DISEASE CARD

Disease group DNA repair disorders
DISEASE NAME COCKAYNE SYNDROME
Synonymous

Cerebro-oculo-facio-skeletal-syndrome (COFS)

Estimated prevalence

The incidence of Cockayne syndrome (CS), including cases showing combined symptoms of CS and xeroderma pigmentosum (XP/CS), has been established at 2.7 per million livebirths in West-Europe and at 1.8 per million livebirths in the autochthonic Western Europe population (Kleijer et al. DNA Repair 7:744-750, 2008).

OMIM

CS: 216400, 133540, 214150

XP/CS: 610651, 278730, 278760, 278780
Inheritance Autosomal recessive
Gene (s)

CS: CSA/ERCC8 (609412), CSB/ERCC6 (609413)

XP/CS: XPB/ERCC3 (133510), XPD/ERCC2 (126340), XPF/ERCC4 (133520), XPG/ERCC5 (133530), ERCC1 (126380)

Definition

Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by pre- or post-natal growth failure, mental retardation and otherwise clinically heterogeneous features which commonly include cutaneous photosensitivity. However, there are no reports of skin cancers in CS patients.
Cultured cells from CS patients are hypersensitive to ultraviolet (UV) light and, following UV irradiation, they are typically unable to restore RNA synthesis rates to normal levels. This is due to a specific deficiency in the ability to carry out preferential repair of damage in actively transcribed regions of DNA and it is linked to mutations in one of two genes, namely CSA/ERCC8 and CSB/ERCC6. Besides to CS cases, there are some cases showing the clinical and cellular features of both CS and xeroderma pigmentosum (XP/CS). These individuals are mutated in either the XPB/ERCC3, XPD/ERCC2, XPF/ERCC4, XPG/ERCC5 or ERCC1 gene. Expression of CS and XP traits in combined presentations is extremely variable and rare cases clinically featuring severe CS with no overt XP signs were found mutated in ERCC1 or XPG/ERCC5.

Clinical Description

The cardinal clinical features of CS are pre- or post-natal growth failure, leading to a characteristic appearance of so-called cachectic dwarfism, and progressive neurological dysfunction. Associated clinical features are gait defects, progressive pigmentary retinopathy and other ocular anomalies such as cataracts and optic disc atrophy, sensorineural hearing loss, dental caries and cutaneous photosensitivity. The disease is clinically heterogeneous, with a wide range in type and severity of symptoms. A subdivision into three clinically different classes of the disease has been suggested by Nance and Berry (American Journal of Medical Genetics, 42, 68-84, 1992): (i) a classical form, or CS I (which includes the majority of cases), showing the first two symptoms listed above and at least three of the others; (ii) a severe CS form, or CS II, characterized by early onset and severe progression of symptoms, with low birth weight and poor or absent physical and neurological development; and (iii) a mild form, characterized by late onset and slow progression of symptoms.
The classical CS type I is characterized by normal prenatal growth with the onset of growth and developmental abnormalities in the first two years of life. By the time the disease has become fully manifest, height, weight, and head circumference are far below the fifth percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system functions lead to severe disability. Death typically occurs in the first or second decade.
Individuals affected by the severe form of CS show growth failure at birth, with little or no postnatal neurological development, congenital cataracts or other structural anomalies of the eye. The mild CS type III is characterized by essentially normal growth and cognitive development or by late onset.With the clinical characterization of a consistent number of patients, it has become evident that CS has a continuous spectrum of severity and that there is no clear threshold between the largely overlapping subgroups. The limits of the clinical spectrum have been pushed even farther following the identification of mutations in the CS genes in very severely affected patients and very mildly affected patients classified as having Cerebro-oculo-facio-skeletal syndrome (COFS) and UV-sensitive syndrome (UVSS). COFS is a rapidly progressive neurological disorder that was explicitly delineated in 1974, as occurring with autosomal recessive inheritance in isolated Manitoba families (Pena and Shokeir, Journal of Pediatrics 85:373-375, 1974). Key features of the disease include arthrogryposis, microcephaly, cataracts, microphtalmia and facial dysmorphism. There is no clear consensus on the diagnostic criteria that differentiate COFS from the severe CS type II and both conditions may be used to describe the severe end of the CS spectrum. UVSS has been first reported as a distinct clinical entity in 1994 (Itoh et al. Mutation Research 314:233-248, 1994) and is characterized by mild skin abnormalities in sun-exposed areas of the skin (see the specific disease card for details).

Pathogenesis

CS is linked to mutations in the CSA/ERCC8 and CSB/ERCC6 genes encoding proteins involved in transcription-coupled repair, i.e. the nucleotide excision repair (NER) sub-pathway that specifically removes DNA damage in actively transcribed regions of DNA (TC-NER). Defective TC-NER readily explains the photosensitivity of the patients and the failure of RNA synthesis to recover following UV irradiation of CS cells. However, it is not so easy to reconcile with many of the clinical features of CS such as neurodegeneration and premature ageing. Accumulating experimental evidence indicates that the CSA and CSB proteins have additional functions including the repair of oxidative damage in DNA and roles in mitochondrial DNA metabolism and in transcription. Recently, a crucial role for the CS proteins in expression of neuronal genes and thereby in neuronal differentiation has been described (Wang et al. Proc Natl Acad Sci USA 111:14454-14459, 2014). This role of CS proteins could account for some of the developmental defects found in CS patients.

Combined XP/CS presentations are associated with mutations in the XPB/ERCC3, XPD/ERCC2, XPF/ERCC4, XPG/ERCC5 and ERCC1 genes. All these genes except ERCC1 are also mutated in XP-only cases. XPB/ERCC3 and XPD/ERCC2 encode distinct subunits of TFIIH, a multifunctional protein complex participating in both NER and transcription. XPG/ERCC5 encodes the XPG protein that associates with TFIIH, thus helping in maintaining the TFIIH architecture. Experimental data indicate that alterations impairing NER but preserving TFIIH transcriptional role result in the photosensitive disorder XP whereas alterations also disturbing TFIIH function in transcription give rise to the severe neurodevelopmental disorder XP/CS. As for the products of the XPF/ERCC4 and ERCC1 genes, they form the ERCC1-XPF heterodimeric complex operating in NER but also in inter-strand crosslink repair and double-strand break repair. In addition, ERCC1 localizes at telomeres. The phenotypic variability associated with ERCC1-XPF deficiency in humans might be linked to variable levels of expression or activity. Intriguingly, mutations in XPF/ERCC4 have been also found in one individual showing the clinical symptoms of XP, CS and of a third disorder, namely Fanconi anemia (FA), as well as in three cases showing FA alone (Kashiyama et al. American Journal of Human Genetics 92:807-819, 2013; Bogliolo et al. American Journal of Human Genetics 92:800-806, 2013; Popp et al. BMC Medical Genetics 19:7, 2018).

Diagnosis

The main diagnostic criteria of CS are low birthweight, little postnatal increase in weight and height, microcephaly, poor or absent psychomotor development, microphthalmia, congenital cataract, retinal degeneration, photosensitivity, arthrogryposis (i.e. congenital joint contractures), abnormal myelin formation, cerebellar hypoplasia, calcifications by cranial CT and reduced motor nerve conduction. The severe form of CS can be diagnosed already at birth, whereas in the classical form physical and mental retardation become manifest in childhood. Mild CS cases may have late onset and slow progression of symptoms. At all stages of disease progression, laboratory testing can be useful for confirming the suspected clinical diagnosis. The lack of cutaneous photosensitivity does not necessarily correlate with a normal cellular response to UV. The presence of repair defects in CS can be conclusively diagnosed by analyzing patient’s cells for the appropriate DNA repair defect. Specific functional assays on in vitro cultured fibroblasts from the patients (obtained from small skin biopsies) are available to evaluate the cellular response to UV light and to define the gene responsible for the DNA repair defect. A recent study in a large cohort of CS patients has shown that the mutation spectrum of the CS genes is not yet saturated, but missense mutations are largely confined to a few relatively short regions. There are no definitive correlations between genotype and phenotype, but truncation mutations C-terminal to the PiggyBac insertion in CSB/ERCC6 are more likely to confer a severe clinical phenotype than mutations N-terminal to this insertion. Also a higher proportion of severely affected patients was found with mutations in CSB/ERCC6 than in CSA/ERCC8 (Calmels et al. J Med Genet doi:10.1136/jmedgenet-2017-104877, 2018).

Treatment

There is currently no cure for CS. Management issues are: 1) comprehensive baseline evaluation at initial diagnosis to establish the extent of disease and serial monitoring; 2) symptomatic care.
Baseline evaluation includes measurement of growth, developmental assessment, dental evaluation, dermatologic, ophthalmologic and audiologic evaluations, brain MRI, skeletal X-rays to document the presence of skeletal dysplasia, EMG to document the presence of a demyelinating neuropathy, yearly reassessment for known potential complications such as declining vision and hearing.
Symptomatic care includes an individualized educational program, assistive devices, and assessment of safety in the home for developmental delay and gait disturbances, physical therapy to prevent contractures and maintain ambulation, feeding gastrostomy tube placement to prevent malnutrition, medication for spasticity. Hearing loss, cataracts and other ophthalmologic complications, and dental caries are treated as in the general population. Use of sunscreens and sunglasses and avoidance of excessive sun exposure are helpful.

 

A schedule for surveillance is provided in Wilson et al. Genetics in Medicine doi:10.1038/gim.2015.110, 2015.