Cockayne syndrome is a rare disorder characterized by an abnormally small head size (microcephaly), a failure to gain weight and grow at the expected rate (failure to thrive) leading to very short stature, and delayed development. The signs and symptoms of this condition are usually apparent from infancy, and they worsen over time. Most affected individuals have an increased sensitivity to sunlight (photosensitivity), and in some cases even a small amount of sun exposure can cause a sunburn or blistering of the skin. Other signs and symptoms often include hearing loss, vision loss, severe tooth decay, bone abnormalities, hands and feet that are cold all the time, and changes in the brain that can be seen on brain scans.

People with Cockayne syndrome have a serious reaction to an antibiotic medication called metronidazole. If affected individuals take this medication, it can cause life-threatening liver failure.

Cockayne syndrome is sometimes divided into types I, II, and III based on the severity and age of onset of symptoms. However, the differences between the types are not always clear-cut, and some researchers believe the signs and symptoms reflect a spectrum instead of distinct types. Cockayne syndrome type II is also known as cerebro-oculo-facio-skeletal (COFS) syndrome, and while some researchers consider it to be a separate but similar condition, others classify it as part of the Cockayne syndrome disease spectrum.

Cockayne syndrome can result from mutations in either the ERCC6 gene (also known as CSB) or the ERCC8 gene (also known as CSA). 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 errors build up in DNA, cells malfunction and eventually die. The faulty DNA repair underlies photosensitivity in affected individuals, and researchers suspect that it also contributes to the other features of Cockayne syndrome. It is unclear how ERCC6 or ERCC8 gene mutations cause all of the varied features of this condition.

Normal Function

The ERCC6 gene provides instructions for making a protein called Cockayne syndrome B (CSB). This protein is involved in repairing damaged DNA and appears to assist with gene transcription, which is the first step in protein production.

DNA can be damaged by ultraviolet (UV) rays from the sun and by toxic chemicals, radiation, and unstable molecules called free radicals. If left uncorrected, DNA damage accumulates, which causes cells to malfunction and can lead to cell death. Although DNA damage occurs frequently, cells are usually able to fix it before it can cause problems. Cells have several mechanisms to correct DNA damage; one such mechanism involves the CSB protein. This protein specializes in repairing damaged DNA within active genes (those genes undergoing gene transcription). When DNA in active genes is damaged, the enzyme that carries out gene transcription (RNA polymerase) gets stuck, and the process stalls. Researchers think that the CSB protein helps remove RNA polymerase from the damaged site, so the DNA can be repaired. The CSB protein may also assist in restarting gene transcription after the damage is corrected.

Health Conditions Related to Genetic Changes

Cockayne syndrome

More than 60 ERCC6 gene mutations that cause Cockayne syndrome have been identified. This rare condition includes a variety of features, including an abnormally small head size (microcephaly), very slow growth resulting in short stature, delayed development, and an increased sensitivity to sunlight (photosensitivity).

Many of the ERCC6 gene mutations that cause Cockayne syndrome lead to the production of an abnormally short version of the CSB protein that cannot function properly. Other mutations change single building blocks (amino acids) in the CSB protein, which also results in a malfunctioning protein.

The mechanism by which ERCC6 gene mutations lead to Cockayne syndrome is not well understood. The altered CSB protein probably hinders DNA repair and may be unable to assist with gene transcription. As a result, damaged DNA is not fixed, which disrupts gene transcription and prevents the normal production of proteins. These abnormalities impair cell function and eventually lead to the death of cells in many organs and tissues. Faulty DNA repair underlies photosensitivity in affected individuals, and researchers suspect that it also contributes to the other features of Cockayne syndrome. It is unclear how ERCC6 gene mutations cause all of the varied features of this condition.

UV-sensitive syndrome

At least one mutation in the ERCC6 gene can cause UV-sensitive syndrome, a condition characterized by unusual sensitivity to UV rays from the sun. People with UV-sensitive syndrome sunburn easily and have freckled skin or other changes in skin coloring (pigmentation). The known mutation, which is written as Arg77Ter or R77X, replaces the amino acid arginine with a premature stop signal at position 77 in the CSB protein. If any protein is produced, it is abnormally short and quickly broken down. Without this protein, skin cells cannot repair DNA damage caused by UV rays, and transcription of damaged genes is blocked. However, it is unclear how a loss of the CSB protein causes UV-sensitive syndrome. Additionally, it is unknown why the Arg77Ter mutation causes photosensitivity without the other features of Cockayne syndrome (described above).

Age-related macular degeneration

MedlinePlus Genetics provides information about Age-related macular degeneration

Other Names for This Gene

• ARMD5
• CKN2
• COFS
• CSB
• ERCC6_HUMAN
• excision repair cross-complementation group 6
• RAD26
• Rad26 (yeast) homolog

Genomic Location

Normal Function

The ERCC8 gene provides instructions for making a protein called Cockayne syndrome A (CSA), which is 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. The damage caused by these agents can block vital cell activities such as gene transcription, which is the first step in protein production. If left uncorrected, DNA damage accumulates, which causes cells to malfunction and can lead to cell death.

Although DNA damage occurs frequently, cells are usually able to fix it before it can cause problems. Cells have several mechanisms to correct DNA damage; one such mechanism involves the CSA protein. This protein specializes in repairing damaged DNA within active genes (those genes undergoing gene transcription). However, its specific role in this process is unclear. The CSA protein interacts with other proteins, probably to identify areas of damaged DNA.

Health Conditions Related to Genetic Changes

Cockayne syndrome

Researchers have identified more than 30 ERCC8 gene mutations that can cause Cockayne syndrome. This rare condition includes a variety of features, including an abnormally small head size (microcephaly), very slow growth resulting in short stature, delayed development, and an increased sensitivity to sunlight (photosensitivity).

Some of the ERCC8 gene mutations result in the production of an abnormally short version of the CSA protein that cannot function properly. Other mutations change one of the building blocks (amino acids) used to make the CSA protein, which also results in a malfunctioning protein.

The mechanism by which ERCC8 gene mutations lead to Cockayne syndrome is not well understood. The altered CSA protein probably disrupts DNA repair. As a result, damaged DNA is not fixed, which disrupts gene transcription and prevents the normal production of proteins. These abnormalities impair cell function and eventually lead to the death of cells in many organs and tissues. Faulty DNA repair underlies photosensitivity in affected individuals, and researchers suspect that it also contributes to the other features of Cockayne syndrome. It is unclear how ERCC8 gene mutations cause all of the varied features of this condition.

UV-sensitive syndrome

At least one mutation in the ERCC8 gene can cause UV-sensitive syndrome, a condition characterized by unusual sensitivity to UV rays from the sun. People with UV-sensitive syndrome sunburn easily and have freckled skin or other changes in skin coloring (pigmentation). The known mutation replaces the amino acid tryptophan with the amino acid cysteine at position 361 in the CSA protein (written as Trp361Cys or W361C). Although the effect of this change on the function of the protein is unknown, it somehow prevents cells from repairing DNA damage caused by UV rays, and transcription of damaged genes is blocked. It is unclear exactly how an abnormal CSA protein causes the signs and symptoms of UV-sensitive syndrome. Additionally, it is unknown why the Trp361Cys mutation causes photosensitivity without the other features of Cockayne syndrome (described above).

Other Names for This Gene

• CKN1
• Cockayne syndrome 1 (classical)
• Cockayne syndrome 1 protein
• Cockayne syndrome, type A
• CSA
• ERCC8_HUMAN
• excision repair cross-complementation group 8
• excision repair cross-complementing rodent repair deficiency, complementation group 8

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

The signs and symptoms of Cockayne syndrome are usually apparent from infancy and worsen over time.

Cockayne Type I
Babies look normal at birth, but symptoms develop within the first two years.

More common signs and symptoms:

• An smaller than normal sized head (microcephaly)
• Failure to gain weight and grow at the expected rate (failure to thrive) leading to very short stature, and delayed development
• Increased sensitivity to sunlight (photosensitivity), and in some cases even a small amount of sun exposure can cause a sunburn or blistering of the skin.
• Developmental delay
• Progressive impairment of vision, hearing, and central and peripheral nervous system function leading to severe disability
• Severe teeth cavities (in up to 86% of individuals)

Symptoms observed in about 10% of the cases:

• Neurological issues: Increased tone/spasticity, increased reflexes or decreased reflexes (hyper- or hyporeflexia), abnormal gait or inability to walk, lack of coordination (ataxia), lack of urination control (incontinence), tremor, abnormal or absent speech, seizures, weak cry/poor feeding (as an infant), muscle wasting (atrophy), and behavioral abnormality
• Skin issues: Lack of sweating (anhidrosis) and facial rash
• Eye and vision issues: Hollow eyes (enophthalmos), pigmentary retinopathy (60%-100%), cataracts (15%-36%), optic atrophy, farsightedness, decreased or absent tears, strabismus, nystagmus, photophobia, and very small eyes (microphthalmia)
• Teeth issues: Absent or very small teeth, delayed eruption of deciduous teeth, and malocclusion
• Kidney issues: Abnormal kidney function and abnormalities
• Hormonal issues: Undescended testes, delayed/absent sexual maturation
• Fertility issues: People with classic or severe CS (types I or II) cannot reproduce
• Other: Enlargement of liver or spleen

Cockayne Type II
This is the most severe subtype.

Symptoms may include:

• Severe growth failure at birth
• Severe
• Severe neurologic development
• Congenital cataracts or other eye anomalies are present in 30% of the cases
• Joint contractures present at birth (congenital) or early postnatal contractures of the spine (kyphosis, scoliosis) and joints

Cockayne Type III
Similar to CS type I but milder.

• Cockayne syndrome Type 1 (type A) is marked by normal development until a child is 1 or 2 years old, at which point growth slows and developmental delays are noticed. Life expectancy for type 1 is approximately 10 to 20 years.
• Cockayne syndrome type 2 (type B), also known as "cerebro-oculo-facio-skeletal (COFS) syndrome" (or "Pena-Shokeir syndrome type II"), is the most severe subtype. Symptoms are present at birth and normal brain development stops after birth. Average lifespan for children with type 2 is up to 7 years of age.
• Cockayne syndrome type 3 (type C) appears later in childhood with milder symptoms than the other types and a slower progression of the disorder. People with this type of Cockayne syndrome live into adulthood, with an average lifespan of 40 to 50 years.

Cockayne syndrome is estimated to occur in 2 to 3 per million newborns in the United States and Europe.