Cockayne syndrome

Definition: Cockayne syndrome is a rare autosomal recessive condition comprising microcephaly, "cachectic dwarfism" and progressive neurological degeneration. CS is characterized by progressive multisystem degeneration and is classified as a segmental premature-aging syndrome.

A prevalent feature of Cockayne syndrome (CS) is photosensitivity, without the pigmentary disturbances or other skin problems that are characteristic of XP. The mean age of death of patients with CS is about 12 years and the few patients who have survived to early adulthood do not manifest skin or other types of cancer.

Cockayne syndrome (CS) is a multisystem condition characterized by short stature, a characteristic facial appearance, premature aging, photosensitivity, progressive neurological dysfunction, and intellectual deficit.

The annual incidence of CS is close to 1/200,000 in European countries. Disease severity and the age of onset are variable.

CLinical synopsis

Common signs of the disease include progressive growth failure, intellectual deficit, cerebellar ataxia, spasticity, peripheral demyelinating neuropathy, pigmentary retinopathy, sensorineural hearing loss and dental anomalies (presence of caries).

The typical facial appearance includes microcephaly, large ears, a thin nose, and enophthalmia. Cataracts and cutaneous photosensitivity are observed in some patients. Subcutaneous lipoatrophy is present and can lead to signs of premature aging of the skin.

Synopsis

 sun sensitivity
 mental retardation
 microcephaly
 dwarfism

 systemic anomalies

• cachectic dwarfism
• intrauterine growth retardation (IUGR)
• severe postnatal growth deficiency
• normally no cancer is associated.

 craniofacial anomalies

• micrognathia
• protruding ears
• dental overcrowding with caries
• prognathism
• loss of facial adipose tissue
• wizened face
• malformed ears
• slender nose
• dental caries
• delayed eruption of deciduous teeth
• malocclusion
• Absent/hypoplastic teeth

 sensorineural hearing loss

 ocular anomalies

• salt and pepper retinal pigmentation
• pigmentary retinopathy
• optic atrophy
• strabismus
• hyperopia
• corneal opacity
• decreased lacrimation
• nystagmus
• cataracts

 cardiac arrhythmias
 hypertension
 hepatomegaly
  splenomegaly
 cryptorchidism
 micropenis
 proteinuria
 renal failure

 skeletal anomalies

• thickened calvarium
• kyphosis
• vertebral body abnormalities
• small, squared off pelvis
• hypoplastic iliac wings
• mild to moderate joint limitation
• sclerotic ivory phalangeal epiphyses

 cutaneous anomalies

• precociously senile appearance
• photosensitivity (increased cellular sensitivity to UV light)
• scarring
• pigmentation
• cutaneous atrophy
• anhidrosis
• dry skin
• decreased subcutaneous adipose tissue
• thin, dry hair

 nervous system anomalies

• mental retardation
• normal pressure hydrocephalus
• dementia
• basal ganglia calcifications
• patchy demyelination of subcortical white matter
• cerebral atrophy
• dysarthric speech
• dysmyelination
• gait disturbance
• ataxia
• tremor
• weakness
• peripheral neuropathy
• abnormal myelination in sural nerve biopsies
• CNS demyelination
• progressive spastic quadriparesis
• progressive neurological degeneration.
• severe developmental regression
• bilateral calcification of the globus pallidus
• global cerebral atrophy

 irregular menstrual cycles
 hypogonadism

COFS syndrome

COFS syndrome is the extreme prenatal form of the CS clinical spectrum characterized by congenital microphthalmia and arthrogryposis.

Etiology

CS belongs to the family of NER (nucleotide excision repair)-related disorders together with xeroderma pigmentosum and trichothiodystrophy.

CS cells show a specific defect in transcription-coupled DNA repair (TCR), a subpathway of NER involved in the removal of UV-induced DNA lesions in actively transcribed genes.

Additional defects in basal transcription or in oxidative repair have also been put forward to account for the noncutaneous symptoms of CS.

Mutations have been described in two major genes, ERCC6 (CSB; 10q11) and ERCC8 (CSA; 5q12.1). So far, no correlation was found between the three types of CS and the genes involved.

Transmission is autosomal recessive.

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.

Types

In classical type I CS, the first symptoms usually appear during the first year of life. Early-onset cases with more severe symptoms (type II) and late-onset cases with milder symptoms (type III) have also been described.

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.

Physiopathology

The photosensitivity of individuals with CS prompted the early idea that they might be defective in DNA repair. Skin fibroblasts from these individuals are, indeed, more sensitive to killing by UV radiation than normal cells. However, measurements of global NER were normal.

Cells from individuals with CS recover from an inhibition of RNA synthesis that accompanies exposure to UV light much more slowly than normal cells do.

Further studies established that this cellular phenotype reflects defective transcription-coupled NER (TCNER), establishing CS as a DNA-repair-defective disorder.

It is now recognized that TCNER specifically requires the products of two genes called CSA and CSB and that defects in either gene can lead to the disease. The molecular pathogenesis of this disease remains uncertain as the precise functions of the CSA and CSB gene products are not known.

The combined XP/CS syndrome presents an equal challenge. So far, only a small number of patients have been identified as having the syndrome, and all of these have mutations in either the XPB, XPD or XPG genes. Skin cancer at a young age has been documented in some, but not all, of these cases.

Etiology

 mutations in the CSA gene
 mutations in the CSB gene. The CS complementation group B (CSB) protein is at the interface of transcription and DNA repair and is involved in transcription-coupled and global genome-DNA repair, as well as in general transcription.

 XPB
 XPD
 XPG

The second human nucleotide excision repair disease is Cockayne syndrome (CS). CS patients are also sun sensitive but show a distinctive array of congenital neurological and skeletal abnormalities, including mental deficiency and dwarfism (Nance and Berry, 1992). Cells from these patients are very sensitive to UV irradiation and have a defective RNA synthesis after UV. Mutations in CSA and CSB genes are responsible for the classical CS. However, the symptoms of the disease are also seen in rare XP patients belonging to the groups B, D and G (Vermeulen et al., 1993).

Pathogeny

 The real function of CSA and CSB genes are not known, yet. However, there are some findings that associate these genes with the preferential repair of transcribed genes.

 Cells from patients with CS are defective in preferential repair (Friedberg, 1996) and the sequence of CSB gene reveal some similarity to the Escherichia coli Mfd gene, a transcription repair coupling factor (TRFC) (Troelstra et al., 1992).

 The homology in the ATPase/helicase motif is high and this motif is essential for the function of the Mfd gene. These observations have led to the suggestion that CSB protein, complexed with the CSA protein, may function as TRFC in human cells.

 The following model is proposed for the action of these proteins: the CSB-CSA heterodimer recognizes the RNA polymerase II stalled at a lesion, backs off this polymerase without dissociating the ternary complex, and then the heterodimer recruits XPA and TFIIH to the lesion site, necessary for the repair of transcribed genes.

Management

Management is purely supportive and includes physiotherapy, sun protection, hearing aids and often tube feeding or gastrostomy.

See also

 Cockayne symdromes

• Cockayne syndrome type I (CKN1)
• Cockayne syndrome type II (CKN2)

References

 Cleaver JE. Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nat Rev Cancer. 2005 Jul;5(7):564-73. PMID: 16069818

 Licht CL, Stevnsner T, Bohr VA. Cockayne syndrome group B cellular and biochemical functions. Am J Hum Genet. 2003 Dec;73(6):1217-39. PMID: 14639525