Embryonal sarcoma of the liver in a girl with Cockayne syndrome.

The first reported malignancy associated with Cockayne syndrome.

COFS type 3 in an Indian family with antenatally detected arthrogryposis.

Fetal akinesia and contractures can be caused by mutations in various genes that lead to overlapping phenotypes with contractures, rocker bottom feet, cerebellar hypoplasia, ventriculomegaly, growth retardation, pulmonary hypoplasia, cystic hygroma and cleft palate in various combinations. Cerebro-oculo-facio-skeletal (COFS) syndrome is a condition resulting from defects in DNA repair pathway, and genes involved include ERCC1 (COFS), ERCC2 (XPD), ERCC5(XPG), and ERCC6 (CSB). It is a severe disorder presenting in fetal or neonatal period with microcephaly, arthrogryposis, prominent nose, and kyphoscoliosis, and leads to early death in childhood. We report a baby with antenatally identified arthrogryposis in which the homozygous pathogenic variant in exon 8 was identified in ERCC5 gene, by targeted next generation sequencing. This was predicted to cause premature chain termination in the protein. ERCC5 gene is mainly implicated in xeroderma pigmentosum, sometimes in COFS syndrome.

Cockayne syndrome, MEN1, and genomic variants: Exome sequencing is changing our view of the genetic landscape.

The availability of genomic sequencing for inherited diseases provides a more complete molecular basis for how an individual's genetic landscape influences clinical outcome. We describe a family where exome sequencing of a 3-year-old boy with clinical features of Cockayne syndrome (CS) confirmed the diagnosis of CS. He also had a mutation consistent with a pre-symptomatic second disease, multiple endocrine neoplasia type 1 (MEN1), each potentially affecting multiple organ systems, in addition to a poorly defined variant in fumarate hydratase (FH). Genomic sequencing may reveal coexisting pathogenic mutations and variants which complicate clinical interpretation.

Early-onset nucleotide excision repair disorders with neurological impairment: Clues for early diagnosis and prognostic counseling.

Nucleotide excision repair associated diseases comprise overlapping phenotypes and a wide range of outcomes. The early stages still remain under-investigated and underdiagnosed, even although an early recognition of the first symptoms is of utmost importance for appropriate care and genetic counseling. We systematically collected clinical and molecular data from the literature and from newly diagnosed NER patients with neurological impairment, presenting clinical symptoms before the age of 12 months, including foetal cases. One hundred and eighty-five patients were included, 13 with specific symptoms during foetal life. Arthrogryposis, microcephaly, cataracts, and skin anomalies are the most frequently reported signs in early subtypes. Non ERCC6/CSB or ERCC8/CSA genes are overrepresented compared to later onset cohorts: 19% patients of this cohort presented variants in ERCC1, ERCC2/XPD, ERCC3/XPB or ERCC5/XPG. ERCC5/XPG is even the most frequently involved gene in foetal cases (10/13 cases, [4/7 families]). In this cohort, the mutated gene, the age of onset, the type of disease, severe global developmental delay, IUGR and skin anomalies were associated with earlier death. This large survey focuses on specific symptoms that should attract the attention of clinicians towards early-onset NER diagnosis in foetal and neonatal period, without waiting for the completeness of classical criteria.

Prenatal diagnosis of cerebro-oculo-facio-skeletal syndrome: Report of three fetuses and review of the literature.

Cerebro-oculo-facio-skeletal syndrome (COFS) is a rare autosomal recessive neurodegenerative disease belonging to the family of DNA repair disorders, characterized by microcephaly, congenital cataracts, facial dysmorphism and arthrogryposis. Here, we describe the detailed morphological and microscopic phenotype of three fetuses from two families harboring ERCC5/XPG likely pathogenic variants, and review the five previously reported fetal cases. In addition to the classical features of COFS, the fetuses display thymus hyperplasia, splenomegaly and increased hematopoiesis. Microencephaly is present in the three fetuses with delayed development of the gyri, but normal microscopic anatomy at the supratentorial level. Microscopic anomalies reminiscent of pontocerebellar hypoplasia are present at the infratentorial level. In conclusion, COFS syndrome should be considered in fetuses when intrauterine growth retardation is associated with microcephaly, arthrogryposis and ocular anomalies. Further studies are needed to better understand XPG functions during human development.

Multimodal imaging in a family with Cockayne syndrome with a novel pathogenic mutation in the ERCC8 gene, and significant phenotypic variability.

BACKGROUND: Cockayne syndrome is a rare autosomal recessive neurodegenerative disorder caused by mutations of either the ERCC6/CSB or ERCC8/CSA genes. Here, we describe two sisters with Cockayne syndrome caused by compound heterozygous mutations in the ERCC8 gene using multimodal imaging. Significant ophthalmic and systemic phenotypic variability is discussed. MATERIALS AND METHODS: Multimodal imaging was performed in two affected sisters and included electroretinography, optical coherence tomography, ultra-wide-field confocal scanning laser ophthalmoscopy, fundus autofluorescence and fluorescein angiography, and magnetic resonance imaging. Genetic analyses were performed on the affected sisters, both parents, and three unaffected siblings. RESULTS: The older sister (Patient 1) had mental retardation, bilateral hearing loss, ataxia, and decreased visual acuity with retinal dystrophy. Radiographic studies revealed microcephaly, cerebral and cerebellar atrophy, ventriculomegaly, and a diffusely thickened skull. Full-field electroretinography waveforms were severely diminished with attenuation of cone and rod responses. The younger sister (Patient 2) had similar clinical features, including ataxia, bilateral hearing loss, and decreased visual acuity with retinal dystrophy. She also had paranoid schizophrenia. Wide-field fundus autofluorescence showed scattered areas of retinal pigment epithelium atrophy, which was different from her sister. Genetic analysis revealed two mutations in the ERCC8 gene shared by the sisters. These include an unreported missense point mutation: p.Thr328Ser:c.983C > G, and another previously reported pathogenic missense mutation: p.Ala205Pro:c.613G > C. Familial testing showed in trans segregation of these mutations with unaffected siblings inheriting one or neither mutation, but not both. CONCLUSION: The clinical presentation and genetic studies confirmed a diagnosis of Cockayne syndrome in both sisters caused by compound heterozygous mutations in the ERCC8 gene on chromosome 10. Multimodal ocular imaging and systemic findings revealed wide phenotypic variability between the affected siblings.

First molecular study in Lebanese patients with Cockayne syndrome and report of a novel mutation in ERCC8 gene.

BACKGROUND: Cockayne Syndrome (CS) is a rare autosomal recessive disorder characterized by neurological and sensorial impairment, dwarfism, microcephaly and photosensitivity. CS is caused by mutations in ERCC6 (CSB) or ERCC8 (CSA) genes. METHODS: Three patients with CS were referred to the Medical Genetics Unit of Saint Joseph University. Sanger sequencing of both ERCC8 and ERCC6 genes was performed: ERCC8 was tested in all patients while ERCC6 in one of them. RESULTS: Sequencing led to the identification of three homozygous mutations, two in ERCC8 (p.Y322* and c.843 + 1G > C) and one in ERCC6 (p.R670W). All mutations were previously reported as pathogenic except for the c.843 + 1G > C splice site mutation in ERCC8 which is novel. CONCLUSIONS: Molecular diagnosis was established in all patients included in our study. A genotype-phenotype correlation is discussed and a link, between mutations and some specific religious communities in Lebanon, is suggested.

Xeroderma Pigmentosum - Cockayne Syndrome Complex (XP-CS) - Another case.

We present the case of a 3-year old girl with clinical manifestations typical of XP-CS, an extremely rare combination of Xeroderma Pigmentosum and Cockayne Syndrome. She had a swelling above the upper lip and multiple brown spots on her face, neck, arms and back. She was globally delayed, deaf, dumb and photophobic. MRI brain showed mild cerebral atrophy and bilateral demyelination. De Sanctis Cacchione variant (dSCS) and Rothmund Thomson syndrome (RTS), which were among the differential diagnosis were ruled out upon careful evaluation. Supportive treatment was given and regular checkups were recommended to monitor the progression of the disease but our patient did not show up for the follow up. This report shows that the diagnosis of XP-CS can be based on clinical features and MRI findings when the genetic testing is not available.

The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care.

PURPOSE: Cockayne syndrome (CS) is a rare, autosomal-recessive disorder characterized by microcephaly, impaired postnatal growth, and premature pathological aging. It has historically been considered a DNA repair disorder; fibroblasts from classic patients often exhibit impaired transcription-coupled nucleotide excision repair. Previous studies have largely been restricted to case reports and small series, and no guidelines for care have been established. METHODS: One hundred two study participants were identified through a network of collaborating clinicians and the Amy and Friends CS support groups. Families with a diagnosis of CS could also self-recruit. Comprehensive clinical information for analysis was obtained directly from families and their clinicians. RESULTS AND CONCLUSION: We present the most complete evaluation of Cockayne syndrome to date, including detailed information on the prevalence and onset of clinical features, achievement of neurodevelopmental milestones, and patient management. We confirm that the most valuable prognostic factor in CS is the presence of early cataracts. Using this evidence, we have created simple guidelines for the care of individuals with CS. We aim to assist clinicians in the recognition, diagnosis, and management of this condition and to enable families to understand what problems they may encounter as CS progresses.Genet Med 18 5, 483-493.

Novel missense mutations in a conserved loop between ERCC6 (CSB) helicase motifs V and VI: Insights into Cockayne syndrome.

Cockayne syndrome is caused by biallelic ERCC8 (CSA) or ERCC6 (CSB) mutations and is characterized by growth restriction, microcephaly, developmental delay, and premature pathological aging. Typically affected patients also have dermal photosensitivity. Although Cockayne syndrome is considered a DNA repair disorder, patients with UV-sensitive syndrome, with ERCC8 (CSA) or ERCC6 (CSB) mutations have indistinguishable DNA repair defects, but none of the extradermal features of Cockayne syndrome. We report novel missense mutations affecting a conserved loop in the ERCC6 (CSB) protein, associated with the Cockayne syndrome phenotype. Indeed, the amino acid sequence of this loop is more highly conserved than the adjacent helicase motifs V and VI, suggesting that this is a crucial structural component of the SWI/SNF family of proteins, to which ERCC6 (CSB) belongs. These comprise two RecA-like domains, separated by an interdomain linker, which interact through helicase motif VI. As the observed mutations are likely to act through destabilizing the tertiary protein structure, this prompted us to re-evaluate ERCC6 (CSB) mutation data in relation to the structure of SWI/SNF proteins. Our analysis suggests that antimorphic mutations cause Cockayne syndrome and that biallelic interdomain linker deletions produce more severe phenotypes. Based on our observations, we propose that further investigation of the pathogenic mechanisms underlying Cockayne syndrome should focus on the effect of antimorphic rather than null ERCC6 (CSB) mutations.

POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome.

Segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ. A prototypic example is the Werner syndrome (WS), caused by biallelic germline mutations in the Werner helicase gene (WRN). While heterozygous lamin A/C (LMNA) mutations are found in a few nonclassical cases of WS, another 10%-15% of patients initially diagnosed with WS do not have mutations in WRN or LMNA. Germline POLD1 mutations were recently reported in five patients with another segmental progeroid disorder: mandibular hypoplasia, deafness, progeroid features syndrome. Here, we describe eight additional patients with heterozygous POLD1 mutations, thereby substantially expanding the characterization of this new example of segmental progeroid disorders. First, we identified POLD1 mutations in patients initially diagnosed with WS. Second, we describe POLD1 mutation carriers without clinically relevant hearing impairment or mandibular underdevelopment, both previously thought to represent obligate diagnostic features. These patients also exhibit a lower incidence of metabolic abnormalities and joint contractures. Third, we document postnatal short stature and premature greying/loss of hair in POLD1 mutation carriers. We conclude that POLD1 germline mutations can result in a variably expressed and probably underdiagnosed segmental progeroid syndrome.

Nationwide survey of Cockayne syndrome in Japan: Incidence, clinical course and prognosis.

In the first nationwide survey of Cockayne syndrome (CS) in Japan, the incidence of CS 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. A total of 47 CS patients (24 surviving and 23 deceased) were identified. Based on clinical course, these 47 patients were classified into CS type 1 (n = 41; 21 surviving, 20 deceased), CS type 2 (n = 2; all deceased), CS type 3 (n = 3; all surviving), and CS/xeroderma pigmentosum type D (n = 1, deceased). In the 41 CS type 1 patients, seven findings (i.e. failure to thrive; photosensitivity; deafness; characteristic facial appearance of CS [sunken eyes]; foot joint contracture; intellectual disability; and basal ganglia calcification on computed tomography [CT]) were observed in >90% of patients. Of these, failure to thrive, photosensitivity, and intellectual disability (language delays) developed before 2 or 3 years of age, whereas deafness, sunken eyes, and basal ganglia calcification on CT occurred later. Features such as bodyweight and height stagnation, language delay, abnormal nutritional pathways (tube feeding), and renal failure were more prominent in the 20 deceased CS type 1 patients than in the 21 surviving CS type 1 patients. Of the 20 deceased CS type 1 patients, nine developed severe renal failure during the terminal stages of their condition. The present findings suggest that the clinical course of CS includes a diverse range of symptoms, but each type has characteristic symptoms. In addition, the management of renal failure and nutrition are very important for ensuring good quality of life throughout the long-term course of CS.

COCKAYNE SYNDROME: ROLE OF GENETIC COUNSELLING.

Cockayne's Syndrome (CS) is a rare autosomal recessive disorder characterized by deficiency in the transcription-couple DNA repair pathway caused by mutations in the genes ERCC6 in 65% of individuals and ERCC8 in 35% of individuals. Here we report a rare case of Cockayne's syndrome in a girl who presented with hallmark features specific to the syndrome. Dissemination of our knowledge about clinical manifestations encountered in Cockayne syndrome is instrumental not only for early evaluation and treatment to prolong life expectancy, but also to initiate early genetic counselling with parents concerning future pregnancies.

A novel homozygous ERCC5 truncating mutation in a family with prenatal arthrogryposis--further evidence of genotype-phenotype correlation.

We report on a family with five fetuses conceived to first cousin parents presenting with abnormal ultrasound findings including contractures and microcephaly. Cerebellar hypoplasia and ventriculomegaly were also present in two and fetal edema developed in the one fetus that survived beyond 24 weeks of gestation. Linkage studies of 15 members of the family, including four affecteds, were undertaken followed by exome sequencing of one affected individual and their parents. Analysis of exome data was restricted to the 9.3 Mb largest shared region of homozygosity identified by linkage; a single novel homozygous mutation in the proband that was heterozygous in the parents (ERCC5 c.2766dupA, p.Leu923ThrfsX7) was identified. This segregated with disease. ERCC5 is a component of the nucleotide excision repair machinery and biallelic mutations in the gene have previously been associated with xeroderma pigmentosum (group G), Cockayne syndrome and the more severe cerebrooculofacioskeletal syndrome. The phenotype in the family we report on is consistent with a severe manifestation of cerebrooculofacioskeletal syndrome. Our data broaden the reported clinical spectrum of ERCC5 mutations and provide further evidence of genotype-phenotype correlation with truncating mutations being associated with severe phenotypes. They also demonstrate the molecular diagnostic power of a combined approach of linkage studies and exome sequencing in families with rare, genetically heterogeneous disorders and a well described pedigree.

[Genetic analysis for a family with Cockayne syndrome].

OBJECTIVE: To identify potential mutations among three sisters from a Chinese family suspected with Cockayne syndrome for growth and psychomotor retardation, and to offer genetic counseling and prenatal diagnosis for the family. METHODS: G-banded karyotyping, microarray comparative genomic hybridization (CM-CGH), whole genome exon high-throughput sequencing and Sanger sequencing were employed to identify potential genetic variations for the three patients and their parents. RESULTS: Whole exome sequencing has identified two novel missense mutations, i.e., c.1595A>G (p.Asp532Gly) and c.1607T>G (p.Leu536Trp), in exon 7 of excision repair cross-complementing rodent repair deficiency, complementation group 6 (ERCC6) gene. Sanger sequencing confirmed that all of the three sisters have inherited one of the mutations (c.1607T>G) from their father and another (c.1595A>G) from their mother. CONCLUSION: Three sisters have all been identified as double heterozygote for mutations c.1607T>G and c.1595A>G and were diagnosed with Cockayne syndrome.

Spectrum of ERCC6-Related Cockayne Syndrome (Type B): From Mild to Severe Forms.

(1) Background: Cockayne syndrome (CS) is an ultra-rare multisystem disorder, classically subdivided into three forms and characterized by a clinical spectrum without a clear genotype-phenotype correlation for both the two causative genes ERCC6 (CS type B) and ERCC8 (CS type A). We assessed this, presenting a series of patients with genetically confirmed CSB. (2) Materials and Methods: We retrospectively collected demographic, clinical, genetic, neuroimaging, and serum neurofilament light-chain (sNFL) data about CSB patients; diagnostic and severity scores were also determined. (3) Results: Data of eight ERCC6/CSB patients are presented. Four patients had CS I, three patients CS II, and one patient CS III. Various degrees of ataxia and spasticity were cardinal neurologic features, with variably combined systemic characteristics. Mean age at diagnosis was lower in the type II form, in which classic CS signs were more evident. Interestingly, sNFL determination appeared to reflect clinical classification. Two novel premature stop codon and one novel missense variants were identified. All CS I subjects harbored the p.Arg735Ter variant; the milder CS III subject carried the p.Leu764Ser missense change. (4) Conclusion: Our work confirms clinical variability also in the ERCC6/CSB type, where manifestations may range from severe involvement with prenatal or neonatal onset to normal psychomotor development followed by progressive ataxia. We propose, for the first time in CS, sNFL as a useful peripheral biomarker, with increased levels compared to currently available reference values and with the potential ability to reflect disease severity.

Ocular manifestations of xeroderma pigmentosum: long-term follow-up highlights the role of DNA repair in protection from sun damage.

OBJECTIVE: Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations in DNA repair genes. Clinical manifestations of XP include mild to extreme sensitivity to ultraviolet radiation resulting in inflammation and neoplasia in sun-exposed areas of the skin, mucous membranes, and ocular surfaces. This report describes the ocular manifestations of XP in patients systematically evaluated in the Clinical Center at the National Institutes of Health. DESIGN: Retrospective observational case series. PARTICIPANTS: Eighty-seven participants, aged 1.3 to 63.4 years, referred to the National Eye Institute (NEI) for examination from 1964 to 2011. Eighty-three patients had XP, 3 patients had XP/Cockayne syndrome complex, and 1 patient had XP/trichothiodystrophy complex. METHODS: Complete age- and developmental stage-appropriate ophthalmic examination. MAIN OUTCOME MEASURES: Visual acuity; eyelid, ocular surface, and lens pathology; tear film and tear production measures; and cytologic analysis of conjunctival surface swabs. RESULTS: Of the 87 patients, 91% had at least 1 ocular abnormality. The most common abnormalities were conjunctivitis (51%), corneal neovascularization (44%), dry eye (38%), corneal scarring (26%), ectropion (25%), blepharitis (23%), conjunctival melanosis (20%), and cataracts (14%). Thirteen percent of patients had some degree of visual axis impingement, and 5% of patients had no light perception in 1 or both eyes. Ocular surface cancer or a history of ocular surface cancer was present in 10% of patients. Patients with an acute sunburning skin phenotype were less likely to develop conjunctival melanosis and ectropion but more likely to develop neoplastic ocular surface lesions than nonburning patients. Some patients also showed signs of limbal stem cell deficiency. CONCLUSIONS: Our longitudinal study reports the ocular status of the largest group of patients with XP systematically examined at 1 facility over an extended period of time. Structural eyelid abnormalities, neoplasms of the ocular surface and eyelids, tear film and tear production abnormalities, ocular surface disease and inflammation, and corneal abnormalities were present in this population. Burning and nonburning patients with XP exhibit different rates of important ophthalmologic findings, including neoplasia. In addition, ophthalmic characteristics can help refine diagnoses in the case of XP complex phenotypes. DNA repair plays a major role in protection of the eye from sunlight-induced damage.

Characterisation of a novel missense mutation in the ERCC5 gene leading to group G xeroderma pigmentosum/Cockayne syndrome overlap.

Xeroderma pigmentosum-Cockayne syndrome complex (XP-CS) is exceedingly rare, with 43 cases described over the past five decades; 21 of these cases exhibited mutations in the ERCC5 endonuclease associated with xeroderma pigmentosum, group G.We report the first known phenotypic characterisation of the homozygous chromosome 13 ERCC5, Exon 11, c.2413G>A (p.Gly805Arg) missense mutation in a female toddler presenting with findings of both XP and CS.Her severe presentation also questions previous hypotheses that only truncating mutations and early missense mutations of XPG are capable of producing the dire findings of XP-CS.