Cockayne Syndrome

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;
• 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 the identification of biallelic pathogenic variants in ERCC6 or ERCC8 on 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. At conception, each sib of an affected individual has 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. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the ERCC6 or ERCC8 pathogenic variants in the family are known.

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 cerebellar atrophy [Koob et al 2010, Koob et al 2016]. Intracranial calcifications (mainly located in the basal ganglia) are seen in some individuals.

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 and tooth 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 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 prenatal microcephaly are associated with arthrogryposis and congenital cataracts as well as other structural defects of the eye (microphthalmos, microcornea, iris hypoplasia).

Establishing the Diagnosis

The diagnosis of Cockayne syndrome is established in a proband by identification of biallelic pathogenic variants in ERCC6 or ERCC8 on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Cockayne syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Cockayne syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Before 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 continuous phenotypic spectrum without clear thresholds, and includes the following [Nance & Berry 1992]:

• 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

Genotype-Phenotype Correlations

To date no genotype-phenotype correlations for ERCC6 or ERCC8 have been clearly identified.

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 native Canadian families from Manitoba, have since been shown to be homozygous for a pathogenic variant in ERCC6. COFS syndrome is now regarded as an allelic and 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 per million births in western Europe; the disease is probably underdiagnosed [Kleijer et al 2008].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Cockayne syndrome (CS), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations