Cockayne syndrome

Definition

Cockayne syndrome (CS) is a rare inherited disorder that results in an extreme sensitivity to ultraviolet (UV) irradiation, mental retardation, and precocious (premature) aging.

Description

Since first reported in 1936 by Dr. Edward A. Cockayne, less than 200 cases of this disorder have been documented in medical literature. At birth, newborns with CS may have microcephaly (small-sized head) and low birth weight. During the first year of life they do not feed well and, as a result, they suffer from growth failure and delayed development. Ultimately, the disease usually results in death during the teenage years.

Genetic profile

CS results from mutations in the CSA gene (also known as the ERCC8 gene) located on chromosome 5. An affected person has inherited one abnormal or nonworking gene from each parent, a pattern that is consistent with autosomal recessive inheritance . When functioning normally, the CSA gene helps cells remove and destroy deoxyribonucleic acid (DNA ) errors from strands undergoing active transcription. Also, the CSA gene allows cells to synthesize ribonucleic acid (RNA ) after exposure to UV light. Although the parents of an affected child are normal, each of them carries an abnormal gene for CS. Therefore, they have a 25% risk with each pregnancy of having another affected child.

Demographics

CS occurs in less than one in 250,000 births and does not affect any one ethnic group more than another. Males and females are equally affected.

Signs and symptoms

The symptoms of CS are very striking. Failure to grow begins during the first year of life and results in the appearance of dwarfism. The patient's weight is affected more than height. Also, some babies do not feed well and require feeding through a gastrostomy tube (a tube inserted through the abdominal wall into the stomach) to prevent malnutrition. As the infant grows, a delay in developmental milestones becomes apparent around the time that walking and talking should occur. Mental retardation in the mild to moderate range is found in all patients with CS. A small number of patients will have severe to profound mental retardation and some never have more than a few words of speech.

Other physical features include sun-sensitive skin, degeneration of retinal pigment, cataracts, and hearing loss. With exposure to sunlight, skin rashes appear and patients develop dry, scaly skin and thin hair. As part of the disease process, the skin develops an aged, leathery appearance. Although the eyes appear normal early in life, the retina later loses its pigment or color and develops a "salt-and-pepper" appearance. If cataracts appear within the first three years of life, the patient usually has the more severe form of CS that leads to death before adolescence. More than half the patients with CS have sensorineural hearing loss. The range of loss is from mild to severe.

Another finding of CS is an unusual gait (walk), caused by a combination of leg spasticity and contractures of the hips, knees, and ankles. The stooped posture often seen in CS results from kyphosis and joint contractures. Some of the first signs of neurologic changes are increased or decreased muscle tone and reflexes.

The most notable sign of CS is precocious senility (premature memory loss and confusion). Patients undergo neurological changes that resemble normal aging; the central and peripheral nervous systems lose myelin and neurons disappear from the central cortex and cerebellum. However, these changes occur at an extremely accelerated pace leading to death during early adolescence.

Diagnosis

Any child who displays these signs should have a genetic examination. CS is diagnosed by excluding other disorders. Specialized testing such as chromosome analysis, chromosome breakage studies, and DNA mutation analysis will rule out other genetic disorders such as Bloom syndrome , Werner syndrome , and xeroderma pigmentosum . A person with CS will have a normal complement of 46 chromosomes. Their chromosomes also will not show any breakage when subjected to specialized laboratory analysis. DNA testing to look for the specific mutations in the CSA gene is also possible.

Only a very limited number of laboratories can perform the specialized testing that exposes cultured skin fibroblasts to UV irradiation. The fibroblasts of an affected person will lack the ability to form colonies.

Treatment and management

No specific treatment exists for CS. Patients should be treated according to the symptoms they have. Physical therapy will help prevent joint contractures that limit walking. Poor feeders may require a gastrostomy tube to prevent malnutrition. Patients should use sunscreen liberally and limit their exposure to sunlight. Special education will help to maximize the child's learning potential.

Prognosis

The prognosis for CS is grim. Most patients die during the early adolescent years. Some survive until early adulthood. However, some patients have a more severe form and may die during early childhood.

Prevention

Since carriers of the gene that causes CS appear normal, and routine testing before pregnancy is not yet available, couples will not be aware of their risk until they have an affected child. For future pregnancies, prenatal diagnosis can determine whether or not the baby has CS.

Resources

PERIODICALS

Cleaver, J. E., et al. "A Summary of Mutations in the UV-sensitive Disorders: Xeroderma Pigmentosum, Cockayne Syndrome, and Trichothiodystrophy." Human Mutation 14, no.1 (1999): 9-22.

Greenhaw, G. A., et al. "Xeroderma Pigmentosum and Cockayne Syndrome: Overlapping Clinical and Biochemical Phenotypes." American Journal of Human Genetics 50, no.4 (April 1992): 677-89.

Higginbottom, M. C., et al. "The Cockayne Syndrome: An Evaluation of Hypertension and Studies of Renal Pathology." Pediatrics 64, no. 6 (December 1979): 929-34.

Mathur, R., M. R. Chowdhury, and G. Singh. "Recent Advances in Chromosome Breakage Syndromes and Their Diagnosis." Indian Pediatrics 37, no. 6 (June 2000): 615-25.

Nance, M. A., and S. A. Berry. "Cockayne Syndrome: Review of 140 cases." American Journal of Medical Genetics 42, no. 1 (January 1, 1992): 68-84.

Sugita, T., et al. "Prenatal Diagnosis of Cockayne Syndrome Using Assay of Colony-forming Ability in Ultraviolet Light Irradiated Cells." Clinical Genetics 22, no. 3 (September 1982): 137-42.

Suzanne M. Carter, MS, CGC