title: Perinatal hypophosphatasia: radiology, pathology and molecular biology studies in a family harboring a splicing mutation (648+1A) and a novel missense mutation (N400S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene.
abstract: We report on a postmortem diagnosis of perinatal lethal hypophosphatasia, an inborn error of metabolism characterized by a liver/bone/kidney alkaline phosphatase (ALP)-related defective bone mineralization due to mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. Radiological and pathological studies identified a perinatal lethal hypophosphatasia showing a generalized bone mineralization defect including asymmetry of the cervical vertebral arches in a 22 +4 weeks' gestation fetus. Both parents revealed low serum ALP activities supporting the diagnosis. Sequencing analysis of the TNSALP gene showed two heterozygous mutations, 648+1A, a mutation affecting the donor splice site in exon 6, and N400S, a novel missense mutation in exon 11, located near the active site and very close to histidins 364 and 437, two crucial residues of the active site. Sequencing of exons 6 and 11 in the parents showed that 648+1A was from maternal origin and N400S from paternal origin. DNA-based prenatal testing in the subsequent pregnancy following a chorionic villous sampling performed at 10 weeks of gestation showed no mutation and a healthy infant was born at term.
authors.affiliation: Paido-Pathologisches Labor, Pathologisches Institut, Universität Heidelberg, Germany. Consolato_Sergi@med.uni-heidelberg.de
authors.forename: C
authors.initials: C
authors.lastname: Sergi
authors.forename: E
authors.initials: E
authors.lastname: Mornet
authors.forename: J
authors.initials: J
authors.lastname: Troeger
authors.forename: T
authors.initials: T
authors.lastname: Voigtlaender
mesh_terms: D000469:Alkaline Phosphatase / Q000032:analysis / Q000235:genetics*; D001483:Base Sequence; D002113:Calcification, Physiologic; D005260:Female; D005269:Femur / Q000473:pathology; D005333:Fetus / Q000002:abnormalities; D006801:Humans; D007014:Hypophosphatasia / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000473:pathology*; D007226:Infant Mortality; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010375:Pedigree; D011247:Pregnancy; D011859:Radiography; D014018:Tissue Distribution
chemical_list: D000469:Alkaline Phosphatase