Cockayne Syndrome

A complex inherited and congenital disorder characterized by the association of dwarfism, deafness, microcephaly, facial anomalies, ataxia, photosensitivity, retinal atrophy, and renal insufficiency with premature aging and atherosclerosis.

Deafness-Dwarfism-Retinal Atrophy; Dwarfism with Renal Atrophy and Deafness; Neill-Dingwall Syndrome; Progeroid Nanism.

First described by the English Physician Edward Alfred Cockayne in 1936.

Occurs in approximately 1:200,000 live births. No ethnic or sexual predilection has been reported.

Autosomal recessive. Cockayne syndrome (CS) type I (also called type A, see Clinical Aspects) results from a defect in the CS type A or CSA or ERCC8 (excision repair cross-complementing rodent repair deficiency, complementation group 8) gene, which is located on chromosome 5. Cells carrying the mutated ERCC8 gene exhibit a hypersensitivity to ultraviolet light. After exposure to ultraviolet light, these cells fail to recover their ability to synthesize ribonucleic acid and to repair or excise and degrade lesions in deoxyribonucleic acid strands. In CS type II (type B), the mutation affects the transcription-coupled and global genome DNA excision repair gene ERCC6 (excision repair cross-complementing rodent repair deficiency, complementation group 6), which has been mapped to 10q11.

A defective transcription-coupled repair of oxidative damages to the DNA contributes to developmental defects.

In classic CS type I, the diagnosis is based on the clinical findings, whereas the “nonclassic” form is confirmed by DNA repair assays in lymphoblasts or skin fibroblasts. In older children, classic CS type I should be suspected in the presence of both major and three minor criteria. In infants or toddlers, the diagnosis is likely when one minor and both major criteria are fulfilled and abnormalities in DNA repair are present. The major criteria consist of (1) postnatal growth retardation (height and weight below the fifth percentile at 2 years of age resulting in “cachectic dwarfism” appearance) and (2) progressive neurologic dysfunction (early developmental delay and progressive deterioration). Intracranial pericapillary calcifications (in cortex and basal ganglia), leukodystrophy with scattered neuronal loss, and normal pressure hydrocephalus may be present. The seven minor criteria are (1) dermal photosensitivity (poikiloderma), (2) pigmentary retinopathy, blindness, and/or cataracts, (3) diffuse and segmental peripheral demyelination with decreased nerve conduction velocity, (4) sensorineural hearing loss, (5) sclerotic epiphyses, vertebral and pelvic abnormalities, thickening of the calvarium, (6) thin skin and brittle hair, sunken eyes, and stooped standing posture, and (7) dental cavities. In CS type II, the diagnosis is based on the findings of failure to thrive beginning right from birth with severely delayed gains in height and weight combined with absent or minimal progress in the neurologic development. Eye anomalies are frequent and include congenital cataracts and other structural ocular defects such as microphthalmos and microcornea.

Premature aging is the hallmark of all types of CS. CS I (type A or “classic” form) presents in infancy and is less severe than CS II (type B or “congenital” or “connatal” form), which presents earlier and is generally apparent already at birth. CS III (type C or “late-onset” form) presents later in life, and there is no universal agreement as to the existence of CS III. The classic form (type I) may involve the head and neck (microcephaly, thickened calvarium, intracranial calcifications, mandibular prognathism, loss of facial adipose tissue with wrinkled face, slender nose, malformed ears, sensorineural hearing loss, hypoplastic teeth with caries, delayed eruption of deciduous teeth), the nervous system (mental retardation, leukodystrophy, normal pressure hydrocephalus, seizures, nystagmus, ataxia, dysarthria, tremor, generalized weakness, peripheral neuropathy), the eyes (“salt and pepper" retinal pigmentation, optic nerve atrophy, strabismus, hypermetropia, corneal opacity, decreased lacrimation; development of cataracts before the age of 3 years is associated with a severe course of the disease and early mortality), the cardiovascular system (arterial hypertension, arrhythmias, premature atherosclerosis), the genitourinary tract (renal failure, proteinuria, cryptorchidism, micropenis), the musculoskeletal system (short stature, vertebral anomalies with kyphosis, small squared-off pelvis with hypoplastic iliac wings, mild-to-moderate limitation of joint movements, sclerotic phalangeal epiphyses), and the skin (precocious senile appearance [wrinkling], photosensitivity, scarring, poikiloderma, anhydrosis and dry skin, thin and dry hair, decreased subcutaneous adipose tissue, café-au-lait spots). Other features include hepatosplenomegaly with elevated liver enzyme serum concentrations. There is no increase in malignancies or susceptibility to infections. Death in CS I patients usually occurs early in the second decade of life. Growth failure in patients with congenital CS type II is obvious at birth (intrauterine and postnatal growth retardation) or shortly after birth. Neurologic development is either absent or severely delayed. Congenital cataracts or other structural ocular anomalies occur in up to one third of patients. Arthrogryposis and/or early joint contractures result in restricted movement and kyphoscoliosis. Death usually occurs before 10 years of age, often as a result of pneumonia. In several aspects, CS type II resembles the Pena-Shokeir Syndrome Type II. A small subset of patients share some features of CS, but show normal growth and neurologic development. These patients have been assigned the diagnosis of “late-onset” CS or CS type III. However, the debate is ongoing whether CS type III is in fact a form of CS or an entirely different syndrome.

In fewer than 10 cases, CS was associated with Xeroderma Pigmentosum (XP). This rare variant shares signs of xeroderma pigmentosum with all the features of the classic form of CS.

Obtaining a complete blood count and serum concentrations of electrolytes, creatinine, and urea is recommended. Advanced generalized and coronary atherosclerosis is part of the disease. An electrocardiogram (arrhythmias, ischemia) and a chest radiograph should be requested. Blood pressure control should be assessed. Evaluate the airway with regard to difficult management. Check for gastroesophageal reflux (frequent) and recurrent aspiration pneumonia. Developmental delay may limit patient cooperation. Sedative and/or anxiolytic premedication and the presence of the primary caregiver during induction of anesthesia may be helpful.

Difficult mask ventilation and direct laryngoscopy and tracheal intubation have been reported. The tracheal diameter may be less than expected, requiring a smaller than predicted endotracheal tube. Maintenance of spontaneous ventilation is desired until the airway has been secured. However, there may be an increased risk of aspiration because of gastroesophageal reflux, and a rapid-sequence induction technique would be preferred. The final decision depends mainly on the clinical findings (severity of facial dysmorphism on the one hand and of gastroesophageal reflux on the other hand). Decreased sweating may lead to thermoregulatory abnormalities. Restricted joint movement may lead to difficult vascular access and patient positioning. Eye protection with eye ointment and taping the eyes shut is imperative secondary to decreased lacrimation.

In a single case report, a dose of nifedipine 2 mg given to a 10-kg female with Cockayne syndrome for control of systemic hypertension resulted in transient cerebral ischemia and loss of consciousness at a systolic blood pressure of 138 mmHg. Anesthesia-related drops in arterial blood pressure should therefore be treated aggressively. Atropine should be avoided because of deficient lacrimation. Consider interaction between anesthetic drugs and antiepileptic treatment and also decreased elimination of drugs with predominantly renal excretion.

Pena-Shokeir Syndrome Type II: A rapidly progressive neurologic disorder leading to brain atrophy with calcifications, cataracts, microcornea, optic atrophy, progressive joint contractures, and growth failure.

Xeroderma Pigmentosum (XP): A syndrome characterized by a defect in ultraviolet radiation induced DNA repair mechanisms. The DNA damage is cumulative and irreversible. This condition may be lethal in infancy or childhood.