title: Cerebro-oculo-facio-skeletal syndrome with a nucleotide excision-repair defect and a mutated XPD gene, with prenatal diagnosis in a triplet pregnancy.
abstract: 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.
authors.affiliation: Medical Genetics Birth Defects Center, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA. john.graham@cshs.org
authors.forename: J M
authors.initials: JM
authors.lastname: Graham
authors.forename: K
authors.initials: K
authors.lastname: Anyane-Yeboa
authors.forename: A
authors.initials: A
authors.lastname: Raams
authors.forename: E
authors.initials: E
authors.lastname: Appeldoorn
authors.forename: W J
authors.initials: WJ
authors.lastname: Kleijer
authors.forename: V H
authors.initials: VH
authors.lastname: Garritsen
authors.forename: D
authors.initials: D
authors.lastname: Busch
authors.forename: T G
authors.initials: TG
authors.lastname: Edersheim
authors.forename: N G
authors.initials: NG
authors.lastname: Jaspers
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D000595:Amino Acid Sequence; D020137:Base Pair Mismatch / Q000235:genetics; D001483:Base Sequence; D002675:Child, Preschool; D003057:Cockayne Syndrome / Q000235:genetics / Q000503:physiopathology; D004265:DNA Helicases; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics / Q000528:radiation effects; D004268:DNA-Binding Proteins; D005260:Female; D005315:Fetal Diseases / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007585:Jews / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D011247:Pregnancy; D011296:Prenatal Diagnosis; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome; D014157:Transcription Factors; D014310:Triplets / Q000235:genetics*; D014466:Ultraviolet Rays / Q000009:adverse effects; D014983:Xeroderma Pigmentosum / Q000235:genetics / Q000503:physiopathology; D051759:Xeroderma Pigmentosum Group D Protein
chemical_list: D004268:DNA-Binding Proteins; D011506:Proteins; D014157:Transcription Factors; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human