Genetics of Cockayne Syndrome

Cockayne syndrome (CS) refers to the spectrum that includes:

• Cockayne syndrome type I, the classic form (also referred to as the moderate form)
• Cockayne syndrome type II, a more severe form with symptoms present at birth; the clinical features of Cockayne syndrome type II overlap with those of cerebro-oculo-facio-skeletal (COFS) syndrome, which is also called Pena-Shokeir syndrome type II
• Cockayne syndrome type III, a milder form
• Xeroderma pigmentosa–Cockayne syndrome (XP-CS).

However, the discussion in this article is limited to Cockayne syndrome types I and II, also termed Cockayne syndrome types A and B, respectively.

Cockayne syndrome type I (CKN1; Online Mendelian Inheritance in Man [OMIM] number 216400) and Cockayne syndrome type II (CSB; OMIM number 133540) are rare autosomal recessive disorders that feature growth deficiency, neurologic dysfunction, premature aging, and pigmentary retinal degeneration, along with a complement of other clinical findings. Cockayne syndrome type II presents at birth, with death within the first decade, whereas Cockayne syndrome type I appears during early childhood, with death occurring in early adolescence, although there are reports of some patients surviving until early adulthood. Cockayne syndrome was first reported in 1936, by Edward Alfred Cockayne.[1]

Cockayne syndrome type I is characterized by normal growth parameters at birth. However, within the first 2 years of life, growth and development become abnormal and continue to progress as such. Height, weight, and head circumference fall below the fifth percentile, while impairment of vision, hearing, and neurologic function leads to severe disability. The characteristic physical appearance of cachectic dwarfism, with thinning of the skin and hair, sunken eyes, and a stooped standing posture, illustrates the aging process. Pathologic studies reveal diffuse and extensive demyelination in the central and peripheral nervous systems. Patients demonstrate pericapillary calcifications in the cortex and basal ganglia at an early age; severe neuronal loss in the cerebral cortex and cerebellum also occurs. These changes correlate with the physiologic changes of aging and the significant degree of neurologic dysfunction. Pigmentary retinopathy, photosensitivity, and other features, such as dental anomalies, vision loss, and hearing loss, also occur. 

Cockayne syndrome type II is referred to as severe Cockayne syndrome. Children with this condition are found at birth to have growth failure. Neurologic development is static, with very little progress. Contractures of the spine and joints, known as arthrogryposis, are present. Other features overlap with those of Cockayne syndrome type I. Death occurs on average by age 7 years. 

Frequency

United States

The incidence of Cockayne syndrome is estimated to be 2.7 cases per million births in the United States and Western Europe.[2]

International

Similarly, a study by Kubota et al found the incidence of Cockayne syndrome in Japan to be an estimated 2.77 cases per million births.[3]  There have also been reported areas in Israel with high carrier rates.[2]

Mortality/Morbidity

Patients are at risk for postnatal growth failure, neurologic deterioration, pigmentary retinal degeneration, and premature death before adulthood. Details are as follows:

• Postnatal growth failure - Profound growth failure begins within the first year of life. Weight is affected more than length, and cachectic dwarfism results, with microcephaly; a rare subset of patients, classified as having severe Cockayne syndrome type II, have low birth weight with almost no postnatal growth

• Neurologic deterioration - Deterioration of the central and peripheral nervous system leads to spasticity, ataxia, tremor, seizures, intellectual disabilities, muscle atrophy, and weak cry and feeding

• Pigmentary retinal degeneration - This diagnostic criterion for Cockayne syndrome type I (salt-and-pepper appearance in the retinas) develops later in childhood; cataracts are the second most common eye finding

• Premature death - The characteristic appearance of aging in children with Cockayne syndrome is striking; the mean and median age of death is 12 years, and most patients die as a result of pneumonia or other respiratory infections

Race

Cockayne syndrome type I is panethnic.

Sex

The male-to-female ratio is 1:1, which is consistent with an autosomal recessive disorder. The pattern of autosomal recessive inheritance is illustrated in the image below.

Autosomal recessive inheritance pattern.

Age

This is a progressive congenital genetic disorder. Cockayne syndrome type I usually becomes evident within the first 2 years of life, when growth and development are notably delayed. Cockayne syndrome type II is usually evident at birth, with growth delays, lack of developmental progress, and congenital cataracts.[4]

In persons with Cockayne syndrome type I, the mean age of death is 12 years, with very few individuals surviving into the third decade.  In the type II form, the mean age of death is 7 years.[2]

Patients with Cockayne syndrome (CS) present with delayed psychomotor development, growth failure, poor feeding, photosensitive rashes, and cataracts.

• Delayed psychomotor development - All patients with Cockayne syndrome type I have intellectual disability and developmental delays. The delay becomes apparent early when motor milestones are not met on time.  

• Growth failure - This is notable within the first 2 years of life in Cockayne syndrome type I and at birth in the type II syndrome; height, weight, and head circumference fall below normal and eventually end up below the fifth percentile. 

• Poor feeding - Some patients present during infancy with weak or poor feeding; however, the diagnosis is usually not made at this time.

• Photosensitive rashes - More than 75% of patients have photosensitivity. Other skin findings include decreased amounts of subcutaneous tissue, dry scaly skin, and thin dry hair.

• Cataracts - The presence of cataracts in children younger than 3 years is associated with the severe form of Cockayne syndrome type I, which demonstrates a poorer prognosis and results in death at an earlier age.[2]

In the first year, all patients with Cockayne syndrome type 1 demonstrate growth failure, which includes progressive microcephaly in most patients.

• Neurologic examination shows increased or decreased muscle tone and reflexes. Ambulant patients present with an unusual gait resulting from leg spasticity, ataxia, and contractures of the hips, knees, and ankles.

• Pigmentary degeneration of the retina is one hallmark of this disorder, with cataracts and optic atrophy or optic disk pallor as frequent findings.

• Ophthalmologic changes are progressive.

• More than one half of patients with Cockayne syndrome type I have mild-to-severe sensorineural hearing loss.

• Many patients have moderate-to-severe dental caries; permanent teeth have short roots.

• Most patients have photodermatitis that leads to dry scaly skin. Patients develop an aged appearance as a result of the disease process.

• Major structural anomalies of the renal system rarely occur. Some patients develop decreased creatinine clearance but usually do not require medical treatment.

• Cryptorchidism or testicular hypoplasia affects approximately one third of males. Females have menses, although cycles are irregular. Puberty may be delayed in both sexes.

Cockayne syndrome type I is caused by a defect in the Cockayne syndrome type A gene (CSA or ERCC8), located on chromosome 5.[5] Affected persons inherit two mutant genes, one from each parent, with ERCC8 mutations accounting for about 35% of Cockayne syndrome cases.[4]  Cells carrying ERCC8 mutations are hypersensitive to ultraviolet (UV) light. They do not recover the ability to synthesize RNA after exposure to UV light. In addition, the cells cannot remove and degrade DNA lesions from strands that have active transcription.

Mutations in the DNA excision repair gene ERCC6 located on band 10q11 cause Cockayne syndrome type II (MIM number 133540; CSB).[6, 7] These mutations account for about 65% of Cockayne syndrome cases.[4]  This gene encodes helicase, a protein that is presumed to have DNA unwinding function.[1]

No genotype-phenotype correlation is known.[4]  ERCC8 and ERCC6 are believed to code for DNA excision repair proteins.

A thorough evaluation is recommended for anyone who is suspected of having Cockayne syndrome to confirm the diagnosis, exclude other possible diagnoses, and establish the extent of the disease. The evaluation includes the following:

• Genetic evaluation
• Developmental evaluation
• Ophthalmologic evaluation
• Neurologic evaluation
• Gastrointestinal evaluation with a nutritionist
• Audiologic evaluation
• Dermatologic evaluation
• Dental evaluation

Unless the clinical suspicion is confirmed, it is difficult to offer the appropriate genetic counseling, discuss associated morbidities and mortality, and refer the patient to available subspecialists and Cockayne syndrome support groups.  

In patients with suspected Cockayne syndrome (CS), perform routine laboratory tests to exclude other disorders and to establish baseline renal function.

For growth failure, request chromosome analysis and chromosome microarray testing to exclude any karyotypic abnormalities. An endocrine evaluation may be helpful to determine any hormonal causes of growth failure, and baseline metabolic studies are useful.

Request chromosome breakage studies if considering Bloom syndrome in the differential diagnosis. Patients with xeroderma pigmentosum (a differential diagnosis for Cockayne syndrome type 1 and Bloom syndrome demonstrate clinical phenotypes that overlap with those found in patients with Cockayne syndrome. Chromosome breakage studies and DNA mutation analysis are necessary to exclude Bloom syndrome and xeroderma pigmentosum.

Cultured skin fibroblasts of patients with Cockayne syndrome type I lack the ability to form colonies when subjected to UV irradiation. Very few laboratory personnel have expertise in this technique, and, given the availability of genetic testing, skin biopsy and analysis have become less important and/or useful.

Mutational analysis of the genes ERCC8 and ERCC6, associated with Cockayne syndrome, are available at a few clinical laboratories across the country.

Computed tomography (CT) or magnetic resonance imaging (MRI) scan findings include increased ventricular size, cerebral atrophy, white matter abnormalities, and normal pressure hydrocephaly.

Skeletal radiographs depict vertebral body and pelvic abnormalities.

Additional tests include the following:

• Audiometry - Used to determine if sensorineural hearing loss has occurred
• Electroencephalography - Used to assess the patient for seizure activity
• Nerve conduction studies - Used to evaluate for the presence of a demyelinating neuropathy
• Electroretinography - Reveals abnormalities in the electric potential of the retina

Ocular histopathologic findings indicate degeneration of all retinal layers. Pigment migrates into the photoreceptor layer. Nerve fiber bundles of the optic nerve head become markedly thin, while partial demyelination of the remaining nerves occurs.

For patients with sensorineural hearing loss, a significant loss of neurons occurs in the spiral ganglion and brainstem, with retrograde atrophy of the auditory pathways.

Treatment of patients with Cockayne syndrome type I depends solely on the presenting symptoms.

Developmental evaluations will allow the individual to receive appropriate services through their county as well as an individualized educational program. Various management strategies include the following:

• Physical therapy - Helps to prevent contractures and maintain ambulation
• Feeding therapy - Including consideration of gastrostomy tube for failure to thrive
• Management of hearing loss - Ie, hearing aids or other devices, if necessary
• Evaluation for and, if necessary, treatment of cataracts
• Administration of antiseizure and antispasticity medications, if necessary
• Limitation of UV radiation exposure - Sunscreen should be applied liberally, and excessive sun exposure should be avoided; sunglasses will help with the photosensitivity of the eyes

No special diet alters the prognosis. A gastrostomy tube may prevent malnutrition in patients who feed poorly.

Physical therapy is essential to enable patients to avoid joint contractures and prolong ambulation.

Evaluations provided yearly, at minimum, are required to assess for known complications or worsening status neurologically, audiologically, and visually.

Drug therapy may be important to aid in the management of spasticity, tremor, and seizures.

Outpatient care includes the following:

• Monitoring patients for hypertension, renal pathology, hearing loss, and dental caries

• Administering physical therapy to delay the onset of joint contractures

• Providing yearly evaluations of neurologic function

• Providing ophthalmologic assessments

See the list below:

• Use of a gastrostomy tube may prevent malnutrition in patients with Cockayne syndrome (CS) who feed poorly.

Advise patients to avoid excessive sun exposure and to use sunscreen liberally when outdoors.

Complications of Cockayne syndrome include the following:

• Intellectual disability

• Developmental delays

• Growth failure

• Progressive pigmentary retinopathy and/or cataracts

• Sensorineural hearing loss

• Joint contractures, ataxia, tremor, seizures and/or spasticity

• Hypertension

• Photosensitivity

• Premature death

Cockayne syndrome type I is an autosomal recessive disorder resulting in growth failure and progressive neurologic dysfunction; death usually occurs during adolescence, but survival into adulthood is possible. In Cockayne syndrome type II, a more severe condition, death occurs in the first decade.

Recommend genetic counseling, because each sibling subsequently born to the parents of an affected child will have a 25% risk of having Cockayne syndrome. Reproduction has not been reported in anyone with known Cockayne syndrome type I or II.

If the disease-causing mutations have been identified in an affected individual, subsequent pregnancies can be tested to determine the status. Such testing can be offered via pre-implantation genetic diagnosis, which is performed prior to conception, or prenatally via chorionic villus sampling or amniocentesis.

Cultured cells obtained from patients with Cockayne syndrome are hypersensitive to the lethal effects of UV radiation. Also, the normal recovery in DNA and RNA synthesis after UV exposure does not occur in those cells. Measuring RNA synthesis and the secondary DNA synthesis of cultured amniocytes after irradiation with UV light has been successful in the prenatal diagnosis of Cockayne syndrome in countries where genetic testing is not available or in those families in whom the disease-causing mutations have not been identified.

Advise parents that treatment is supportive and based on symptoms.

Optimize neurologic and neurosensory abilities in the patient.

Provide contact information for the Share & Care Cockayne Syndrome Network so that the patient's family can utilize community support.