Cockayne syndrome …

Arushi Gahlot Saini MD DM MNAMS

Neurogenetic Disorders

Updated 03.22.2024
Released 04.07.1995
Expires For CME 03.22.2027

Cockayne syndrome

Author: Arushi Gahlot Saini MD DM MNAMS

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Editor: Ganeshwaran H Mochida MD

Cockayne syndrome

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Introduction

Overview

Cockayne syndrome is a rare, autosomal recessive, multisystem, progressive degenerative brain disease caused by pathogenic variations in the excision repair cross complementation group 8 (ERCC8; OMIM# 609412) and excision repair cross complementation group 6 (ERCC6; OMIM# 609413) leading to Cockayne syndrome type A (OMIM# 216400) and type B (OMIM# 133540), respectively. The features of Cockayne syndrome include cachectic dwarfism, cataracts, optic atrophy, intellectual disability, unusual facies and body habitus, hearing loss, a peculiar form of fine pigmentary retinitis without the typical spicules of retinitis pigmentosa, and some similarities to the condition progeria. The neurologic abnormalities observed in patients with Cockayne syndrome are often collectively referred to as Cockayne syndrome neurologic disease. The phenotypic spectrum of Cockayne syndrome has been divided into three clinical presentations.

Cockayne syndrome type I (“classic” form) is a moderate form that presents with growth and developmental abnormalities in the first 2 years of life. The prenatal period of growth is normal, and death occurs by the first or second decade of life.

Cockayne syndrome type II is more severe form in which major abnormalities are recognized at birth or in the early neonatal period, with little or no postnatal development. Death occurs by 5 years of age.

The term cerebro-oculo-facio-skeletal (COFS) syndrome and its synonym, Pena-Shokeir syndrome type II, have been used to refer to a heterogeneous group of disorders characterized by congenital neurogenic arthrogryposis (multiple joint contractures), microcephaly, microphthalmia, and cataracts. The original cases of COFS syndrome described by Pena and Shokeir in 1974 among native Canadian families from Manitoba harbor homozygous pathogenic variants in ERCC6. COFS syndrome is now regarded as an allelic and prenatal form of Cockayne syndrome, partly overlapping with Cockayne syndrome type II, and includes the most severe cases of the Cockayne syndrome phenotypic spectrum (61).

Cockayne syndrome type III is a milder or late-onset form that presents after 2 years of age, and growth and cognition are relatively better as compared to other forms. Some very mild patients even reach a normal height and weight and a normal intellectual level but show late-onset cerebellar ataxia and secondary cognitive decline. This adult-onset subgroup of Cockayne syndrome is sometimes named Cockayne syndrome type IV and often represents a very difficult diagnostic challenge (35). Both Cockayne syndrome type III and type IV show purely neurodegenerative symptoms of the Cockayne syndrome spectrum.

A subset of patients presenting with mutations in one of several xeroderma pigmentosum genes, including ERCC3 (encodes XPB), ERCC2 (encodes XPD), ERCC4 (encodes XPF), ERCC5 (encodes XPG), and ERCC1 (DNA excision repair protein that works with ERCC4), also experience neurologic disease that is characteristic of Cockayne syndrome, along with the elevated risk of skin cancer observed in xeroderma pigmentosum. Such patients are classified as having xeroderma pigmentosum–Cockayne syndrome and belong to complementation group Cockayne syndrome type C.

Cockayne syndrome is extremely rare, with approximately 200 cases in the literature. In Europe, its annual incidence is estimated at 1 case per 200,000 births (84; 87). In a nationwide survey of Cockayne syndrome in Japan, the incidence was estimated to be 2.77 per million births (95% CI: 2.19–3.11), and the prevalence was approximately 1 in 2,500,000 (58). No race or sex predilection is reported for Cockayne syndrome; the male-to-female ratio is equal. Cockayne syndrome type 1 manifests in childhood, whereas type 2 has a worse prognosis and manifests at birth or in infancy. Death generally occurs by the age of 30 years, secondary to inanition or infection. Current management focuses on symptomatic therapy, although the possibility of gene therapy is under investigation.

Key points

	• Cockayne syndrome is an autosomal recessive multisystem disorder, predominantly characterized by neurologic and sensory impairment, cachectic dwarfism, and photosensitivity.
	• Based on the complementation groups, Cockayne syndrome is divided into types A, B, and C. The clinical features represent a spectrum of severity, and Cockayne syndrome is divided into clinical types I to III based on the features.
	• Clinically, the most typical form is known as Cockayne syndrome type I. A severe form seen at birth is known as Cockayne syndrome type II (also includes COFS). A much milder form is known as Cockayne syndrome type III, including the anecdotal adult-onset type IV). In addition, an entity known as xeroderma pigmentosum–Cockayne syndrome is recognized.
	• Diagnosis is made on clinical grounds and confirmed by molecular genetic testing. Molecular prenatal diagnosis of Cockayne syndrome has been successful. Carrier detection (50% chance of being an asymptomatic carrier) is available once the mutations have been identified in the proband.
	• Treatment consists of purely supportive care.
	• Cockayne syndrome is characterized by a deficiency in the transcription-couple DNA repair pathway caused by mutations mainly in the Cockayne syndrome group B gene (ERCC6 or CSB).

Historical note and terminology

Cockayne syndrome, or Cockayne-Neill-Dingwall syndrome, was first reported by English physician Edward Alfred Cockayne (1880–1956) in 1936 and re-described in 1946 in a brother and sister with dwarfism and retinal atrophy (18). He made a follow-up report in 1946, at which time he reported that the children were markedly different than at the first presentation (19). The features of the condition included the postnatal onset of dwarfism, cataracts, optic atrophy, mental retardation, unusual facies and body habitus, hearing loss, and a peculiar form of fine pigmentary retinitis without the typical spicules seen in retinitis pigmentosa. Neill and Dingwall later reported on another child and commented on some similarities to the condition of progeria (80), hence, the other name of the syndrome, “Neill-Dingwall syndrome.” Macdonald and colleagues reported three additional patients in a family (67). They saw a clear and sharp distinction between Cockayne syndrome and progeria, a point that has been clearly borne out by the discovery of the underlying pathogenesis in Cockayne syndrome.

The first step towards the development of experimental models of Cockayne syndrome was the in vitro culture of skin fibroblasts derived from patients with Cockayne syndrome in the 1970s. These fibroblasts were shown to be extremely sensitive to UV light (98; 03) and displayed a marked defect in the recovery of RNA synthesis after UV irradiation (62) due to a failure in the repair of transcriptionally active genes (116; 114). Subsequently, evaluation of post-UV RNA synthesis recovery in multinucleated cells obtained by the fusion of cells from different Cockayne syndrome donors led to the identification of three complementation groups (A, B, and C) (106; 62). In the 1990s, the genes corresponding to A and B were characterized and termed CSA and CSB, respectively. Group C identified by Lehmann corresponded to the xeroderma pigmentosum–Cockayne syndrome spectrum. CSB was originally termed ERCC6 (excision repair cross-complementation group 6) because it was found to complement the nucleotide excision repair (NER) defect in the complementation group 6 of rodent cell lines defective in excision repair (111). Subsequently, Troelstra demonstrated that ERCC6 gene expression could reverse UV sensitivity and rescue post-UV RNA synthesis in CSB but not in CSA (112). In 1995, the second gene ERCC8 encoding CSA protein was identified, which reversed the UV sensitivity of Cockayne syndrome cells from group A (42). Subsequently, it became clear that both genes interacted with each other and played critical roles in the transcription-coupled nucleotide excision repair (TC-NER) of damaged DNA (47).

Clinical manifestations

Presentation and course

Cockayne syndrome is a genetic condition characterized by short stature, microcephaly, mental retardation, characteristic senile appearance, retinopathy, sensorineural hearing loss, and the development of a leukodystrophy that results from a defect in the repair mechanism of actively transcribed DNA (63). Formal clinical diagnostic criteria originally proposed for Cockayne syndrome type I (76) have been revised and extended in more recent publications (75; 59). Clinical diagnosis requires three major criteria (progressive growth failure, mental retardation, and microcephaly) together with two minor criteria from the following: cataracts or pigmentary retinopathy, sensorineural hearing loss, dental abnormalities, loss of subcutaneous fat, and skin photosensitivity. Diagnostic and severity scores for Cockayne syndrome have been proposed that facilitate early diagnosis and longitudinal evaluation of possible therapeutic interventions (102). The following are important features.

Postnatal growth failure. Growth slows in the first year of life so that by early childhood they are two standard deviations below the mean for weight and height (76). The profound dwarfing, failure of brain growth, cachexia, selectivity of tissue degeneration, and poor correlation between genotypes and phenotypes are not understood (91). Specific Cockayne syndrome growth charts have been proposed to monitor growth and nutrition in these patients (06). These studies show that individuals with Cockayne syndrome type I initially have normal growth parameters. Microcephaly occurs from 2 months, whereas onset of weight and height restrictions appear later, between 5 and 22 months. In Cockayne syndrome type II, growth parameters are already below standard references at birth or drop below the fifth percentile before 3 months. Microcephaly is the first parameter to show a delay, appearing around 2 months in Cockayne syndrome type I and at birth in Cockayne syndrome type II. Height and head circumference are more severely affected in Cockayne syndrome type II compared to type I, whereas weight curves are similar in patients with Cockayne syndrome types I and II (06).

Typical progeroid facies. The facial appearance of patients with Cockayne syndrome is distinctive as they grow older. A loss of subcutaneous periorbital fat of the face occurs as they mature, giving a wizened look. The eyes are sunken. The ears and nose are prominent. The ears are cupped and large, the nose long and angulated. The teeth are carious (18; 19; 80; 67; 76).

Photosensitivity. Because of the impaired ability to repair DNA damage resulting from ultraviolet exposure, the skin is extremely sensitive to sunlight, often burning even after a trivial exposure. This photosensitivity has been reported in three fourths of affected individuals (76). There may be secondary reaction by the skin to this photosensitivity, but there is no increase in skin malignancy. This stands in contrast to the related condition xeroderma pigmentosa. Other skin manifestations include dry, scaly skin and thin hair; diminished subcutaneous tissue; dry, scaly skin; and occasionally anhidrosis (76). Sonmez and colleagues reported six patients with Cockayne syndrome type B without photosensitivity. They are all from the same inbred family and exhibit variable clinical features, including progressive encephalopathy, intracranial calcification and white-matter lesions, dwarfism without growth hormone deficiency, senile appearance, mental and motor retardation, atrophy of subcutaneous fat tissue, severe pectus carinatus, and spasticity. Clinical photosensitivity was not observed in any patient. The onset of the disease was between three and six months of age. Molecular genetic analyses in the family established linkage to ERCC6, confirming the clinical diagnosis, Cockayne syndrome type B (101). Tinsa and colleagues described a rare case of Cockayne syndrome that started in early infancy and presented with no photosensitivity (108).

Eye involvement. Eye involvement includes retinopathy, enophthalmos, strabismus, amblyopia, and cataract (109). The pigmentary changes in the retina are fine, involve the periphery, and are progressive. Studies utilizing electroretinogram and retinography in older patients show diffuse pigmentary retinopathy and macular atrophy (30). Bone spicules have been seen in older patients. Retinal dystrophy is seen in 60% of patients (76). Cockayne's original patients had cataracts, a feature seen in only 15% of patients (109). Visual acuity may be preserved in spite of significant retinal changes and optic atrophy. Other ophthalmological involvements have been optic atrophy, nystagmus, corneal lesions, band keratopathy, recurrent erosions, and poor pupillary response to dilating agents (109).

Sensorineural hearing loss. Sensorineural hearing loss occurs in over half of the individuals, with involvement ranging from mild to severe (76). Cellular degeneration of multiple components of the temporal bone has been reported (39). As with other features in this condition, the onset may be delayed and not apparent until late childhood or adolescence.

Neurocognitive impairment. The coexistence of impairment of hearing and vision make cognitive ability difficult to evaluate but, with few exceptions, individuals are moderately to severely impaired. Milestones in the first year of life may be near normal, but later, delays become evident. Many speak, although language is often reported as immature. There may be surprisingly good social interaction and ability to make interpersonal contact (67).

Motor impairment. The development of a leukodystrophy results in progressive neurologic deterioration. Often spasticity, ataxia, or choreoathetosis are experienced. Tremor may be prominent. The demyelination is both central and peripheral, with the peripheral neuropathy demonstrated by muscle weakness and wasting (76). Young patients may manifest epilepsy (36).

Contractures of the large joints. Contractures of the large joints result in a stooped posture with splayed legs. A bow-legged or horse-riding stance and a peculiar gait can be seen in those who walk (67). The limbs themselves are long, with large hands and feet, and may be held in flexion (36). Kyphoscoliosis is often present.

Dentition anomalies. Deficient hygiene, gingivitis, cervical caries, enamel hypoplasia, abnormal position of the upper and inferior lateral incisors, and macrodontia of the upper central teeth have been described (04).

Other features. Other features include functional renal abnormalities and signs of endocrine dysfunction, including undescended testes, micropenis, and irregular menses (76). A retrospective study of 136 genetically confirmed patients with Cockayne syndrome showed that 69% had a renal disorder or elevated blood pressure, 62% had proteinuria, 45% had a decreased glomerular filtration rate, and 72% had hyperuricemia (105). There was no correlation with the genetic background or clinical types of Cockayne syndrome. Funaki and colleagues described Cockayne syndrome with recurrent acute tubulointerstitial nephritis, suggesting that rapid deterioration of the renal function in Cockayne syndrome patients might be the result of acute tubulointerstitial nephritis (32). The nephrotic syndrome in their patient seemed to be accompanied by acute tubulointerstitial nephritis, as in other reports. Variability in the renal findings of siblings indicates that no obvious genotype-phenotype correlation exists; some renal changes may be related to premature aging (07).

A case of dilated cardiomyopathy has been reported, but cardiac involvement in general, has not been described in Cockayne syndrome patients. Ovaert and colleagues report one patient in whom marked ascending aorta dilatation was observed together with mild aortic regurgitation (82). Some atypical presentations, such as familial hemiplegic migraine, have been described in three full siblings with CSB who repeatedly presented with transient focal neurologic deficits and headache (14).

Prognosis and complications

The disease is progressive, although it often remains at a plateau for years. Many of the individuals die in late childhood or early adulthood of inanition, infection, or atherosclerosis. Rarely, and for unexplained reasons, the course for some patients with Cockayne syndrome is slower than usual, resulting in survival into adulthood. Rapin and colleagues report the clinical course and pathology of a man with Cockayne syndrome group A who died at the age of 31-and-a-half years with 15 adequately documented other adults with Cockayne syndrome and five with xeroderma pigmentosum-Cockayne syndrome complex (91).

Death generally occurs by the age of 30, secondary to inanition or infection.

Biological basis

Etiology and pathogenesis

Progeroid syndromes, including Cockayne syndrome, constitute a group of disorders characterized by clinical features mimicking physiological aging at an early age. All the characterized progeroid syndromes enter in the field of rare monogenic disorders, and several causative genes have been identified. These can be separated in subcategories corresponding to: (1) genes encoding DNA repair factors, in particular, DNA helicases; and (2) genes affecting the structure or post-translational maturation of lamin A, a major nuclear component (78).

Cockayne syndrome is an autosomal recessive condition that results from a defect in the repair of transcriptionally active genes. It is considered to be a heterogeneous condition based on complementation in cell fusion studies (38; 96). The reason patients with mutations in xeroderma pigmentosum genes present with the Cockayne syndrome phenotype is still not known. Some 43 patients with the rare xeroderma pigmentosum-Cockayne syndrome complex have been summarized (77).

Cleaver and colleagues posit that the complex symptoms of Cockayne syndrome may be due to multiple, independent, downstream targets of the E3 ubiquitylation system that result in increased DNA damage, reduced transcription coupled repair, and inhibition of cell cycle progression and growth (17). They have found that the Cockayne syndrome type B defect results in altered expression of anti-angiogenic and cell cycle genes and proteins at the level of both gene expression and protein lifetime. They also find an overabundance of p21 due to reduced protein turnover, possibly due to the loss of activity of the Cockayne syndrome type A/type B E3 ubiquitylation pathway (17). Increased levels of p21 are thought to result in growth inhibition, reduced repair from the p21-PCNA interaction, and increased generation of reactive oxygen.

In their study, Andrade and colleagues reveal that the induced pluripotent stem cells from CSB skin fibroblasts they generated, modulated by CSB, exhibited elevated cell death rate and higher reactive oxygen species production accompanied by an up-regulation of TXNIP and TP53 transcriptional expression (02). This offers some evidence for premature aging due to oxidative stress in induced pluripotent stem cells from Cockayne syndrome. Further evidence for this comes from the recognition that XPD-mutated cell lines are also sensitive to oxidative stress (64).

Because cells from Cockayne syndrome patients have a defect in transcription-coupled nucleotide excision repair (TC-NER), Cockayne syndrome is typically considered to be a DNA repair disorder. It appears, though, that defects in base excision DNA repair and certain mitochondrial functions may also be important (50). UV-sensitive, NER-deficient xeroderma pigmentosum patients mimic the sun-sensitive phenotype of Cockayne syndrome, but these patients do not suffer from the neurologic and other abnormalities that Cockayne syndrome patients do. Brooks proposes that the defects in transcription by both RNA polymerases I and II that have been documented in Cockayne syndrome cells provide a better explanation for many of the severe growth and neurodevelopmental defects in Cockayne syndrome patients than defective DNA repair (12).

Cockayne syndrome results from a specific defect in the DNA repair system. Cellular studies in fibroblasts from patients with Cockayne syndrome have shown hypersensitivity to the lethal effects of ultraviolet radiation. After irradiation, RNA synthesis is depressed in both normal and Cockayne syndrome cells. However, RNA synthesis recovers rapidly in normal cells, but fails to do so in cells from patients with Cockayne syndrome. This rapid recovery in normal cells is due to the preferential repair of DNA in transcribed regions, which does not occur in Cockayne syndrome (63). Ultraviolet (genotoxic) stress stops the transcription of about 70% of both genes (27). Researchers from the University of Strasbourg showed that defective transcription of ATF3-responsive genes could serve as prominent molecular markers to discriminate between patient cells in Cockayne syndrome and non-Cockayne syndrome (28).

Researchers have shown that RNA polymerase I transcription and processing of the pre-rRNA are disturbed in the cells of patients with Cockayne syndrome, leading to an accumulation of 18S intermediates (89). This results in severe protein synthesis malfunction, which, together with a loss of proteostasis, constitutes the underlying pathophysiology in Cockayne syndrome.

The repair of DNA lesions is an extremely important process for the integrity of the cell. Although several mechanisms exist for DNA repair, the most important is nucleotide excision repair. Nucleotide excision repair removes all types of lesions from DNA and is carried out by the coordinated action of eight to 10 protein subunits (26). Much of what has been learned about the nucleotide excision system in humans has come from the study of Cockayne syndrome and xeroderma pigmentosum. Xeroderma pigmentosum is a heterogeneous group (seven complementation groups identified) characterized by defects in DNA repair with the common clinical problem of photosensitivity and a predisposition for skin cancer. Although xeroderma pigmentosum is defective in repairing all ultraviolet-induced damage, Cockayne syndrome patients are unable to perform gene-specific repair (26).

Using complementation analysis, two complementation groups, Cockayne syndrome complementation group A and Cockayne syndrome complementation group B, have been identified. Stefanini and colleagues analyzed complementation as defined by restoration of normal RNA synthesis rates in ultraviolet-irradiated heterokaryons. They studied cell cultures from 22 patients with Cockayne syndrome. Cultures from five patients were assigned to complementation group A and the remaining 17 were assigned to complementation group B. There were no distinctions in terms of race, clinical presentation, or cellular characteristics between the two complementation groups (104).

The genes for both complementation groups, Cockayne syndrome complementation group A (or Cockayne syndrome A) and Cockayne syndrome complementation B (Cockayne syndrome B), have been identified. The gene for Cockayne syndrome B has been identified as one of the excision repair genes. Originally referred to as ERCC6, it is now called CSB. This gene encodes a 160 kd protein that is essential for nucleotide excision repair and the relief of oxidative stress. Without CSB, cells accumulate oxidative DNA lesions. Mutations in the gene encoding the CSB protein are responsible for most cases of Cockayne syndrome (09). The specific role of this protein is still under investigation. The gene for Cockayne syndrome A encodes a polypeptide of 396 amino acids with a calculated molecular mass of approximately 44 kd (42). The predicted structure of the putative protein indicates that it is a WD repeat protein and is associated with a variety of cellular regulatory functions. This group has the potential for interaction with other proteins and many are components of multiprotein complexes. Like CSB, CSA is involved in DNA repair and offers protection from senescence for keratinocytes (22). Although CSA and CSB share certain functions, they appear to act at different times during the DNA repair process (84).

From the study of these conditions as well as mutations in bacteria and yeast, it has been determined that transcription, RNA synthesis, and DNA repair are coupled. When the transcription enzymes encounter a DNA lesion such as a bulky pyrimidine dimer, they will stall and transcription ceases. This interferes with the smooth reading and transcription of active genes.

The role of the Cockayne syndrome A and Cockayne syndrome B proteins in transcription and repair is understood incompletely. Although it has been postulated that the senile aging of the skin, retinal degeneration, and nervous system degeneration are the result of the accumulation of somatic mutations with age, failure of DNA repair of active genes and resultant senescence or “genosenium” (38; 66), other evidence suggests a primary transcription defect (42; 31).

The Cockayne syndrome B protein is involved in ultraviolet-induced transcription coupled repair, base excision repair, and general transcription. Cockayne syndrome B also has a DNA-dependent ATPase activity that may play a role in remodeling chromatin in vivo. Muftuoglu and colleagues report the novel finding that Cockayne syndrome B catalyzes the annealing of complementary single-stranded DNA molecules with high efficiency and has strand exchange activity (73). The rate of Cockayne syndrome B-catalyzed annealing of complementary single-strand DNA is 25-fold faster than the rate of spontaneous single-strand DNA annealing under identical in vitro conditions, and the reaction occurs with a high specificity in the presence of excess non-homologous single-strand DNA. The specificity and intrinsic nature of the reaction is also confirmed by the observation that it is stimulated by dephosphorylation of Cockayne syndrome B, which occurs after ultraviolet-induced DNA damage, and is inhibited in the presence of ATP[gamma]S. Falik-Zaccai and colleagues have identified six Cockayne syndrome patients in one large, highly consanguineous, Druze kindred who descended from a single ancestor; all six patients presented with the congenital severe phenotype of the syndrome (29). They had no language skills, could not sit or walk independently, and died by the age of five years. Cellular studies of the fibroblasts from three patients showed a significant defect in transcription-coupled DNA repair (TCR) and a marked correction of the abnormal cellular phenotype with a plasmid containing the cDNA of the ERCC6 gene. Molecular studies led to identification of a novel insertion mutation, c.1034-1035insT in exon 5 of the ERCC6 gene (p.Lys345Asnfs*24). This mutation was identified in one in 15 healthy individuals from the same village, indicating an extremely high carrier frequency. The authors feel that identification of the causative mutation enables comprehensive genetic counseling among the population at risk from this village.

The neuropathology involves both the central and peripheral nervous system and is characterized by striking atrophy, demyelination, and the presence of mineralization (70; 95; 100). The brain at autopsy is very small for the age of the patient, consistent with the marked microcephaly in life. The skull is thickened. Atrophy of the cerebrum and cerebellum occurs, along with a reduction in the white matter with dilatation of the ventricles. Demyelination is patchy with a tigroid pattern of involvement. This pattern is also seen in Pelizaeus-Merzbacher disease and is not specific (70). The arcuate fibers are not spared, and no evidence is seen of inflammation. The demyelination has been seen throughout the nervous system, including brainstem, spinal cord, and peripheral nerve (95). Mineralization surrounding the vasculature is present. These widespread encrustations are positive for both calcium and iron and occasionally can form sizable brain stones in the basal ganglia (95).

Microscopically, ferruginated neurons are seen and others may contain lipofuscin pigment. Unusual astroglial cells, some multinucleated, have been reported (100). Macroglial cells are hyperchromatic and demyelination is patchy (118). In the cerebellum, severe atrophy of the internal granular layer and Purkinje cells occurs (95; 100). The inner layer of the retina is also gliotic, with the outer retina relatively spared (95). Using the TUNEL staining method and other immunohistochemical methods, it has been demonstrated that cerebellar granule cells undergo apoptotic cell death (55). Arteriosclerosis in the brain and subdural hemorrhage have been reported in a few Cockayne syndrome cases. By performing elastica van Gieson (EVG) staining and immunohistochemistry for collagen type IV, CD34, and aquaporin 4 in autopsy cases of Cockayne syndrome, Hayashi and colleagues showed an increase in the small arteries without arteriosclerosis in the subarachnoid space, in addition to string vessels (twisted capillaries) in the cerebral white matter and increased density of CD34-immunoreactive vessels (40). They speculate that the increased subarachnoid artery space may be the cause of subdural hemorrhage in Cockayne syndrome.

In peripheral nerve, mixed axonal and demyelinating neuropathy is seen. The density of myelinated fibers is diminished. Chronic demyelination and remyelination with onion-bulb formation is seen. These changes are age-dependent, being most pronounced in older individuals (99). Membrane-bound inclusions of polymorphous material have been seen in Schwann cells (34; 119).

Jaarsma and colleagues conclude that Cockayne syndrome mouse models mice develop a range of Cockayne syndrome phenotypes and open promising perspectives for testing interventional approaches (48). Mice deficient for CSA or CSB genetically mimic Cockayne syndrome in humans, and develop mild Cockayne syndrome symptoms, including reduced fat tissue, photoreceptor cell loss, and mild but characteristic nervous system pathology. These mild Cockayne syndrome models are converted into severe Cockayne syndrome models with short life span, progressive nervous system degeneration, and cachectic dwarfism after simultaneous complete inactivation of global genome NER. A spectrum of mild-to-severe Cockayne syndrome-like symptoms occurs in Xpb, Xpd, and Xpg mice that genetically mimic patients with a disorder that combines Cockayne syndrome symptoms with another NER syndrome, xeroderma pigmentosum. Cockayne syndrome is caused by mutations in CSA and CSB genes and is a hallmark feature of CSB patients is neurodegeneration. The precise molecular cause continues to remain elusive, but it has been suggested that damage to mitochondria could be involved, either as part of the accelerated aging that is manifest in Cockayne syndrome or accumulated damages that are part of normal aging (97). Altered ribosomal biogenesis may lead to stressed endoplasmic reticulum and apoptosis (86). By using the human neural progenitor cells that have self-renewal and differentiation capabilities, Ciaffardini and colleagues have shown that stable CSB knockdown dramatically reduced the differentiation potential of human neural progenitor cells revealing a key role for CSB in neurogenesis (15). In addition, neurite outgrowth, a characteristic feature of differentiated neurons, was also greatly abolished in CSB-suppressed cells. Based on the data, they conclude that CSB has a crucial role in coordinated regulation of transcription and chromatin remodeling activities that are required during neurogenesis. In Cockayne syndrome, the encoded ERCC6 protein is more commonly referred to as Cockayne syndrome B protein (CSB). Vessoni and colleagues successfully derived functional Cockayne syndrome neural networks from human Cockayne syndrome induced pluripotent stem cells (iPSCs), providing a new tool to facilitate studying this disease (117). They identified dysregulation of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) pathway, as well as pathways related to synapse formation, maintenance, and neuronal differentiation in CSB-neurons using unbiased RNA-seq gene expression analyses. Also, when compared to unaffected controls, CSB-deficient neural networks displayed altered electrophysiological activity, including decreased synchrony and reduced synapse density, suggesting that CSB is required for normal neuronal function.

As DNA methylation remodeling is a major aging marker, genome-wide analysis of DNA methylation of fibroblasts from healthy, UV-sensitive individuals with Cockayne syndrome showed that Cockayne syndrome shared DNA methylation changes with normal aging more than other progeroid diseases and included genes functionally validated for regular aging, supporting the accelerated aging hypothesis in Cockayne syndrome (23). Similarly, the epigenomic signature of accelerated ageing in progeroid Cockayne syndrome is being explored.

Human fibroblasts from CSB patients have been reprogrammed to generate integration-free induced pluripotent stem cells (iPSCs), thus, providing a powerful tool to dissect the molecular mechanisms underlying Cockayne syndrome caused by mutations in ERCC6 (68). Evidence of blood-brain barrier disruption, increased senescence of brain endothelial cells, and upregulation of inflammatory markers, such as ICAM-1, TNFalpha, p-p65, and glial cell activation, have emerged from Cockayne syndrome mouse models (49).

Differential diagnosis

Hereditary diseases characterized by genetic defects of DNA repair include ataxia telangiectasia, Nijmegen breakage syndrome, Werner syndrome, Bloom Syndrome, Fanconi anemia, xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. They share many clinical features such as growth retardation; neurologic disorders; premature aging; skin alterations including abnormal pigmentation; telangiectasia; xerosis cutis; pathological wound healing; as well as an increased risk of developing different types of cancer (53).

Cockayne syndrome is distinctive, especially in older individuals, but may overlap with xeroderma pigmentosum. Xeroderma pigmentosum is generally distinguished from Cockayne syndrome by the increased incidence of skin neoplasms in xeroderma pigmentosum. There have now been at least three forms of xeroderma pigmentosum determined by complementation where the individual has had some features of Cockayne syndrome. There have also been reports of two patients with the features of DeSanctis-Cacchione syndrome, a subtype of xeroderma pigmentosum with complementation studies consistent with a defect in Cockayne syndrome type B, or ERCC6, indicating some degree of phenotype heterogeneity (46). The difference in incidence of cancer may be due to the fact that UV exposure in Cockayne syndrome results in cell lethality but not mutagenesis (93). Owing to phenotypic overlap with other DNA repair disorders, such as subsets of xeroderma pigmentosa and trichothiodystrophy, individuals who present with clinical signs of Cockayne syndrome may also have pathogenic variants in ERCC1, ERCC2 (XPD), ERCC3 (XPB), ERCC4 (XPF), ERCC5 (XPG), and XPA.

As a leukodystrophy, the tigroid pattern of involvement needs to be distinguished from the connatal form of Pelizaeus-Merzbacher. However, the other clinical features should allow discernment.

When cardinal features are lacking, the diagnosis of Cockayne syndrome should be considered if presented with growth retardation, microcephaly, and one of the suggesting features, such as enophthalmia, limb ataxia, abnormal auditory evoked responses, or increased ventricular size on cerebral imaging (85).

A study has indicated that some forms of MORC2-related disorder have phenotypic similarities to Cockayne syndrome, including features of accelerated aging (103). Microrchidia CW-type zinc finger 2 (MORC2; MIM 616688), is part of a superfamily of proteins involved in chromatin remodeling, epigenetic transcriptional regulation, DNA repair, and fatty acid biosynthesis. Hence, MORC2 should be included in diagnostic genetic test panels targeting the evaluation of microcephaly or suspected DNA repair disorders. Further studies are needed to elucidate the specific molecular mechanisms by which these phenotypes arise.

Diagnostic workup

The diagnosis is established by the identification of biallelic pathogenic variants in the ERCC6 or ERCC8 genes. Mutations in the ERCC6 gene make up approximately 70% of cases. The majority of pathogenic variants are picked by sequence analysis, and 10% to 12% may need gene-targeted deletion/duplication analysis (60; 13). Most variants are predicted loss-of-function variants.

DNA repair assay. The hallmark of Cockayne syndrome is the failure of RNA synthesis to recover after ultraviolet irradiation. After irradiation, RNA synthesis is depressed in both normal and Cockayne syndrome cells but recovers rapidly in normal cells. It fails to do so in cells with the biochemical defect of Cockayne syndrome. This rapid recovery in normal cells is due to the preferential repair of DNA in transcribed regions, which does not occur in Cockayne syndrome (62). If the diagnosis of Cockayne syndrome is strongly suspected, but the molecular genetic testing does not identify pathogenic variants in one of the associated genes, an assay of the cellular phenotype can be considered. DNA repair assay is performed on skin fibroblasts (74).

Very early prenatal diagnosis of Cockayne syndrome has been done by coelocentesis at 8 weeks of gestation by aspiration of coelomic fluid from the coelomic cavity (33).

Additional studies that aid in the diagnosis include ophthalmological examination for cataracts and retinopathy (109); nerve conduction velocity or nerve biopsy examining for peripheral neuropathy (99; 34; 119); electromyography for the identification of demyelinating peripheral myopathy (08); CT scan for cerebral calcifications (24); MRI showing abnormalities of myelination (10); and skeletal radiographs showing thickened skull, intracranial calcifications, marble epiphyses in the terminal phalanges of the hands, protrusion of the anterior aspect of the vertebral bodies, and hypoplasia of the iliac wings (16).

Adachi and colleagues describe MRI findings of small patchy subcortical lesions visualized as areas of high intensity on diffusion-weighted images and low intensity on FLAIR images, suggestive of active demyelinating lesions (01). Koob and colleagues describe the neuroimaging characteristics of Cockayne syndrome (56). Hypomyelination was more severe in early onset disease than the late onset, though the latter also showed less cerebral atrophy. Atrophy involves the supratentorial white matter, cerebellum, corpus callosum, and brain stem. Calcifications seen were characteristically in the sulcal depths of the cortex. Putamen and dentate nuclei calcifications can occur as well. SPECT scans revealed presence of lactate and decreased choline and NAA ratios. Diffusion tensor imaging with volumetric analysis has been used to quantify atrophy and white matter abnormalities (57).

Kleijer and colleagues evaluated the results of 29 prenatal diagnoses for Cockayne syndrome in a consecutive series. They conclude that reliable prenatal diagnosis of the Cockayne syndrome can be made by the demonstration of a strongly reduced recovery of DNA-synthesis in ultraviolet-irradiated cultured chorionic villus cells or amniocytes (52). Assessment of the recovery of RNA-synthesis was needed as an adjunctive method in rare cases of poor cell growth and DNA-synthesis. Performing immunohistochemistry in autopsy brains and ELISA in the cerebrospinal fluid and urine of patients with hereditary DNA repair disorders, Hayashi and colleagues report that increased oxidative DNA damage and lipid peroxidation were noted in the presence of degeneration of basal ganglia, intracerebral calcification, and cerebellar degeneration in patients with xeroderma pigmentosum, Cockayne syndrome, and ataxia-telangiectasia-like disorder, respectively (41).

Genetic counseling. Genetic counseling is an integral part of patient care in those with this syndrome or those suspected of having it. Cockayne syndrome is inherited in an autosomal recessive manner. Reproduction has not been reported in any individual with Cockayne syndrome. Atypical cases may require molecular genetic testing. The two genes responsible for Cockayne syndrome are ERCC6 for 65% to 75% of individuals (110) and ERCC8 for 25% to 35% of individuals (42; 83). Sequence analysis for both genes is clinically available. Prenatal testing is available through laboratories offering custom prenatal testing. Carrier detection (50% chance of being an asymptomatic carrier) is available once the mutations have been identified in the proband.

Family support groups are an important adjunct and can be collaborative, assuming appropriate boundaries—ethical, professional, geographic, and other—are recognized (122).

Management

Treatment is symptomatic and multidisciplinary and aimed at preventing complications.

Feeding assistance. Some patients have required feeding tubes or even gastrostomy to avoid malnutrition because of poor oral intake, muscle weakness, or neurologic impairment.

Photosensitivity. Individuals with photosensitivity should avoid UV light from the sun or some artificial lights, including neon and halogen. Preventive measures include hats with a large brim, clothes that block UV, closed collars, and use of sunscreen with greater than 50 SPF during activities and trips outside, even in the winter or late afternoon when the brightness seems low. The eyes must also be protected by special glasses or a mask filtering the UV.

Ocular abnormalities. A significant proportion will require cataract extraction at an early age, which may present technical difficulties due to enophthalmos, which is a constant finding, with poor pupillary dilation and growth retardation. The fitting and assessment of aphakic contact lenses during the postoperative period also requires great skill. Strabismus, when it exists, must be taken care of very early.

Dental care. Horbelt reports that the dental care, procedures, and intervention offered to patients with Cockayne syndrome do not differ much from that given to any other patient (43).

Other measures. Patients should be monitored for treatable complications, including progressive hearing and visual loss, hypertension, and renal problems. Cochlear implants are successful in managing progressive hearing loss (115).

In their study, Motojima and colleagues evaluated the longitudinal changes in serum creatinine and serum cystatin C levels in three patients with Cockayne syndrome and found that the serum creatinine level in these patients gradually exceeded the reference level from five to seven years of age, after correcting for body length (72). The cystatin C level of the Cockayne syndrome patients increased to above the reference level whereas their estimated glomerular filtration rate remained within stage 2 or 3, showing that serum creatinine level is useful for the evaluation of renal function in Cockayne syndrome, which further helps in clinical management of patients.

Use of appropriate psychomotor rehabilitation, physiotherapy, and assistive devices to support the body in a good position (eg, corset) and allow movement (eg, canes, walker, wheelchair), even with neurologic decline, optimize the patient's well-being. Neilan and colleagues studied the effect of carbidopa-levodopa therapy in three patients with Cockayne syndrome (79). Main outcome measures included status of tremors, ability to perform daily tasks, serial physical examinations, and results of handwriting samples. They found that all three patients had a clear reduction in tremors and improvements in handwriting and manipulation of utensils and cups. GPi-pallidal stimulation has been used to treat generalized dystonia in Cockayne syndrome (37). Botulinum toxin injection has been used in a child with lower limb spasticity with encouraging results (44). Deep brain stimulation for Cockayne syndrome–associated movement disorder has also been tried for symptomatic relief (25).

Use of weight-appropriate rather than age-appropriate airway equipment must be a consideration in the perioperative management of Cockayne syndrome. Because of premature aging, the “adult” plateau in development is often attained in early childhood in severe cases. Hence, in these patients, recognition of advanced physiological age vis-à-vis their somatic appearance is essential for successful management (90).

As more information regarding genetic mechanisms is obtained, molecular therapy may become available. A number of signaling pathways are involved in nucleotide excision repair and could be used in future therapies (54). Studies have shown evidence for mitochondrial dysfunction in Cockayne syndrome, which likely contributes to the severe premature aging phenotype of this disease (81). NAD+ has been shown to be reduced in Cockayne syndrome, and short-term treatment (10 days) with the NAD+ precursor nicotinamide riboside has been shown to prevent hearing loss, restore outer hair cell loss, and improve cochlear health in mouse models of Cockayne syndrome (81). One model for gene rescue has proven successful in Cockayne stem cells (120). Information gained from this approach could have ramifications, not only for Cockayne syndrome, but for general aging as well (50). Because CSB is often overexpressed in cancer cells, its clinically induced downregulation may prove to be therapeutic (88). Necdin, a member of the melanoma-associated antigen protein family, has recently been identified as a target for the CSB protein (65). Loss of functional CSB leads to aberrant hyperactivation of Necdin that adversely affects neurogenesis and survival of postmitotic neurons. Thus, Necdin could serve as a prominent molecular marker for therapeutic intervention. Senomorphic drugs, such as trametinib, reduced senescent cell load and affected other aspects of the senescence phenotype (including splicing factor expression) in Cockayne syndrome cell cultures (11) and could be a useful adjunct to therapy for progeroid diseases.

Agents and circumstances to avoid

Excessive sun exposure should be avoided.

Patients who receive the antibiotic metronidazole may suffer acute neurologic deficits within weeks of administration. However, of greater concern is hepatotoxicity, which can be lethal within days of administration (05). A report of a 21-year-old patient with Cockayne syndrome who presented with jaundice following 1 week of treatment with metronidazole combined with spiramycin for dental care described the histopathological findings of the portal and lobular inflammation with a predominance of neutrophils, ballooning degeneration, and severe cholestasis without bile duct damage in the liver (45). The jaundice regressed over the next 6 weeks. An exact mechanism has not been identified, although hepatic difficulties are recognized in patients with Cockayne syndrome and could be exacerbated by the drug (121).

Extra vigilance is needed for opioid and sedative use.

Use of growth hormone treatment is not recommended in those with Cockayne syndrome. Growth hormone has not improved stature (76).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Arushi Gahlot Saini MD DM MNAMS

Dr. Saini of Postgraduate Institute of Medical Education and Research, Chandigarh, India, has no relevant financial relationships to disclose.
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Editor

Ganeshwaran H Mochida MD

Dr. Mochida of Boston Children's Hospital and Harvard Medical School has no relevant financial relationships to disclose.
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Former Authors

Gerald V Raymond MD
Tarakad S Ramachandran MD
Joseph R Siebert PhD

Patient Profile

Age range of presentation: 0 month to 18 years
Sex preponderance: male=female
Heredity: heredity typical

heredity may be a factor

autosomal recessive
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Other specified congenital anomalies, Cockayne’s disease or syndrome: 759.89
ICD-10: Cockayne syndrome: Q87.11
OMIM: Cockayne syndrome type A: #216400

Cockayne syndrome type B: #133450

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Cockayne syndrome

Associated Disorders

Cataracts
Deafness
Dwarfism
Leukodystrophy
Lowry syndrome
- Mental retardation
- Optic atrophy
- Peripheral neuropathy
- Xeroderma pigmentosum

Differential Diagnosis

xeroderma pigmentosum
DeSanctis-Cacchione syndrome
Pelizaeus-Merzbacher disease
Hutchinson-Gilford syndrome

Also Relevant

Adrenoleukodystrophy
Cerebro-oculo-facio-skeletal syndrome
Idiopathic basal ganglia calcification
Intellectual disability
Leukodystrophies
- Nondominant hereditary ataxias
- Pelizaeus-Merzbacher disease

Cockayne syndrome …

Cockayne syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Agents and circumstances to avoid

Special considerations

Pregnancy

Anesthesia

Malignancy

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
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to access the full version.

Questions or Comment?

Also in This Category

Vanishing white matter disease

Wilson disease

White matter abnormalities in the brain

Hypermethioninemia

POLG-related mitochondrial disorders

Multiple acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency

Long-chain fatty acid oxidation defects

Cockayne syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Agents and circumstances to avoid

Special considerations

Pregnancy

Anesthesia

Malignancy

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Vanishing white matter disease

Wilson disease

White matter abnormalities in the brain

Hypermethioninemia

POLG-related mitochondrial disorders

Multiple acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency

Long-chain fatty acid oxidation defects

This is an article preview.
Start a Free Account
to access the full version.