Clinical characteristics of 16 patients with nucleotide excision repair disorders and literature review / 中华实用儿科临床杂志

Objective:To summarize the clinical manifestations and gene mutation features of patients with nucleotide excision repair (NER) disorders.Methods:A retrospective analysis was made on clinical data of patients with NER disorders who were admitted to the Chinese People′s Liberation Army General Hospital from October 2008 to February 2022 and diagnosed in the Outpatient Department of Beijing Children′s Hospital, Capital Medical University from October 2015 to February 2022.Literature on previously reported Chinese patients with NER disorders was reviewed.Results:(1)A total of 16 patients with NER disorders were enrolled, including 6 males and 10 females.The onset age was 7.5 (4.0, 12.0) months and the age at diagnosis was 42.0 (21.5, 77.0) months.There were 3 types of NER disorders: Cockayne syndrome (CS) in 13 cases, Xeroderma Pigmentosum (XP) in 2 cases and Cerebro-Oculo-Facio-Skeletal syndrome (COFS) in 1 case.Four disease-causing genes were detected: CSA gene in 11 cases, CSB gene in 3 cases, XPG gene in 1 case, and XPD gene in 1 case.The first symptoms of the 16 patients were photosensitivity and developmental delay, and neurological symptoms were observed in all the 3 NER disorder types.XP and CS patients had skin symptoms.CS patients presented typical facial features, visual and auditory impairment, microcephaly and changes in neuroimaging features.COFS patients showed intrauterine growth retardation.(2)Results of literature review: a total of 96 Chinese patients reported were retrieved, involving 6 disease types, including CS in 45 cases, XP in 44 cases, trichothiodystrophy in 4 cases, COFS in 1 case, XP-CS in 1 case, and ultraviolet sensitive syndrome in 1 case.Nine mutated genes were identified: CSA in 33 cases, XPA in 15 cases, CSB in 13 cases, XPV in 10 cases, XPC in 9 cases, XPG in 7 cases, XPD in 7 cases, XPF in 1 case, and MPLKIP in 1 case.The common symptoms were growth failure (62 cases), skin photosensitivity (61 cases), typical facial features (52 cases), mental retardation (49 cases) and microcephaly (48 cases). Among 36 cases had imaging data 33 cases(91.7%)had calcification of basal nucleus or globus pallidus.Three cases had intrauterine growth retardation and microcephaly during pregnancy. Conclusions:Patients with such prenatal manifestations as intrauterine growth retardation and microcephaly or with typical symptoms like skin photosensitivity, typical facial features, growth failure, mental retardation, hypertonia, and calcifications of basal ganglia should be suspected of NER disorders.Early genetic testing is recommended to confirm the diagnosis.

Anesthesia for a cesarean section on a pregnant patient with Cockayne syndrome: case report / Anestesia para cesárea em gestante com síndrome de Cockayne: relato de caso

Abstract Cockayne syndrome is an autosomal recessive multi-systemic disorder due to DNA repair failure. It was originally described in 1936 in children of small stature, retinal atrophy and deafness, characterized by dwarfism, cachexia, photosensitivity, premature aging and neurologic deficits. The most typical feature is described as birdlike facies: protruding maxilla, facial lipoatrophy, sunken eyes, large ears and thin nose. Difficult airway management with subglottic stenosis and risk of gastric content aspiration has been described. Although the clinical characteristics of Cockayne syndrome have been well described in pediatric publications, there is only one report in the literature on anesthesia for an obstetric patient. We report the case of a pregnant patient diagnosed with Cockayne syndrome, submitted successfully to spinal anesthesia for a cesarean section due to cephalopelvic disproportion. In view of the difficult decision between inducing general anesthesia in a patient with a likely difficult airway, or neuraxial anesthesia in a patient with cardiovascular, respiratory and neurocognitive limitations, we suggest tailored management to reach the best results for the mother and newborn.

Resumo A síndrome de Cockayne é doença multissistêmica autossômica recessiva devido à falha no reparo do DNA. Originalmente descrita em 1936 em crianças com baixa estatura, atrofia retiniana e surdez, é caracterizada por nanismo, caquexia, fotossensibilidade, envelhecimento acelerado e déficits neurológicos. O mais típico é a fácies, descrita como similar à de um pássaro: maxila proeminente, atrofia do coxim adiposo bucal, olhos profundos, orelhas grandes e nariz fino. Tem sido descrita dificuldade no manejo da via aérea com estreitamento subglótico e risco de aspiração gástrica. Embora as características clínicas da síndrome de Cockayne sejam bem relatadas em publicações pediátricas, há apenas um relato de anestesia em paciente obstétrica na literatura. Relatamos o caso de gestante com diagnóstico de síndrome de Cockayne, submetida com sucesso a raquianestesia para parto cesariano por desproporção cefalopélvica. Diante da difícil decisão entre induzir anestesia geral em paciente com provável via aérea difícil ou anestesia neuroaxial, em meio a limitações cardiovasculares, respiratórias e neurocognitivas da paciente, conduta individualizada é sugerida para alcançar os melhores resultados para a gestante e o neonato.

Advance of clinical and genetic studies on Cockayne syndrome / 中华实用儿科临床杂志

Cockayne syndrome is a rare autosomal recessive disorder with multisystem degenerative disorders caused by DNA repair defect. The patients usually presented with developmental delay,failure to thrive,premature aging,cutaneous photosensitivity and microcephaly. The phenotype was a continuous spectrum,with severity from severe to mild as Cerebro - oculofacio - skeletal syndrome (COFS),Cockayne syndrome type Ⅱ,Cockayne syndrome type Ⅰ, Cockayne syndrome type Ⅲ and ultraviolet ray(UV)- sensitive syndrome. In addition,there is xeroderma pigmentosum -Cockayne syndrome type. Cockayne syndrome manifested as the defect of DNA repair after UV damage cytologically. The main pathogenic genes of Cockayne syndrome are CSA (ERCC8)and CSB (ERCC6). Now,the progress of clinical and genetic studies on Cockayne syndrome were reviewed.

Clinical and molecular genetic study of Cockayne syndrome accompanied with nephrotic syndrome in a family / 中华实用儿科临床杂志

Objective To analyze the clinical and genetics characteristics in twin sisters with Cockayne syn-drome.Methods The identical twin sisters visited the Affiliated Children's Hospital of Capital Institute of Pediatrics in December 2016.The clinical presentations,course of treatment,blood biochemistry,metabolic screening and whole exon sanger sequencing were analyzed.Results These two patients were referred at 4 years and 5 months of age for growth failure and developmental delay.The younger sister manifested short stature(only 97 cm),low weight(14.0 kg)and little head circumference(43 cm),and the elder sister manifested short stature(only 98 cm),low weight(15.5 kg) and little head circumference(43 cm).They were born with out adverse event,and then they kept the head up at 8 months of age.They could sit at 10 months of age,but they had not acquired independent walking ability up till now. They spoke their first words at 2 year of age,and made little progress after that.They had a variety of abnormal clinical features including cognitive deficits,microcephaly,thin pointy nose,sunken eyes,small chin,photosensitive rash,hearing impairment,volitional tremor and hypermyotonia.They had been diagnosed as nephrotic syndrome at 4.5 years old,with little response to prednisone.The renal biopsy revealed minimal change nephropathy.Cerebrum and cerebellum atrophy was detected by magnetic resonance image scanning. Two heterozygous ERCC8 mutations in both patients,c.394_398delTTACA and large fragment deletion,were identified in the patient.The c.394_398delTTACA mutation originated from his father. The exon 4 deletion from his mother caused the defection of the protein. Conclusions Cockayne syndrome is a rare autosomal recessive disease. It is not only characterized by developmental delay,microcephaly, sunken eyes,photosensitive rash and auditory abnormalities,but also can be involved in nephrotic syndrome.Cockayne syndrome can be caused by compound heterozygous mutation,including c.394_398delTTACA and a large fragment deletion of exon 4 in ERCC8.

Clinical characteristics, treatment and follow-up of Cockayne syndrome with renal involvement / 临床儿科杂志

Objective To explore the clinical features, treatment and follow-up of Cockayne syndrome with renal involvement. Method The clinical data of one child with Cockayne syndrome confirmed by gene detection with renal injury were reviewed, and the clinical features of renal involvement in Cockayne syndrome were summarized. Results A male child aged 3 years and 8 months had clinical manifestations of mental retardation, growth retardation, special face and photosensitive dermatitis, and renal involvement was manifested by nephrotic syndrome. Cranial CT showed symmetrically calcification in bilateral basal ganglia. The targeted next generation sequencing results showed homozygous mutations of c.394_398del and p.Leu132Asnfs in ERCC8 gene (NM_000082) of the child, and the same heterozygous mutation was found in both his parents (non-consanguineous marriage). After the diagnosis of nephrotic syndrome, full dose prednisone was given for experimental treatment. The urine protein decreased but did not disappear, which was considered hormone resistance. After 4 months of combined treatment with cyclosporin, the urine protein turned negative. During 20 months of follow-up, urine protein remained negative and renal function remained stable. The renal involvement in Cockayne syndrome was seldomly reported, and its clinical manifestations are heterogeneous. Condusion Renal involvement in Cockayne syndrome may be manifested with nephrotic syndrome which should be noticed.

Identifying of the ERCC8 gene mutations in a pedigree with Cockayne syndrome / 中华检验医学杂志

Objective To identify the pathogenesis gene mutation of a pedigree with Cockayne syndrome.Methods The peripheral blood samples of the patient and his family members were collected and the genomic DNA was then extracted.Whole exome sequencing(WES)was performed for proband′s DNA.The disease-causing mutations were identified by bioinformatics analysis and pedigree analysis. Meanwhile,the mutations were confirmed by Sanger sequencing.Results Two novel mutations in ERCC8 gene,including c.400-2A >G and c.394_398delATGTA(p.L132fs)were identified in proband.The splicing mutation originated from his father and changed the splice acceptor site AG to GG, thus possibly caused alternative splicing.The c.394_398delATGTA(p.L132fs)frameshifting mutation was inherited from his mother.The proband′s sister also carried the same compound heterozygous mutation and had the same phenotype as proband.Conclusion The pathogenesis ERCC8 gene mutation of this pedigree with Cockayne syndrome was identified by using whole exome sequencing.

A case of Cockayne syndrome caused by ERCC8 gene mutation / 临床儿科杂志

Objective To explore the clinical,radiological and gene mutation features ofERCC8 gene in one patient with Cockayne syndrome.Methods Clinical and radiological data of a girl diagnosed with Cockayne syndrome through gene detection were retrospectively analyzed.Next-generation sequencing was used to detect genetic cause.Sanger sequencing was used to confirm the candidate variants and detect mutations in her parents and sister.ResuRs The patient showed psychomotor retardation,growth failure,special face,and light sensitivity.Neurological examination revealed noticeable developmental delay,motor impairment,spastic paralysis,and cerebellar ataxia.Brain MRI revealed symmetrical demyelination of bilateral centrum semiovale and periventricular white matter.The cerebellum was atrophic.The patient was found to have compound heterozygous mutations of c.397C＞T(p.Q133X) and c.394_398del(p.L132fs).Sanger sequencing showed these two mutations were inherited from her mother and father respectively.Conclusions Next-generation sequencing technology is a useful tool for the detection of mutation in ERCC8 gene,which is valuable for the diagnosis of Cockayne syndrome.These two mutations expanded the mutation spectrum of Cockayne syndrome in Chinese population.

A Rare Case of Cockayne Syndrome.

Background: Cockayne syndrome is a rare autosomal recessive congenital disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight (photosensitivity), and premature aging. Case: In this report we present a 24 year old male with decreased height, weight & reduced head circumference measuring 124 cm, 20 kg and 20 cm respectively. Cachectic dwarfism, ataxic gait, mental retardation, sunken eyes, hypoplastic maxilla, and parrot beak shaped nose giving “bird like facies” were other key features observed in our patient. Oral examination revealed congenital missing teeth and multiple dental caries teeth are also seen. Magnetic resonance imaging and computed tomography findings were also contributory to our diagnosis. Conclusion: This case report aims to rekindle and emphasis the diagnostic features of Cockayne syndrome & highlights the role of various investigations done by both medical & dental professionals to diagnose and manage the patient.

Síndrome de Cockayne: relato de dois casos / Cockayne?s syndrome: report of two cases

Objetivos: Relatar casos de síndrome de Cockayne em dois irmãos, descrevendo a apresentação e a evoluçãoclínica.Descrição dos casos: Apresentam-se os casos de dois irmãos, uma menina de 8 anos e um menino de 13 anos, ambos com deficiência global do desenvolvimento, microcefalia, nanismo e facies peculiar (face triangular, microftalmia, microstomia e micrognatia). No seguimento, surgiram novos problemas, como surdez neurossensorial, hipermetropia e fotossensibilidade. Pela clínica foi sugerida a hipótese de síndrome de Cockayne, que foi confirmada por teste genético molecular.Conclusões: A síndrome de Cockayne é um distúrbio raro (1/100.000), autossômico recessivo. Seu diagnóstico pode ser moroso, pois os sinais e sintomas vão surgindo progressiva e lentamente. A conjugação dos critérios de diagnóstico pode levar anos, sendo de extrema importância a suspeição clínica.

Aims: To report cases of Cockayne syndrome in two siblings, describing the clinical presentation and evolution.Case description: We describe the cases of two siblings, an 8 years old girl and a 13 years old boy, both with global developmental disability, microcephaly, dwarfism and peculiar facies (triangular face, microphthalmia, microstomia and micrognathia). New problems emerged during follow-up: sensorineural hearing loss, hypermetropia and photosensitivity. Clinical features suggested Cockayne syndrome, which was confirmed by molecular genetictesting.Conclusions: Cockayne?s syndrome is a rare (1/100,000), recessive autosomal disorder. Its diagnosis may be delayed because the signs and symptoms arise gradually and slowly. Obtaining the diagnostic criteria can take years and clinical suspicion is extremely important.

Cockayne syndrome–xeroderma pigmentosum complex with demyelination: A rare association.

Xeroderma pigmentosum–Cockayne syndrome (XP–CS) includes facial freckling and early skin cancers typical of XP and some features typical of CS, such as mental retardation, spasticity, short stature, and hypogonadism. XP–CS does not include skeletal involvement, the facial phenotype of CS, or CNS demyelination and calcifications. We present a rare patient whose genome probably harbored a specific combination of mutations producing a rare double syndrome of XP–CS, with facial phenotype of CS, and CNS demyelination.

Cockayne‟s Syndrome: a case report

Cockayne's syndrome (CS) is a rare, autosomal recessive disease resembling progeria. The features of CS do not appear until 4 to 5 years of age. Most patient presents with cachectic dwarfism, cutaneous photosensitivity, loss of adipose tissue, mental retardation, skeletal and neurological abnormalities, similar to the current case. The additional feature observed in the present case was actinic chelitis. We report a case of Cockayne‟s syndrome with pronounced oral manifestations and an unusual feature of actinic chelitis.

Síndrome de Cockayne: informe de dos casos clínicos y revisión de la literatura / Cockayne syndrome: report of two clinical cases and review of the literature

Introducción: el síndrome de Cockayne es un trastorno genético autosómico recesivo, caracterizado por detención del crecimiento, retraso del desarrollo, envejecimiento prematuro y fotosensibilidad. La prevalencia es de 1/100.000 nacidos vivos; es más frecuente en el sexo masculino con una relación 3:1. Desde el punto de vista genético se han descrito dos grupos: A: mutación del gen CSA (CKN1, ERCC8) en el cromosoma 5q12; B: mutación del gen CSB (ERCC6) en el cromosoma 10q11. Presentamos dos casos diagnosticados sobre bases clínicas pero en los que carecemos de estudios genéticos. Caso 1. Niña escolar producto de padres consanguíneos quien desde el nacimiento presenta hipotonía e hipomotilidad, retardo global del desarrollo, déficit pondoestatural, cara envejecida, rasgos dismórficos, fotosensibilidad, espasticidad e hipoacusia neurosensorial y hallazgos tomográficos característicos del síndrome. Actualmente está en rehabilitación. Caso 2. Adolescente de sexo femenino con crisis convulsivas desde los dos meses, poco progreso en el desarrollo psicomotor y pondoestatural, rasgos dismórficos y cara envejecida, hipoacusia neurosensorial bilateral, distonías repetitivas; en varias oportunidades sufrió procesos infecciosos respiratorios uno de los cuales, con neumonía bilateral, la llevó a la muerte a los 14 años. Conclusión: se presentan estos casos y se revisa la literatura para llamar la atención sobre este síndrome de modo que se lo sospeche tempranamente en pacientes con retardo del desarrollo psicomotor, envejecimiento prematuro y fotosensibilidad. El diagnóstico temprano es la base para brindar consejería genética a los padres.

Introduction: Cockayne syndrome is an autosomal, recessive genetic disorder, characterized by poor growth, development impairment, premature aging, and photosensitivity. Prevalence is 1/100.000 live births, and it is more frequent in males with a ratio of 3:1. From the genetic point of view two groups have been described: Group A: mutation of the CSA gene (CKN1, ERCC8) on chromosome 5q12. Group B: mutation of the CBS gene (ERCC6) on chromosome 10q11. We report two cases that were diagnosed solely on clinical bases because no genetic studies were available. Case 1. A school-girl, born from consanguineous parents. Since birth she has suffered from hypotonia and hypomotility. She has development delay, low weight and height gain, aged face, dysmorphic features, photosensitivity, spasticity, sensorineural hearing loss, and typical findings in the CT scan. She is currently on rehabilitation. Case 2. A female teenager with seizures from the age of two months; she made slow progress in psychomotor development, and had low weight and height gain. Her features were dysmorphic and her face aged. She had bilateral sensorineural hearing loss, and repeated dystonias. She suffered from repeated respiratory infections and died, aged 14, from respiratory failure secondary to bilateral pneumonia. Conclusion: We report these two cases and a review of the literature in order to attract attention to Cockayne syndrome so that early diagnoses can be made in children with psychomotor development delay, premature aging and photosensitivity. Early diagnoses are the basis for genetic counseling.

Swallowing in Cockayne Syndrome: A Case Report / Oral Science International

The case of a 20-year-old female with Cockayne syndrome, presenting with reduced intake of food, is described. At admission, her intake of food and her body weight were low. The patient's food swallowing function was recorded by video fluorography and evaluated. Reduced transfer of food boluses to the posterior site of the oral cavity, incomplete formation of boluses in the oral phase, and residual food after swallowing in the pharynx phase were observed. No aspiration was observed, however, during video fluorography. The patient's nutrition was managed by changing her meals to fluid-type food to shorten the eating time.

Swallowing in Cockayne Syndrome / Oral Science International

The case of a 20-year-old female with Cockayne syndrome, presenting with reduced intake of food, is described. At admission, her intake of food and her body weight were low. The patient's food swallowing function was recorded by video fluorography and evaluated. Reduced transfer of food boluses to the posterior site of the oral cavity, incomplete formation of boluses in the oral phase, and residual food after swallowing in the pharynx phase were observed. No aspiration was observed, however, during video fluorography. The patient's nutrition was managed by changing her meals to fluid-type food to shorten the eating time.

A Case of Cockayne Syndrome with Focal Segmental Glomerulosclerosis

Cockayne syndrome is a rare autosomal recessive disorder characterized by cachectic dwarfism, mental retardation, loss of facial subcutaneous adipose tissue, microcephaly and photosensitive dermatitis. It is associated with renal abnormalities characterized by hyalinization of glomeruli, atrophy of tubules and interstitial fibrosis. To our knowledge, this is the first report of a case of Cockayne syndrome with FSGS in Korea. A 7-year old boy was admitted for evaluation of hypertension and proteinuria, which were detected 2 month ago. He was followed for short stature(<3 percentile), mental retardation(IQ 55), strabismus and dental caries since 3 years ago. He also showed microcephaly, a bird-like face and relatively large hands and feet. Laboratory findings showed decreased creatinine clearance(CCr 76.1 mL/min/1.73m2) and proteinuria(1,548 mg/day). Renal biopsy demonstrated focal segmental glomerulosclerosis of the hilar type with large hyaline deposits, moderate tubular atrophy and interstitial fibrosis. His cardinal features, mental retardation, and renal biopsy findings were consistent with Cockayne syndrome. We report here a very rare case of Cockayne syndrome with FSGS presenting with proteinuria and hypertension.