Cockayne syndrome

Synonyms

2

Overview

Cockayne syndrome (CS ,Neill-Dingwall syndrome), is a rare autosomal recessive neurodegenerative disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight (photosensitivity), eye disorders and premature aging. Failure to thrive and neurological disorders are criteria for diagnosis, while photosensitivity, hearing loss, eye abnormalities, and cavities are other very common features. Problems with any or all of the internal organs are possible. It is associated with a group of disorders called leukodystrophies, which are conditions characterized by degradation of neurological white matter. The underlying disorder is a defect in a DNA repair mechanism. Unlike other defects of DNA repair, patients with CS are not predisposed to cancer or infection. Cockayne syndrome is a rare but destructive disease usually resulting in death within the first or second decade of life. The mutation of specific genes in Cockayne syndrome is known, but the widespread effects and its relationship with DNA repair is yet to be well understood.

It is named after English physician Edward Alfred Cockayne (1880–1956) who first described it in 1936 and re-described in 1946. Neill-Dingwall syndrome was named after Mary M. Dingwall and Catherine A. Neill. These women described the case of two brothers with Cockayne syndrome and asserted it was the same disease described by Cockayne. In their article the women contributed to the symptoms of the disease through their discovery of calcifications in the brain. They also compared Cockayne syndrome to what is now known as Hutchinson-Gilford progeria syndrome (HGPS), then called progeria, due to the advanced aging that characterizes both disorders.

Symptoms

• CS Type I (CSA), the classic form, is characterized by normal fetal growth with the onset of abnormalities in the first two years of life. Impairment of vision, hearing, and the central and peripheral nervous systems progressively degenerate until death in the first or second decade of life.
• CS Type II (CSB), otherwise known as connatal CS, involves very little neurological development after birth. Death usually occurs by age seven. This specific type has also been designated as cerebro-oculo-facio-skeletal (COFS) syndrome. COFS syndrome can be further subdivided into several conditions (COFS types 1, 2, 3 (associated with xeroderma pigmentosum) and 4).
• CS Type III (CSC), characterized by late onset, is rare and milder than Types I and II.
• Xeroderma pigmentosum-Cockayne syndrome (XP-CS) occurs when an individual also suffers from xeroderma pigmentosum, another DNA repair disease. Some symptoms of each disease are expressed.

Causes

Cockayne syndrome can result from mutations in either the ERCC6 gene (also known as the CSB gene) or the ERCC8 gene (also known as the CSA gene). These genes provide instructions for making proteins that are involved in repairing damaged DNA. DNA can be damaged by ultraviolet (UV) rays from the sun and by toxic chemicals, radiation, and unstable molecules called free radicals. Cells are usually able to fix DNA damage before it causes problems. However, in people with Cockayne syndrome, DNA damage is not repaired normally. As more abnormalities build up in DNA, cells malfunction and eventually die. The increased cell death likely contributes to the features of Cockayne syndrome, such as growth failure and premature aging.

Diagnosis

Diagnosis is based on detection of the specific TCR defect that can be identified using a radioactive assay in cultured fibroblasts that measures the recovery of RNA synthesis after UV irradiation. This DNA repair test is a decisive tool for the diagnosis of CS. Brain imaging reveals diffuse hypomyelination of the cerebral white matter, calcifications in the putamen, and vermian atrophy. The differential diagnosis mainly includes mitochondrial diseases that may show similar clinical features to those seen in CS. Prenatal diagnosis can be performed on amniocytes or chorionic cells (using the same cellular test as that employed in fibroblasts) or by direct molecular sequencing if the causative mutations in the family have already been identified. Management is purely supportive and includes physiotherapy, sun protection, hearing aids and often tube feeding or gastrostomy. In CS type I, death occurs before the end of the second decade as a result of progressive neurologic degeneration. Patients with type II present with a more severe prognosis, whereas patients with type III live into adulthood.

Treatment

There is no permanent cure for this syndrome, although patients can be treated according to their specific symptoms. The prognosis for those with Cockayne syndrome is poor, as death typically occurs by the individual's twenties. Treatment usually involves physical therapy and minor surgeries to the affected organs, like cataract removal. Also wearing high-factor sunscreen and protective clothing is recommended as patients with Cockayne syndrome are very sensitive to UV radiation. Optimal nutrition can also help. Genetic counseling for the parents is recommended, as the disorder has a 25% chance of being passed to any future children, and prenatal testing is also a possibility. Another important aspect is prevention of recurrence of CS in other sibling. Identification of gene defects involved makes it possible to offer genetic counseling and antenatal diagnostic testing to the parents who already have one affected child.