Cockayne syndrome

Overview

Cockayne syndrome (CS) is a rare, autosomal recessive genetic disorder characterized by impaired growth, neurological dysfunction, premature aging (progeria), and extreme sensitivity to sunlight (photosensitivity). Unlike some other DNA repair disorders, individuals with Cockayne syndrome do not have a significantly increased risk of cancer. The condition is progressive and typically presents in early childhood, although severity and age of onset can vary. It is classified into three types based on clinical severity: CS type I (classic), CS type II (severe, congenital), and CS type III (mild, late-onset).

Causes

Cockayne syndrome is caused by mutations in the ERCC6 (also known as CSB) or ERCC8 (also known as CSA) genes. These genes are involved in the transcription-coupled nucleotide excision repair (TC-NER) pathway, which repairs DNA damage that blocks transcription. Mutations in these genes result in an inability to properly repair DNA damage, especially from ultraviolet (UV) light, leading to cell dysfunction and premature cell death. Both parents must carry a mutated copy of the gene for a child to be affected (autosomal recessive inheritance).

Symptoms

Symptoms of Cockayne syndrome vary in severity but commonly include:

• Growth failure: Intrauterine growth retardation and poor postnatal growth

• Neurological abnormalities: Progressive microcephaly, intellectual disability, developmental delay, and sensorineural hearing loss

• Photosensitivity: Severe sensitivity to sunlight, often resulting in burns or skin damage without tanning

• Vision problems: Cataracts, retinal degeneration, and optic atrophy

• Facial features: A characteristic appearance with a thin, aged face, deep-set eyes, and a small head

• Dental abnormalities: Including delayed tooth eruption and dental caries

• Premature aging: Loss of subcutaneous fat, hair thinning, and joint contractures

• Feeding difficulties and cachexia: Due to neurological decline

• Motor dysfunction: Ataxia, spasticity, and tremors

Diagnosis

Diagnosis of Cockayne syndrome is based on clinical features, supported by laboratory and genetic testing. Steps include:

• Clinical evaluation: Based on growth patterns, neurological signs, and photosensitivity

• Genetic testing: To identify mutations in the ERCC6 or ERCC8 genes

• Cellular studies: Skin fibroblast cultures show hypersensitivity to UV light and defective transcription-coupled DNA repair

• Neuroimaging: MRI may show brain atrophy, calcifications, and white matter abnormalities

• Ophthalmologic and audiologic exams: To assess vision and hearing loss

Treatment

There is currently no cure for Cockayne syndrome. Treatment is supportive and focuses on managing symptoms and improving quality of life. Common strategies include:

• Sun protection: Use of protective clothing, sunglasses, and broad-spectrum sunscreen to prevent UV-related skin damage

• Physical and occupational therapy: To maintain mobility and manage contractures

• Speech and developmental therapy: To support communication and cognitive skills

• Nutritional support: Including feeding tubes if needed to address malnutrition

• Vision and hearing aids: To assist with sensory deficits

• Regular medical monitoring: For complications such as infections, neurological decline, and cataracts

Prognosis

The prognosis for Cockayne syndrome depends on the severity of the condition. Type I (classic form) typically leads to death in the second or third decade of life, often due to infections or neurological decline. Type II (congenital form) is more severe, with many affected children dying in infancy or early childhood. Type III (mild form) allows for longer survival into adulthood but with significant disability. While life expectancy is reduced, early intervention and supportive care can improve quality of life and reduce complications.