Cockayne Syndrome

Etiology

Cockayne syndrome is an autosomal recessive rare genetic disorder associated with mutations in ERCC genes. Based on the affected gene, this syndrome encompasses 2 complementation groups—CSA and CSB. Eighty percent of affected patients appear to be in the CSB complementation group, involving the ERCC6 gene on band 10q11 or the CSB gene. The remaining cases are in the CSA complementation group, involving the ERCC8 gene on band 5q12.1 or the CSA gene. To date, more than 30 CSA and 78 CSB mutations have been identified.

The participation of CSA and CSB proteins is essential for transcription-coupled repair (TCR), representing a subpathway within nucleotide-excision repair (NER). Alterations in the CSB gene result in the altered expression of antiangiogenic and cell cycle genes and proteins. A notable impact is observed on p21—an inhibitor of cyclin-dependent kinase—that links DNA damage to cell cycle arrest. This impact has the potential to hinder cell cycle progression and growth. Another variant—the xeroderma pigmentosum-Cockayne syndrome overlap complex—emerges from mutations in distinct ERCC genes such as ERCC2, ERCC3, and XPD.[4][5][6] These genetic abnormalities lead to compromised DNA repair mechanisms and increased sensitivity to UV light and cause various cellular consequences, including reduced DNA and RNA synthesis, increased sister chromatid exchanges, and heightened chromosomal breaks. 

Epidemiology

Cockayne syndrome is a rare disorder with an unknown prevalence. The annual estimate in Europe is 1 case per 200,000 births.[4][5] No racial or sexual predilection has been reported for Cockayne syndrome. 

Pathophysiology

The underlying pathophysiology of Cockayne syndrome, as well as xeroderma pigmentosum and trichothiodystrophy, involves cellular sensitivity to UV irradiation due to a defect in DNA repair. These disorders arise from genetic defects that affect NER and RNA transcription. The NER pathway is involved in protection against UV-induced DNA damage. In individuals with Cockayne syndrome, the NER of most genomic DNA remains unaffected, thereby mitigating the heightened risk of skin cancer. Unlike xeroderma pigmentosum, which is associated with an increased risk of skin cancer, Cockayne syndrome and trichothiodystrophy do not exhibit such susceptibility. 

The CSA or CSB genes are necessary for the TCR pathway—a subtype of NER involved in repairing UV-induced DNA damage in actively transcribed genes. Individuals with Cockayne syndrome exhibit alterations in either the CSA or CSB genes.[4][7][8] Mutations in ERCC genes can cause defective DNA repair following exposure to UV radiation. However, the pathogenesis of this syndrome is more complicated, as changes can manifest at birth, even before UV exposure. Typically, the impact involves the nervous system, where cells have not encountered UV light exposure. 

Defects in the CSB gene lead to altered expression of antiangiogenic and cell cycle genes and proteins, potentially inhibiting cell cycle progression and growth. Cyclin-dependent kinase inhibitor 1 (p21) is notably affected and actively participates in repairing cellular damage caused by radiation-induced DNA damage. Cyclin-dependent kinase inhibitor 1 connects DNA damage to cell cycle arrest. Specifically, when exposed to UVB, p21 binds to proliferating cell nuclear antigen, hindering DNA replication and preventing entry into mitosis. This mechanism lowers the risk of malignancy, as cells undergoing apoptosis do not form tumors. The surviving cells display perfectly normal global genomic repair.

The severe developmental challenges are likely explained by endogenous oxidative damage in certain metabolically active cells, such as neurons, which obstruct transcription. The lack of TCR subsequently triggers apoptosis in these crucial cells. Researchers propose these alterations to elucidate the non-cutaneous symptoms of Cockayne syndrome that cannot be solely attributed to deficiencies in DNA repair. 

History and Physical

Classification

Although affected individuals typically appear normal at birth, the severity and age of onset age show significant variability across the clinical spectrum. Hence, researchers classify Cockayne syndrome into 3 types based on the age of presentation and clinical features, as mentioned below.

Cockayne syndrome type I: This is the most common form of Cockayne syndrome that manifests during childhood.

Cockayne syndrome type II: This type manifests at birth and presents with more severe symptoms compared to other types of the syndrome.

Cockayne syndrome type III: This type appears later in childhood but with less severe symptoms than other types of the syndrome.

In cases where Cockayne syndrome presents in adulthood, affected individuals may exhibit gait and cognitive impairments, chorea, and neuropathy. Neuroimaging might reveal global atrophy.

Clinical Features

Growth disorders and physical features: Progressive growth restriction occurs between the ages of 1 and 2 and is characterized by failure to thrive and microcephaly. As children age, they lose subcutaneous fat, resulting in a prematurely aged face and dysmorphic features such as prominent ears, sunken eyes, a beaked nose, and a cachectic body with thin, slender limbs.[3][9][10]

Neurological disorders and intellectual development: Neurological manifestations progress gradually and result from demyelination. Affected children may endure a range of symptoms, including progressive sensorineural hearing loss leading to profound deafness,[11] intellectual disabilities, difficulty walking, unsteady gait, poor balance, ataxia, tremors, spasticity in the lower limbs, constant flexure of the arms and legs, variations in muscle tone and reflexes, epilepsy in some cases, labored and unintelligible speech, and polyneuropathies—with sensorimotor demyelinating polyneuropathy being the most common.[3][12][10]

Skin Findings

Children with this condition exhibit thin and sensitive skin, making them susceptible to severe sunburns. Even minimal exposure to UV rays can lead to sunburns with subsequent scarring. The increased photosensitivity also impacts the eyes, with photosensitive eruptions presenting as erythema and scaling. The skin may also exhibit hyperpigmentation, telangiectasia, and atrophy. Subcutaneous lipoatrophy contributes to the development of sunken eyes and a prematurely aged progeric appearance. Common findings include cyanotic acral edema of the extremities, nail dystrophies, and hair anomalies.[13] 

Dental Abnormalities

The deciduous teeth may appear late and exhibit characteristics such as being small, irregular, and abnormally spaced. In certain instances, permanent teeth may not develop; when they do, they remain small or poorly implanted. Children affected by this condition are more prone to cavities than the average population.

Musculoskeletal

Children affected by Cockayne syndrome may display an atypical gait attributed to leg spasticity, ataxia, and contractures in the hips, knees, and ankles. Additional features include microcephaly, short stature, elongated limbs with joint contractures, oversized hands and feet, kyphosis, thickened calvariae, sclerotic epiphyses in the fingers, and possible osteoporosis.[9][10][14]

Ocular

Retinal degeneration, marked by pigmented retinopathy and optic atrophy, is common. Anophthalmia often arises due to losing the typical fat pad behind the eyeball. Observations may include miotic pupils, strabismus, cataracts, optic atrophy, corneal opacity, blepharokeratoconjunctivitis, and nystagmus.

The distinctive "salt and pepper pattern" in progressive retinal pigmentation is associated with Cockayne syndrome. Although vision is typically normal, the development of cataracts and optic nerve atrophy in pigmentary retinopathy can impair it. Moreover, the onset of uveitis or conjunctivitis may further exacerbate visual impairments.[10]

Fragile Livers

Cockayne syndrome can affect the liver and is primarily asymptomatic, manifesting as elevated plasma transaminase levels. Owing to several reported cases of hepatotoxicity in patients with Cockayne syndrome, methotrexate is contraindicated and should be avoided. Occasionally, hepatomegaly may be evident during physical examination.

Renal Disease

Renal disease, increased blood pressure, and hyperuricemia may also be present.[15]

Endocrine Dysfunction

Endocrine dysfunction in individuals can lead to a range of problems, including hypogonadism in males, which occurs in around 30% of cases, and irregular menses in females as a result of endocrine dysfunction.

Evaluation

Children with suspected Cockayne syndrome undergo a multidisciplinary evaluation, incorporating laboratory and imaging studies primarily to exclude other diagnoses. The comprehensive evaluation includes genetic, developmental, ophthalmological with electroretinography, neurological with electroencephalography and nerve conduction studies, gastrointestinal with a nutritionist, audiological with audiometry, dermatological, dental, endocrinology, and baseline and annual renal function studies.

The genetic evaluation includes chromosome analysis, chromosome microarray, chromosome breakage studies, mutational analysis of ERCC8 and ERCC6 genes, and cell culturing from amniotic fluid or skin biopsy.

Chromosome breakage studies and DNA mutation analysis are crucial for excluding Bloom syndrome and xeroderma pigmentosum. Cell fluid culturing is a means to conduct a prenatal or postnatal evaluation. This method illustrates the deficiency in RNA synthesis in fetal or the cells of a child following UV irradiation and measures the rate of DNA repair on fibroblasts. A biopsy of skin specimens is required to perform this technique. In cases of Cockayne syndrome, the test reveals a lower-than-normal repair rate.[16]

Cell fluid culturing, less commonly chosen due to the widespread availability of genetic testing for ERCC8 and ERCC6 variants, may not be readily available at most labs. An endocrinological evaluation is essential to rule out any hormonal causes of failure to thrive.

Computed tomography (CT) and magnetic resonance imaging (MRI) scans can unveil a range of changes, including central nervous system white matter demyelination, severe cerebral white matter atrophy, cerebellar atrophy, perivascular calcifications in the cerebellum and basal ganglia, patchy demyelination often referred to as "tigroid leukodystrophy," increased ventricular size, and normal pressure hydrocephaly.

Treatment / Management

The management of Cockayne syndrome is supportive and focuses on managing and preventing complications. The fundamental elements include sun protection for the skin and eyes, physical and occupational therapies, nutritional support, dental and eye care, hearing assessment, blood pressure monitoring, and routine monitoring of kidney and liver functions and blood sugar levels.[15][17]

Feeding Assistance

Many affected infants require feeding assistance in the initial months of life due to muscle weakness and neurological impairment. In some cases, the use of a nasogastric tube or even a gastrostomy may be deemed necessary.[12]

Treatment of Ocular Anomalies

Cataracts often develop by age 4 and can be treated through surgery to remove the opaque lens. In such surgeries, surgeons generally refrain from implanting a transparent artificial lens.

When strabismus is present, early intervention is crucial. Orthoptists play a key role in re-education sessions as a foundational aspect of the treatment. To encourage the affected eye to work, masking the healthy eye with an eye mask or an opaque eyeglass lens is utilized. In cases of persistent deviation, surgery may be required to remove or reduce the misalignment.[13]

Dental Care

Affected children should have regular dental evaluations due to their increased risk of dental caries. 

Prevention Against the Sun's Harmful Effects

Individuals affected by this condition should safeguard themselves from UV light exposure. Certain artificial lights, including neon and halogen, emit harmful UV radiation, requiring protection for affected individuals. Recommendations include wearing broad-brimmed hats, UV-resistant clothing with collars, and sunscreen with a sun protection factor of 50 or higher during outdoor activities and outings. This precaution is advisable even during winter or late afternoon when light intensity may appear lower. Furthermore, special glasses or a UV-filtering mask should be worn to protect the eyes.[13]

Additional Measures

As hearing disorders may necessitate an auditory prosthesis, it is crucial to incorporate auditory-verbal therapy along with the equipment to facilitate the acquisition of reading and writing.[12] Many patients typically require psychomotor rehabilitation and physiotherapy tailored to the extent of their impairment. Additional supportive equipment such as a corset, wheelchair, walker, or cane may be essential to maintain proper body positioning and facilitate movement.

Specific socio-educational support is essential for addressing intellectual disabilities, considering factors such as the child's personality, age, intellectual level, and behavioral characteristics. Psychological support is also crucial, and genetic counseling may be recommended for family members.[11][14][15][18] 

Medications

In managing Cockayne syndrome, a strategic approach involves considering specific medications such as carbidopa-levodopa for tremors and anti-seizure or antispasmodic medications based on individual indications. Notably, it is crucial to avoid metronidazole, as it is contraindicated.

Differential Diagnosis

The differential diagnosis is mainly with the other syndromes characterized by photosensitivity and premature aging.

• Xeroderma pigmentosum: Cockayne syndrome is distinguished from xeroderma pigmentosum by its unusual facies, demyelination with delayed nerve conduction velocity, and lack of cutaneous malignancy.

• Progeria: Dwarfism and premature senile appearance are the characteristic features of progeria. However, photosensitivity, ocular defects, and disproportionately large extremities are absent from progeria.

• Bloom syndrome: Individuals with Bloom syndrome display erythema on the face and hands. This genetic disorder is marked by growth restriction and typically average intelligence, with some patients experiencing neurological development issues.

• Werner syndrome: Affected children with Werner syndrome have an abnormally slow growth rate, which stops at puberty. As a result, affected individuals have short stature and low weight relative to height and exhibit progeria.

• Rothmund-Thomson syndrome: Rothmund-Thomson syndrome is distinguished from Cockayne syndrome by the presence of poikiloderma and involvement of buttocks and extremities.

• Hartnup disease: Hartnup disease is an autosomal recessive disorder resulting in impaired functioning of transport protein in the intestines and kidneys. As a result, neutral amino acids are wasted, leading to cutaneous and neurological clinical symptoms.[3][18]

Prognosis

Children with Cockayne syndrome type I usually maintain good communication skills for an extended period despite the illness. Although death commonly occurs during adolescence, survival into adulthood is possible. Encouraging socialization and age-appropriate schooling is recommended. On the other hand, children with Cockayne syndrome type II face limited possibilities for interaction with their surroundings due to the severity of sensory and intellectual impairment, and death typically occurs within the first decade. In contrast, patients with Cockayne syndrome type III exhibit a relatively normal early development, attending formal schooling. However, visual and auditory impairments, along with weakness, develop in adolescence.[13][17][18]

Complications

Complications arising from Cockayne syndrome may include dental anomalies such as caries, enamel hypoplasia, abnormal tooth shape or number, hypertension, renal failure, premature atherosclerosis, gastroesophageal reflux, progressive peripheral motor and sensory neuropathy causing difficulty walking, bladder and bowel disturbances, acute liver failure due to the administration of metronidazole, intellectual disability, developmental delays, growth failure, progressive pigmentary retinopathy, cataracts, sensorineural hearing loss, joint contractures, ataxia, tremor, seizures, spasticity, photosensitivity, and premature death.[19]