1/34. Cerebro-oculo-facio-skeletal syndrome with a nucleotide excision-repair defect and a mutated XPD gene, with prenatal diagnosis in a triplet pregnancy.Cerebro-oculo-facio-skeletal (COFS) syndrome is a recessively inherited rapidly progressive neurologic disorder leading to brain atrophy, with calcifications, cataracts, microcornea, optic atrophy, progressive joint contractures, and growth failure. cockayne syndrome (CS) is a recessively inherited neurodegenerative disorder characterized by low to normal birth weight, growth failure, brain dysmyelination with calcium deposits, cutaneous photosensitivity, pigmentary retinopathy and/or cataracts, and sensorineural hearing loss. Cultured CS cells are hypersensitive to UV radiation, because of impaired nucleotide-excision repair (NER) of UV-induced damage in actively transcribed DNA, whereas global genome NER is unaffected. The abnormalities in CS are caused by mutated CSA or CSB genes. Another class of patients with CS symptoms have mutations in the XPB, XPD, or XPG genes, which result in UV hypersensitivity as well as defective global NER; such patients may concurrently have clinical features of another NER syndrome, xeroderma pigmentosum (XP). Clinically observed similarities between COFS syndrome and CS have been followed by discoveries of cases of COFS syndrome that are associated with mutations in the XPG and CSB genes. Here we report the first involvement of the XPD gene in a new case of UV-sensitive COFS syndrome, with heterozygous substitutions-a R616W null mutation (previously seen in patients in XP complementation group D) and a unique D681N mutation-demonstrating that a third gene can be involved in COFS syndrome. We propose that COFS syndrome be included within the already known spectrum of NER disorders: XP, CS, and trichothiodystrophy. We predict that future patients with COFS syndrome will be found to have mutations in the CSA or XPB genes, and we document successful use of dna repair for prenatal diagnosis in triplet and singleton pregnancies at risk for COFS syndrome. This result strongly underlines the need for screening of patients with COFS syndrome, for either UV sensitivity or DNA-repair abnormalities.- - - - - - - - - - ranking = 1keywords = sensitivity (Clic here for more details about this article) |
2/34. xeroderma pigmentosum/cockayne syndrome complex: first neuropathological study and review of eight other cases.This is the first detailed description of the neuropathology of a patient with xeroderma pigmentosum/cockayne syndrome complex (XP/CS). This 6-year-old boy's clinical course, followed from infancy to death, is compared with that of the eight other known cases of XP/CS. Normal at birth, he developed the cutaneous sun sensitivity of XP in infancy and the infantile CS phenotype in early childhood. He had the characteristic CS facies, cachexia, failure of somatic and brain growth, spasticity, ataxia, pigmentary retinopathy, hearing loss, mixed peripheral neuropathy, and myopathy. Like his clinical phenotype, the neuropathology was also that of CS despite an XPG genotype. His brain weighed 350 grams (considerably less than the expected weight at birth) and revealed hydrocephalus, tigroid-type demyelination, dystrophic calcification and widespread neuronal loss and gliosis with hyperchromatic glial and endothelial nuclei. Peripheral nerve showed myelinopathy with axonal degeneration, and skeletal muscle had mixed myopathic and neuropathic features. Ophthalmic pathology disclosed cataracts, iris and ciliary body atrophy, inner retinal atrophy and gliosis, retinal pigment epithelial atrophy, and optic nerve atrophy. Molecular studies, which have appeared elsewhere, do not provide full understanding of the pathophysiology of the postnatal growth failure, cachexia, precocious aging, selectivity of tissues affected (such as myelinated axons), and other manifestations of this devastating illness.- - - - - - - - - - ranking = 0.33333333333333keywords = sensitivity (Clic here for more details about this article) |
3/34. cockayne syndrome in a family.cockayne syndrome is one of the families of rare progeroid syndromes. We report on two female siblings suffering from cockayne syndrome. At birth, they both appeared normal, although both demonstrated a low birth weight and breech presentation. The first-born child died at the age of eight months with associated contracted limbs, brain calcification, and photosensitivity. The younger sibling exhibited short stature, microcephaly, a beaked nose and malformed ears, spasticity, photosensitivity, pigmented degeneration of the retina, and psychomotor retardation at the age of six years. Intracranial calcification and the absence of a brain stem-evoked potential were also noted. Testing her skin fibroblasts, which showed a moderate UV sensitivity and a severe deficiency of transcription-coupled repair established the diagnosis of Cockayne syndrome. genetic counseling was offered for the family.- - - - - - - - - - ranking = 1keywords = sensitivity (Clic here for more details about this article) |
4/34. Relationship of neurologic degeneration to genotype in three xeroderma pigmentosum group G patients.We studied three newly diagnosed xeroderma pigmentosum complementation group G patients with markedly different clinical features. An Israeli-Palestinian girl (XP96TA) had severe abnormalities suggestive of the xeroderma pigmentosum/cockayne syndrome complex including sun sensitivity, neurologic and developmental impairment, and death by age 6 y. A Caucasian girl (XP82DC) also had severe sun sensitivity with neurologic and developmental impairment and died at 5.8 y. In contrast, a mildly affected 14-y-old Caucasian female (XP65BE) had sun sensitivity but no neurologic abnormalities. XP96TA, XP82DC, and XP65BE fibroblasts showed marked reductions in post-ultraviolet cell survival and dna repair but these were higher in XP65BE than in XP82DC. XP96TA fibroblasts had very low XPG mRNA expression levels whereas XP65BE fibroblasts had nearly normal levels. Host cell reactivation of an ultraviolet-treated reporter assigned all three fibroblast strains to the rare xeroderma pigmentosum complementation group G (only 10 other patients previously reported). XP96TA and XP82DC cells had mutations in both XPG alleles that are predicted to result in severely truncated proteins including stop codons and two base frameshifts. The mild XP65BE patient had an early stop codon mutation in the paternal allele. The XP65BE maternal allele had a single base missense mutation (G2817A, Ala874Thr) that showed residual ability to complement xeroderma pigmentosum complementation group G cells. These observations agree with earlier studies demonstrating that XPG mutations, which are predicted to lead to severely truncated proteins in both alleles, were associated with severe xeroderma pigmentosum/cockayne syndrome neurologic symptoms. Retaining residual functional activity in one allele was associated with mild clinical features without neurologic abnormalities.- - - - - - - - - - ranking = 1.0022752688966keywords = sensitivity, contrast (Clic here for more details about this article) |
5/34. cockayne syndrome: review of 140 cases.To define diagnostic criteria for cockayne syndrome (CS) and to identify in detail the complications of the condition, a comprehensive review of 140 cases of CS was performed. Criteria required for the diagnosis include poor growth and neurologic abnormality; other very common manifestations include sensorineural hearing loss, cataracts, pigmentary retinopathy, cutaneous photosensitivity, and dental caries. The mean age of death in reported cases is 12 3/12 years, though a few affected individuals have lived into their late teens and twenties. Prenatal growth failure, congenital structural eye anomalies, severe neurologic dysfunction from birth, and the presence of cataracts within the first 3 years of life are predictors of severe disease and early death. In contrast with other disorders of chromosome or dna repair, cancer has never been reported in a classical CS patient, and there appears to be no predisposition to infectious complications. The wide spectrum of symptoms and severity of the disease suggest that biochemical and genetic heterogeneity exist. CS is an uncommon but devastating genetic condition which will be better understood as the biochemical interrelationships between dna replication and repair, and between growth, homeostasis, and oncogenesis are unraveled.- - - - - - - - - - ranking = 0.33560860222995keywords = sensitivity, contrast (Clic here for more details about this article) |
6/34. xeroderma pigmentosum and cockayne syndrome: overlapping clinical and biochemical phenotypes.Two siblings are described whose clinical presentation of cutaneous photosensitivity and central nervous system dysfunction is strongly reminiscent of the DeSanctis-Cacchione syndrome (DCS) variant of xeroderma pigmentosum. An extensive clinical evaluation supported a diagnosis of DCS and documented previously unreported findings. in vitro fibroblast studies showed UV sensitivity that was two to three times that of normal controls. However, neither a post-UV-irradiation DNA excision-repair defect indicative of XP nor a semiconservative dna replication defect indicative of XP variant was found. Rather, a failure of rna synthesis to recover to normal levels after UV exposure was observed, a biochemical abnormality seen in cockayne syndrome (CS), one of the premature-aging syndromes with clinical UV sensitivity. These patients, therefore, clinically have XP, but their biochemical characteristics suggest CS. The reason(s) for the severe neurologic disease, in light of the relatively mild cutaneous abnormalities, is unclear. Other cases with unusual fibroblast responses to irradiation have been noted in the literature and, along with the data from our patients, reinforce the notion of the complexity of DNA maintenance and repair.- - - - - - - - - - ranking = 1keywords = sensitivity (Clic here for more details about this article) |
7/34. Comparison of MRI white matter changes with neuropsychologic impairment in cockayne syndrome.The neuropsychologic function and white matter changes observed on magnetic resonance imaging (MRI) in cockayne syndrome were studied. MRI with T2-weighted sequences revealed periventricular hyperintensity and white matter hyperintensity in all 3 cockayne syndrome patients examined; in contrast, 8 age-matched controls had no periventricular or white matter hyperintensity. MRI scans were graded according to the severity of periventricular or white matter hyperintensity using a scale applied to an elderly patient population. There was no difference in the severity of MRI white matter changes in these 3 cockayne syndrome patients, 2 of whom had severe neuropsychologic functions and one a relatively milder one. There was no correlation between neuropsychologic impairment and MRI white matter changes.- - - - - - - - - - ranking = 0.0022752688966142keywords = contrast (Clic here for more details about this article) |
8/34. Muscle involvement in the cerebro-oculo-facio-skeletal syndrome.We report a 14-year-old male, born to consanguineous parents, with microcephaly, intracranial calcification, severe mental retardation, cataracts, optic atrophy, pigmentary retinopathy, contractures, scoliosis, and failure to thrive. His brain imaging revealed extensive basal ganglia calcifications. He has normal ultraviolet sensitivity. These features are consistent with the autosomal recessive cerebro-oculo-facio-skeletal syndrome. In addition, he has severe muscle weakness with end-stage muscle changes on biopsy. There have been few reports of muscle involvement in cerebro-oculo-facio-skeletal syndrome, and this is the first time it has been described in a cerebro-oculo-facio-skeletal patient with normal ultraviolet sensitivity. This case extends the extensive phenotypic similarities between cerebro-oculo-facio-skeletal syndrome patients with and without abnormal ultraviolet sensitivity, and highlights the cerebro-oculo-facio-skeletal syndrome in the differential diagnosis of congenital muscular dystrophies.- - - - - - - - - - ranking = 1keywords = sensitivity (Clic here for more details about this article) |
9/34. A kindred with cockayne syndrome caused by multiple splicing variants of the CSA gene.cockayne syndrome (CS) is an autosomal recessive disorder, which is associated with abnormal UV hypersensitivity, growth retardation, and psycho-neural abnormalities. Recently, CSA protein was found to be associated with CS. We obtained mRNAs from immortal lymphoblasts derived from members of the kindred, and sequenced the CSA gene of all family members after reverse transcription (RT) of the coding region. The intact length of the CSA transcript was found in all family members except the proband with CS. Multiple abnormal splicing variant forms were revealed in all cases. No mutation was found in the sequences of the splice donor and acceptor sites of each exon in the CSA gene. UVA irradiation suppressed cell growth in the proband. There was no significant alteration of UVA sensitivity among the normal control and the family members except for the proband. These data suggest that multiple splicing variant forms of CSA mRNA, in the absence of the full-length form of the mRNA, are associated with CS.- - - - - - - - - - ranking = 0.66666666666667keywords = sensitivity (Clic here for more details about this article) |
10/34. A neuropathological study of early onset cockayne syndrome with chromosomal anomaly 47XXX.We present the clinical and neuropathological findings in a female patient with early onset cockayne syndrome and a chromosomal anomaly (47XXX). The girl was the only child of healthy, unrelated parents. She was born with a birth weight of 1,930 gm. She had progeroid facial features with bilateral cataracts. A diagnosis of 47XXX was made on the basis of a chromosomal study. Physical shortness became increasingly prominent while her weight remained stationary. Psychomotor retardation was noted, and she could never sit alone. A brain CT scan showed cerebral atrophy and calcification of the basal ganglia. Cultured skin fibroblast exhibited significant sensitivity to the ultraviolet light. She died from a chest infection at the age of 7 years and 4 months. Microscopically, the renal glomeruli showed diffuse sclerotic changes with thick capillary basement membranes. A neuropathological examination revealed a very small brain (295 gm), extensive myelin deficiency, gliosis in the white matter, and calcifications in the basal ganglia, and cerebral and cerebellar cortices. The loss of both Purkinje and granular cells was noticed in the cerebellar cortex. This is the first report of a case with the cockayne syndrome and 47XXX, and the 47XXX in this patient seems to be coincidental.- - - - - - - - - - ranking = 0.33333333333333keywords = sensitivity (Clic here for more details about this article) |
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