe dental caries [Bloch-Zupan et al 2013].
  • Skeletal. Radiographic findings of thickened calvarium (due to microcephaly), sclerotic epiphyses, vertebral and pelvic abnormalities
  • Renal. Abnormal renal function, proteinuria, nephrotic syndrome, hyperuricemia, hypertension [Stern-Delfils et al 2020]
  • Endocrine. Undescended testes, delayed/absent sexual maturation, diabetes
  • Gastrointestinal. Elevated liver function tests, enlargement of liver or spleen, gastroesophageal reflux

Death typically occurs in the first or second decade. The mean age of death is 16 years, although survival into the third decade has been reported [Natale 2011].

CS Type II

Children 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% of individuals. Affected individuals may have some contractures of the spine (kyphosis, scoliosis) and joints in neonatal or early postnatal life. Affected children typically die by age five years [Natale 2011]. CS type II partly overlaps with cerebrooculofacioskeletal (COFS) syndrome.

CS Type III

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 [Natale 2011, Baez et al 2013]. Major features only become apparent after age two years.

COFS Syndrome

COFS syndrome is the most severe subtype of the CS spectrum and can be identified during fetal life. Similar to individuals with CS type II, individuals with COFS syndrome present with severe prenatal growth failure, severe developmental delay / intellectual disability from birth, axial hypotonia, peripheral hypertonia, and neonatal feeding difficulties. COFS syndrome is additionally defined by the presence of arthrogryposis and usually the combination of extreme congenital microcephaly and congenital cataracts [Laugel et al 2008].

COFS syndrome can be recognized during prenatal surveillance and is responsible for cases of spontaneous fetal deaths.

Neuropathology

In all forms of Cockayne syndrome, 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, has been observed together with arteriosclerosis [Weidenheim et al 2009, Hayashi et al 2012].

Genotype-Phenotype Correlations

To date no clear genotype-phenotype correlations for ERCC6 or ERCC8 have been identified. In one study, individuals with pathogenic variants in ERCC8 appeared to have significantly less severe manifestations than ERCC6 at the time of the diagnosis [Spitz et al 2021].

For individuals with pathogenic variants in ERCC6, variants upstream of a transposon called PiggyBac transposable element-derived protein 3 in intron 5 of ERCC6 were found to be associated with less severe features than pathogenic variants downstream of that transposon insertion [Damaj-Fourcade et al 2022].

Nomenclature

The term "cerebrooculofacioskeletal (COFS) syndrome" and its former synonym, Pena-Shokeir syndrome type II, have been used to refer to a heterogeneous group of disorders characterized by congenital neurogenic arthrogryposis (multiple joint contractures), microcephaly, microphthalmia, and cataracts. The original cases of COFS syndrome, described by Pena & Shokeir [1974] among First Nations families from Manitoba, have since been shown to be homozygous for a pathogenic variant in ERCC6. COFS syndrome is now regarded as a prenatal form of CS, partly overlapping with CS type II and including the most severe cases of the CS phenotypic spectrum [Laugel et al 2008].

Prevalence

The minimum incidence of CS has been estimated at 2.7 in 1 million births in Western Europe; the disease is probably underdiagnosed [Kleijer et al 2008].

Differential Diagnosis

The differential diagnosis of Cockayne syndrome (CS) depends on the presenting features of the 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.

Table 4.

Disorders to Consider in the Differential Diagnosis of Cockayne Syndrome

Gene(s)DisorderMOIKey Feature(s) Overlapping w/CSDistinguishing Features
PLP1 Severe "connatal" Pelizaeus-Merzbacher disease (See PLP1 Disorders.) 1XLWhite matter abnormalities & growth restrictionSevere growth failure & distinctive physical appearance in CS
ATR
CPAP (CENPJ)
CEP152
CEP63
DNA2
NSMCE2
RBBP8 (CTIP)
TRAIP		Seckel syndrome (OMIM PS210600)ARProfound growth restrictionDistinctive physical appearance in CS
BRD4
HDAC8
NIPBL
RAD21
SMC1A
SMC3 		Cornelia de Lange syndrome AD
XL
CREBBP
EP300 		Rubinstein-Taybi syndrome AD
POLR3A Wiedemann-Rautenstrauch syndrome (OMIM 264090)AR
Genetically heterogeneous 2 Silver-Russell syndrome See footnote 2.
ANAPC1
RECQL4 		Rothmund-Thompson syndrome ARProminent photosensitivity &/or thinning of skin & hairWhite matter abnormalities, brain calcifications, ataxia, spasticity, & neurodegenerative features in CS
BLM Bloom syndrome AR
DDB2
ERCC1
ERCC2
ERCC3
ERCC4
ERCC5
POLH
XPA
XPC 		Xeroderma pigmentosum AR
LMNA Hutchinson-Gilford progeria syndrome AD
WRN Werner syndrome AR
>350 genes 3 Primary mitochondrial disorders AD
AR
Mat
XL		Early presence of pigmentary retinopathy, brain calcifications, & neurodegenerationSkin photosensitivity & distinctive physical appearance in CS
RAB3GAP1
RAB3GAP2
RAB18
TBC1D20 		RAB18 deficiency (molecular deficit underlying both Warburg micro syndrome & Martsolf syndrome)ARMicrocephaly, microcornea, & cataracts (RAB18 deficiency may resemble CS type II / COFS syndrome at birth)RAB18 deficiency is not assoc w/rapidly progressive neurodegeneration & has normal DNA nucleotide excision repair.
MORC2 MORC2-related disorder 4ADClinical presentation is very similar to CS in some persons & can incl microcephaly, growth restriction, & neurodevelopmental delays.Normal DNA nucleotide excision repair & no skin photosensitivity

AD = autosomal dominant; AR = autosomal recessive; COFS = cerebrooculofacioskeletal syndrome; CS = Cockayne syndrome; Mat = maternal; MOI = mode of inheritance; XL = X-linked

1.

Most leukodystrophies are not associated with growth restriction, with the exception of the severe or "connatal" form of Pelizaeus-Merzbacher disease, in which children may have short stature and poor weight gain.

2.

Genetic testing confirms clinical diagnosis in approximately 60% of affected individuals. Hypomethylation of the imprinted control region 1 (ICR1) at 11p15.5 causes Silver-Russell syndrome (SRS) in 35%-50% of individuals, and maternal uniparental disomy causes SRS in 7%-10% of individuals. Accurate assessment of SRS recurrence requires identification of the causative genetic mechanism in the proband.

3.
4.

Other disorders and acquired conditions include the following:

  • Profound growth restriction is seen in Dubowitz syndrome (OMIM 223370) and Hallerman-Streiff syndrome (OMIM 234100). However, neither disorder is associated with the distinctive physical appearance observed in individuals with CS. The genetic causes of Dubowitz syndrome and Hallerman-Streiff syndrome are unknown.
  • Calcifications on brain imaging can be associated with congenital infections (e.g., rubella or toxoplasmosis) and disorders of calcium and phosphate metabolism. These conditions are distinguished from CS by the absence of white matter abnormalities and the distinctive physical appearance observed in individuals with CS.
  • Growth restriction can also be seen in chromosome disorders and endocrine, metabolic, or gastrointestinal disorders, including malnutrition.

Management

No clinical practice guidelines for Cockayne syndrome (CS) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CS, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for CS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).

Table 6.

Cockayne Syndrome: Treatment of Manifestations

Manifestation/ConcernTreatment
Poor growth
  • Feeding support
  • Gastrostomy tube placement as needed. Note: Avoid rapid ↑ in volume of feeds.
Developmental delay /
Intellectual disability 		See Developmental Delay / Intellectual Disability Management Issues.
Tremor Consider treatment of tremor (carbidopa-levodopa 1) & spasticity (baclofen) if needed.
Spasticity
  • PT to prevent joint contractures
  • Home safety assessments to prevent falls
Abnormal vision &/or cataracts
  • Standard treatment(s) per ophthalmologist
  • Use of sunglasses for lens & retina protection
Hearing loss
  • Hearing aids may be helpful per otolaryngologist.
  • Cochlear implants may be used. 2
Dental caries Aggressive dental care to minimize caries
Cutaneous photosensitivity Use of sunscreens & limitation of sun exposure
Hypertension Amlodipine, ACE inhibitor
Gastroesophageal reflux Proton pump inhibitor

PT = physical therapy

1.
2.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine if any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be reassessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses or feeding refusal that is not otherwise explained. Assuming that the individual is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Social/Behavioral Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended. Yearly assessment for known potential complications (e.g., hypertension, renal or hepatic dysfunction, declining vision and hearing) is appropriate [Laugel 2013, Wilson et al 2015].

Agents/Circumstances to Avoid

Excessive sun exposure should be avoided.

Use of metronidazole should be avoided in any circumstance (risk of severe hepatitis) [Wilson et al 2015].

Extra vigilance is needed for opioid and sedative use due to exaggerated response to these types of medications [Wilson et al 2016].

Growth hormone (GH) levels in individuals with CS may be elevated or decreased [Park et al 1994, Hamamy et al 2005]. While individuals with CS do not appear to be at increased risk for 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.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

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].

In pregnant women 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 pregnancy outcome. Prevention of premature labor and cesarean section under spinal anesthesia are usually needed [Lahiri & Davies 2003, Rawlinson & Webster 2003].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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. There is currently no therapy that has been proved useful in this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Cockayne syndrome (CS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are presumed to be heterozygous for an ERCC6 or ERCC8 pathogenic variant.
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CS-related pathogenic variant and to allow reliable recurrence risk assessment.
  • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
    • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
    • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for a CS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Affected sibs will most likely be recognizable as affected within the first few years of life.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

  • Individuals with CS types I or II are not known to reproduce.
  • The offspring of an individual with CS type III are obligate heterozygotes (carriers) for a pathogenic variant in ERCC6 or ERCC8.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ERCC6 or ERCC8 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the ERCC6 or ERCC8 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
  • Carrier testing should be considered for the reproductive partners of individuals known to be heterozygous for a CS-related pathogenic variant, particularly if both partners are of the same ancestral background. ERCC6 and ERCC8 founder variants have been identified in some populations (see Table 8).

Prenatal Testing and Preimplantation Genetic Testing

Once the CS-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Amy and Friends
    United Kingdom
    Email: info@amyandfriends.org
  • Amy and Friends
    Netherlands
  • Cockayne Syndrome Network
    Phone: 703-727-0404; 865-466-4634
    Email: cockaynesyndrome@gmail.com
  • L’Association Les P’tits Bouts
    France
    Phone: 06 81 82 28 03
  • MedlinePlus
  • NCBI Genes and Disease
  • Xeroderma Pigmentosum Society, Inc (XP Society)
    XP Society has material on their site related to UV protection/avoidance.
    Phone: 877-XPS-CURE (877-977-2873); 518-851-2612
    Email: xps@xps.org
  • GenIDA (Genetically determined Intellectual Disabilities and Autism Spectrum Disorders) Registry
    A website for patients, families, and professionals; GenIDA hosts a specific registry for Cockayne syndrome.
    Email: genida@igbmc.fr
  • Myelin Disorders Bioregistry Project
    Phone: 215-590-1719
    Email: sherbinio@chop.edu

Molecular Genetics

Information 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 Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ERCC6 10q11​.23 DNA excision repair protein ERCC-6 ERCC6 database ERCC6 ERCC6
ERCC8 5q12​.1 DNA excision repair protein ERCC-8 ERCC8 database ERCC8 ERCC8

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Cockayne Syndrome (View All in OMIM)

133540COCKAYNE SYNDROME B; CSB
216400COCKAYNE SYNDROME A; CSA
609412ERCC EXCISION REPAIR 8, CSA UBIQUITIN LIGASE COMPLEX SUBUNIT; ERCC8
609413ERCC EXCISION REPAIR 6, CHROMATIN REMODELING FACTOR; ERCC6

Molecular Pathogenesis

The 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.

ERCC6 encodes DNA excision repair protein ERCC-6, which has 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.

ERCC8 encodes DNA excision repair protein ERCC-8, which is a WD repeat (tryptophan aspartate repeats) protein component of a large cullin4-mediated E3 ubiquitin ligase complex.

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, it has been suggested that CS proteins have other functions, including roles in transcription reinitiation after genotoxic stress [Epanchintsev et al 2017], repair of oxidative DNA damage [Nardo et al 2009, Ranes et al 2016], and mitochondrial metabolism [Kamenisch & Berneburg 2013, Chatre et al 2015, Scheibye-Knudsen et al 2016].

Mechanism of disease causation. Loss of function

Table 8.

Pathogenic Variants Referenced in This GeneReview by Gene

Gene 1Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]

ERCC6 		NM_000124​.3
NP_000115​.1 		c.1034_1035insTp.Lys345AsnfsTer24Founder variant in Druze population
c.3862C>Tp.Arg1288TerAssoc w/COFS; founder variant in Finnish population [Jaakkola et al 2010, Laugel et al 2010]
c.2709+1G>T--Founder variant in Amish population
ERCC8 NM_000082​.3
NP_000073​.1 		c.966C>Ap.Tyr322TerFounder variant in Arab population [Khayat et al 2010, Chebly et al 2018]

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Genes from Table 1 are in alphabetic order.

Chapter Notes

Author Notes

Vincent Laugel (rf.gruobsarts-urhc@legual.tnecniv) is actively involved in clinical research regarding individuals with Cockayne syndrome (CS). He would be happy to communicate with persons who have any questions regarding diagnosis of CS or other considerations.

Dr Laugel is also interested in hearing from clinicians treating families affected by DNA repair and transcription disorders in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr Laugel to inquire about review of ERCC6 and ERCC8 variants of uncertain significance.

Acknowledgements

The author wishes to thank "Amy and friends" and "Les P'tits Bouts" family support groups for continuous support.

Author History

Vincent Laugel, MD, PhD (2012-present)
Martha A Nance, MD; Park Nicollet Clinic (2000-2006)
Edward G Neilan, MD, PhD; Children's Hospital Boston (2006-2012)

Revision History

  • 29 August 2024 (gm) Comprehensive update posted live
  • 29 August 2019 (ha) Comprehensive update posted live
  • 14 June 2012 (me) Comprehensive update posted live
  • 7 March 2006 (me) Comprehensive update posted live
  • 31 July 2003 (me) Comprehensive update posted live
  • 28 December 2000 (me) Review posted live
  • June 2000 (mn) Original submission

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