Cockayne Syndrome 

Updated: Jun 25, 2018
Author: Suguru Imaeda, MD; Chief Editor: William D James, MD 

Overview

Background

Cockayne syndrome[1] is a rare autosomal recessive (see diagram below), heterogeneous, multisystem disorder characterized by dwarfism, progressive pigmentary retinopathy, birdlike facies, and photosensitivity. The syndrome is divided into two subtypes. Cockayne syndrome I, or classic Cockayne syndrome, presents in childhood with characteristic facies and somatic features that occur late in the first decade of life. Cockayne syndrome II, or severe Cockayne syndrome, presents at birth with accelerated facial and somatic features. Individuals who are affected with Cockayne syndrome I typically have progressive neurologic degeneration with death occurring by the second or third decade of life, whereas patients with Cockayne syndrome II typically die by age 6-7 years.[2, 3]

Autosomal recessive inheritance pattern. Autosomal recessive inheritance pattern.

Also see the pediatrics article, Cockayne Syndrome.

Pathophysiology

Cockayne syndrome is an autosomal recessive disorder. A DNA repair defect is a prominent feature of Cockayne syndrome.

Cockayne syndrome, xeroderma pigmentosa, and trichothiodystrophy are 3 distinct syndromes with cellular sensitivity to ultraviolet (UV) irradiation. These syndromes arise from mutations of genes critical for nucleotide-excision repair and RNA transcription. At least 28 genes are involved in the nucleotide excision repair pathway, which is involved in protection against UV-induced DNA damage.[4, 5, 6]

Cockayne syndrome is not associated with skin cancer, despite the photosensitivity and DNA repair defect, unlike xeroderma pigmentosa. Trichothiodystrophy patients have sulfur-deficient brittle hair with a normal skin cancer risk. Progressive sensorineural deafness is an early feature of both Cockayne syndrome and xeroderma pigmentosa, but not trichothiodystrophy. Furthermore, the main neuropathology of xeroderma pigmentosa is a primary neuronal degeneration, while in Cockayne syndrome and trichothiodystrophy, myelination of the brain is reduced, suggesting that the neurological abnormalities may be caused by both developmental defects and faulty DNA repair of neuronal cells damaged by oxidative stress.[4, 5, 7, 8]

Cockayne syndrome group A or B (CSA or CSB) genes are required for transcription-coupled repair, a subpathway of nucleotide-excision repair.[9] At least 30 known CSA mutations have been characterized to date, primarily mutations in group 8 excision-repair cross-complementation gene (ERCC8) on band 5q12.[10] CSB gene defects (ERCC6) (at least 78 different mutations) result in altered expression of antiangiogenic and cell cycle genes and proteins, particularly p21, which can result in inhibition of cell cycle progression and growth.[11, 12] These may account for signs and symptoms not readily related to DNA repair deficiencies.[13, 14]

See Causes.

Etiology

Cells with a defective DNA repair mechanism are sensitive to UV light.

Decreased DNA and RNA synthesis, increased sister chromatid exchanges, and increased chromosomal breaks may occur.

In Cockayne syndrome II, the defective CS group B protein, an SNF2-family DNA-dependent ATPase, is implicated in transcription elongation, transcription coupled repair, and DNA base excision repair.[15]

Epidemiology

Frequency

Cockayne syndrome is rare worldwide.

Race

No racial predilection is reported for Cockayne syndrome.

Sex

No sexual predilection is described for Cockayne syndrome; the male-to-female ratio is equal.

Age

Cockayne syndrome I (CS-A) manifests in childhood. Cockayne syndrome II (CS-B) manifests at birth or in infancy, and it has a worse prognosis.

Prognosis

Patients with Cockayne syndrome I have progressive, unremitting, neurologic deterioration usually leading to death by the second or third decade of life. Patients with Cockayne syndrome II typically have a worse prognosis, with death occurring earlier, typically by age 6 or 7 years.

Patient Education

A genetic counselor should educate the parents of the Cockayne syndrome patient.

 

Presentation

History

Patients with Cockayne syndrome usually appear normal at birth. Eventually, they present with a typical facial appearance of a pinched, narrow face and a beaked nose. Mental retardation, microcephaly, and growth failure become evident over time. Photosensitivity and progressive worsening neurologic signs and symptoms of ataxia and quick jerky movements are also noted.

In Cockayne syndrome I, the phenotypic features of Cockayne syndrome may be subtle early in the disease course. The signs become evident later in the first decade of life.

In CS-II, severe developmental delays are evident in the immediate postnatal period, and characteristic facies may be present by age 2 years.

Physical Examination

Appearance and habitus in Cockayne syndrome

Microcephaly, a thin nose, and large ears give the patient a Mickey Mouse appearance.

Patients may be cachectic.

Skin findings in Cockayne syndrome

Photosensitive eruption with erythema and scale may be observed.

Affected areas show hyperpigmentation, telangiectasia, and atrophy.

Subcutaneous lipoatrophy results in sunken eyes and an aged progeric appearance.

Cyanotic acral edema of the extremities[16]

Nail dystrophies and hair anomalies[16]

Musculoskeletal findings in Cockayne syndrome

Microcephaly, short stature, long limbs with joint contractures, large hands and feet, kyphosis, thickened calvariae, sclerotic epiphyses of the fingers, and osteoporosis may be observed.

Neurologic findings in Cockayne syndrome

Intracranial calcifications and diffuse demyelination of the central nervous system and the peripheral nerves result in progressive neurologic deterioration, such as ataxia, tremors, and cog wheeling.

Mental retardation may be noted.

Progressive sensorineural deafness may occur.

Ophthalmologic findings in Cockayne syndrome[17]

Salt and pepper retinal pigment, miotic pupils, cataracts, optic atrophy, corneal opacity, and nystagmus may be observed.

Vision is preserved.

Blepharokeratoconjunctivitis has been reported.[18]

Dental findings in Cockayne syndrome

Caries may be present.

Endocrinologic findings in Cockayne syndrome

Hypogonadism occurs in 30% of males.

Irregular menses occur in females.

Complications

In Cockayne syndrome, death by the second or third decade of life occurs as a result of progressive neurologic degeneration.

 

DDx

Diagnostic Considerations

Other considerations include Seckel syndrome (bird-headed dwarfism) and UV-sensitive syndrome.[19]

Differential Diagnoses

 

Workup

Laboratory Studies

In Cockayne syndrome patients, UV-irradiated cells show decreased DNA and RNA synthesis.

Laboratory studies are mainly useful to eliminate other disorders. For example, skeletal radiography, endocrinologic tests, and chromosomal breakage studies can help in excluding disorders included in the differential diagnosis.

Imaging Studies

Brain CT scanning in Cockayne syndrome patients may reveal calcifications and cortical atrophy.[20]

Other Tests

Prenatal evaluation is possible. Amniotic fluid cell culturing is used to demonstrate that fetal cells are deficient in RNA synthesis after UV irradiation.

 

Treatment

Medical Care

Medical care for Cockayne syndrome patients includes photoprotection with sunscreens and clothing.

Studies showing hepatic toxicity associated with metronidazole use suggests that metronidazole is contraindicated in patients with Cockayne syndrome.[21]

Surgical Care

Cochlear implantation can help minimize the effects of auditory impairment.[22, 23]

Perioperative management of Cockayne syndrome patients requires special consideration of the characteristic growth arrest, with failure to grow coupled with accelerated aging. Weight-appropriate rather than age-appropriate airway equipment is necessary for airway management.[24] Depending on the severity of the Cockayne syndrome, it may not be uncommon to encounter adult diseases, such as myocardial ischemia,[25] renal impairment, and diabetes mellitus, even in early childhood.[26]

Consultations

Consult the following specialists for Cockayne syndrome patients:

  • Neurologist for neurologic deterioration, ataxia, and deafness

  • Ear, nose, and throat specialist for sensorineural deafness

  • Ophthalmologist for optic atrophy and cataracts

  • Dentist for caries

  • Geneticist for prenatal evaluation and genetic counseling