title: X-linked VACTERL with hydrocephalus syndrome: further delineation of the phenotype caused by FANCB mutations.
abstract: X-linked VACTERL-hydrocephalus syndrome (X-linked VACTERL-H) is a rare disorder caused by mutations in the gene FANCB which underlies Fanconi Anemia (FA) complementation group B. Cells from affected males have increased chromosome breakage on exposure to DNA cross-linking agents. Only five FANCB mutations found in six affected males, including an affected uncle and nephew, have been reported. We have identified FANCB mutations in a further four affected families. The VACTERL-H phenotype segregates as an X-linked recessive trait in three of these. Each mutation is predicted to truncate the FANCB open reading frame and results in highly skewed X-inactivation in unaffected carrier females. Phenotypic data were available on six affected males. Comparison of the clinical findings in our patients with published clinical data (total 12 patients) shows that ventriculomegaly, bilateral absent thumbs and radii, vertebral defects, renal agenesis, and growth retardation are the major phenotypic signs in affected males. Less frequent are brain, pituitary, ear and eye malformations, gastrointestinal atresias (esophageal, duodenal and anal), tracheoesophageal fistula, lung segmentation defects, and small genitalia. Three of six of our patients survived the perinatal period. One boy lived up to 2 years 10 months but developed aplastic anemia and died of renal failure. These data show that loss-of-function FANCB mutations result in a recognizable, multiple malformation phenotype in hemizygous males for which we propose clinical criteria to aid diagnosis.
authors: Molecular Genetics Laboratory, GSTS Pathology, Guy's Hospital, London, UK.
authors: Joanna
authors: J
authors: McCauley
authors: Navta
authors: N
authors: Masand
authors: Ruth
authors: R
authors: McGowan
authors: Sulekha
authors: S
authors: Rajagopalan
authors: Alasdair
authors: A
authors: Hunter
authors: Jacques L
authors: JL
authors: Michaud
authors: Kate
authors: K
authors: Gibson
authors: Jeremy
authors: J
authors: Robertson
authors: Fiona
authors: F
authors: Vaz
authors: Stephen
authors: S
authors: Abbs
authors: Simon T
authors: ST
authors: Holden
mesh_terms: D001003:Anal Canal / Q000002:abnormalities / Q000473:pathology; D018376:Cardiovascular Abnormalities; D004252:DNA Mutational Analysis; D004065:Digestive System Abnormalities; D004947:Esophagus / Q000002:abnormalities / Q000473:pathology; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000473:pathology*; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D006849:Hydrocephalus / Q000235:genetics* / Q000473:pathology*; D007668:Kidney / Q000002:abnormalities / Q000473:pathology; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000473:pathology*; D008297:Male; D009139:Musculoskeletal Abnormalities; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D013131:Spine / Q000002:abnormalities / Q000473:pathology; D014132:Trachea / Q000002:abnormalities / Q000473:pathology; D049951:X Chromosome Inactivation / Q000235:genetics
chemical_list: C515775:FANCB protein, human; D051856:Fanconi Anemia Complementation Group Proteins