DISEASE CARD

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.

Clinical Description

CS is a clinically heterogeneous multisystem disorder, with a wide range in type and severity of symptoms. The cardinal clinical features of CS are pre- or post-natal growth failure (comprising height, weight and head circumference), leading to a characteristic appearance of so-called cachectic dwarfism, and progressive neurological and psychomotor dysfunction. Associated signs/symptoms 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 (no elevated risk of skin cancer). Affected individuals usually have a characteristic facies that includes a thin ace, flat cheeks and prominent tapering nose (bird-like face).^3-5

A subdivision into three clinically different classes of the disease has been suggested by Nance and Berry³: 
a)    CSI, classical form: includes the majority of cases; presence of the two cardinal symptoms (severe growth failure, neurodevelopmental dysfunctions) and at least three of the other features (see diagnosis); death typically occurs in the first or second decade;
b)    CSII, severe form: early onset and severe progression of symptoms, with low birth weight and poor or absent physical and neurological development; most patients die at 6 or 7 years of age due to cachexia; cutaneous signs as well as auditory and dental pathologies are less commonly present.
c)    CSIII, mild form: late onset and slow progression of symptoms

The classical type CSI 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 CSII show growth failure at birth, with little or no postnatal neurological development, congenital cataracts or other structural anomalies of the eye. 

Patients with CSIII usually show normal growth or normal cognitive development. 

It has become evident that CS encompasses a continuous spectrum of severity and that there is no clear threshold between the 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), respectively.

COFS is a rapidly progressive neurological disorder that was delineated in 1974, as occurring with autosomal recessive inheritance in isolated Manitoba families.⁶ 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 and is characterized by mild skin abnormalities in sun-exposed areas of the skin (see the specific disease card for details). ⁷

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. A crucial role for the CS proteins in expression of neuronal genes and thereby in neuronal differentiation has been described.⁸ 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 can also be 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. The products of the XPF/ERCC4 and ERCC1 genes 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 mutations 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 a third disorder, namely Fanconi anemia (FA), as well as in three cases showing FA alone.^9-11 

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. In addition, there are some cases showing the clinical and cellular features of both CS and xeroderma pigmentosum (XP/CS). These individuals have mutations 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 can show mutations in ERCC1 or XPG/ERCC5.
 

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 becomes obvious at birth, whereas in the classical form physical and mental retardation usually manifest in childhood. 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 diagnosed by analyzing patient’s cells for the specific 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 study in a large cohort of CS patients has shown that the mutational 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. Further, a higher proportion of severely affected patients showed mutations in CSB/ERCC6 rather than in CSA/ERCC8¹²

Differential Diagnosis

Chromosomal abnormalities, Hallermann–Streiff syndrome, Russell–Silver syndrome, Brachmann–deLange syndrome, Dubowitz syndrome, Tyrosinaemia, Leucodystrophies, Peroxisomal disorders

Treatment

There is currently no cure for CS.

Management includes: 1) baseline evaluation at time of diagnosis to measure the extent of disease for 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 comprises 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, sunglasses and avoidance of excessive sun exposure are recommended.¹³

References

^{1.    Kleijer WJ, Laugel V, Berneburg M, Nardo T, Fawcett H, Gratchev A, et al. Incidence of DNA repair deficiency disorders in western Europe: Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. DNA Repair (Amst). 2008;7(5):744-750.
2.    Kubota M, Ohta S, Ando A, Koyama A, Terashima H, Kashii H, et al. Nationwide survey of Cockayne syndrome in Japan: Incidence, clinical course and prognosis. Pediatr Int. 2015;57(3):339-347.
3.    Nance MA, Berry SA. Cockayne syndrome: review of 140 cases. Am J Med Genet. 1992;42(1):68-84.
4.    Karikkineth AC, Scheibye-Knudsen M, Fivenson E, Croteau DL, Bohr VA. Cockayne syndrome: Clinical features, model systems and pathways. Ageing Res Rev. 2017;33:3-17.
5.    Natale V. A comprehensive description of the severity groups in Cockayne syndrome. Am J Med Genet A. 2011;155a(5):1081-1095.
6.    Pena SD, Shokeir MH. Syndrome of camptodactyly, multiple ankyloses, facial anomalies, and pulmonary hypoplasia: a lethal condition. J Pediatr. 1974;85(3):373-375.
7.    Itoh T, Ono T, Yamaizumi M. A new UV-sensitive syndrome not belonging to any complementation groups of xeroderma pigmentosum or Cockayne syndrome: siblings showing biochemical characteristics of Cockayne syndrome without typical clinical manifestations. Mutat Res. 1994;314(3):233-248.
8.    Wang Y, Chakravarty P, Ranes M, Kelly G, Brooks PJ, Neilan E, et al. Dysregulation of gene expression as a cause of Cockayne syndrome neurological disease. Proc Natl Acad Sci U S A. 2014;111(40):14454-14459.
9.    Kashiyama K, Nakazawa Y, Pilz DT, Guo C, Shimada M, Sasaki K, et al. Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia. Am J Hum Genet. 2013;92(5):807-819.
10.    Bogliolo M, Schuster B, Stoepker C, Derkunt B, Su Y, Raams A, et al. Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. Am J Hum Genet. 2013;92(5):800-806.
11.    Popp I, Punekar M, Telford N, Stivaros S, Chandler K, Minnis M, et al. Fanconi anemia with sun-sensitivity caused by a Xeroderma pigmentosum-associated missense mutation in XPF. 2018;19(1):7.
12.    Calmels N, Botta E, Jia N, Fawcett H, Nardo T, Nakazawa Y, et al. Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome. J Med Genet. 2018;55(5):329-343.
13.    Wilson BT, Stark Z. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. 2016;18(5):483-493.}