Cockayne syndrome is a rare genetic disorder that affects multiple body systems and includes features of premature aging. The disorder is estimated to affect 2 to 3 per million newborns in the United States and Europe. Signs of the condition become apparent in infancy and progress over time.
Genetic Origins of Cockayne Syndrome
Cockayne syndrome arises from mutations in the ERCC6 gene (also known as CSB) or, less frequently, the ERCC8 gene (CSA). These genes provide instructions for proteins involved in a DNA repair process called transcription-coupled nucleotide excision repair (TC-NER). This pathway removes DNA damage, like that from ultraviolet (UV) radiation, from active genes.
When a mutation occurs in these genes, the resulting protein is non-functional or has reduced function, which disrupts the TC-NER pathway. Consequently, DNA damage accumulates within active genes, leading to cell malfunction and death. This accumulation of unrepaired DNA is thought to cause the syndrome’s various features.
The condition is inherited in an autosomal recessive pattern. This means an affected individual must inherit two mutated copies of the gene, one from each parent. The parents, known as carriers, each carry one copy of the mutated gene and typically do not show signs or symptoms of the disorder.
Identifying the Symptoms and Features
The clinical presentation of Cockayne syndrome is a spectrum of features affecting growth, development, and physical appearance. One of the earliest signs is a failure to grow at the expected rate after birth, leading to short stature and an abnormally small head size (microcephaly). This is accompanied by significant developmental delays that become more apparent over time.
A distinct facial appearance develops, giving a “prematurely aged” look. This is caused by the loss of subcutaneous fat, which results in sunken eyes and thin, wrinkled skin. The face may also appear narrow with a thin, beaked nose, which combined with the small head size and large-appearing ears, contributes to a characteristic appearance.
Progressive neurological problems are a central part of the disorder. Demyelination, the loss of the protective fatty sheath around nerve fibers, leads to worsening neurological function. This can manifest as problems with balance and coordination (ataxia), tremors, jerky movements, and progressive intellectual disability.
Sensory impairments are also prevalent. Progressive sensorineural hearing loss is a frequent finding. Vision problems are also common and can include the development of cataracts, which is a clouding of the lens of the eye, and pigmentary retinopathy, a condition affecting the light-sensing tissue at the back of the eye. Another feature is photosensitivity, where the skin reacts severely to even minimal sun exposure, resulting in bad sunburns or blistering.
The severity and age of onset of symptoms are used to classify Cockayne syndrome into different types. Type I, the classic form, presents within the first two years of life. Type II is a more severe, congenital form with symptoms apparent at birth and little to no neurological development postnatally. Type III is a milder, later-onset form that is less common.
The Diagnostic Process
The diagnosis of Cockayne syndrome begins with a physician’s recognition of its characteristic clinical features. A pattern of postnatal growth failure, progressive neurological issues, and the distinct facial appearance prompts suspicion. The progressive nature of the condition means the clinical picture becomes clearer as more symptoms develop.
To confirm a suspected diagnosis, specific laboratory tests are performed. The most definitive method is molecular genetic testing, which analyzes DNA from a blood sample to identify mutations in the ERCC6 or ERCC8 genes. Identifying mutations on both copies of one of these genes establishes the diagnosis. Testing may involve sequencing the two known genes or using a broader multigene panel.
If genetic testing is inconclusive but suspicion remains high, a functional test using skin cells can be performed. This involves taking a small skin biopsy and growing the cells, called fibroblasts, in a laboratory. The fibroblasts are then exposed to UV radiation, and their ability to repair the resulting DNA damage is measured. A deficient recovery of RNA synthesis in these cells after UV exposure confirms a defect in the transcription-coupled repair pathway.
Management and Supportive Care
There is no cure for Cockayne syndrome, so treatment is focused on managing symptoms and providing supportive care to improve quality of life. This requires a multidisciplinary team of specialists to address the wide range of health issues, including pediatricians, neurologists, ophthalmologists, audiologists, and dentists.
A primary management strategy is rigorous protection from sunlight due to severe photosensitivity. This includes using high-SPF sunscreens, wearing protective clothing like hats and long sleeves, and avoiding sun exposure during peak hours. Some families may install UV-filtering films on home and car windows.
Nutritional support is another important aspect of care, as many individuals experience feeding difficulties that contribute to growth failure. A high-calorie diet may be recommended, and in cases of severe feeding problems, a gastrostomy tube (G-tube) may be surgically placed to deliver nutrition directly to the stomach. Other therapies are used to manage specific symptoms:
- Physical and occupational therapies to help maintain mobility and prevent joint stiffness.
- Hearing aids or cochlear implants for hearing loss.
- Surgical removal of cataracts to address vision problems.
- Regular dental care to manage the high risk of severe tooth decay.