title: Unexpected high intrafamilial phenotypic variability observed in hypophosphatasia.
abstract: Hypophosphatasia (HPP) is a clinically heterogeneous rare, inherited disorder of bone and mineral metabolism with extensive allelic heterogeneity in the ALPL gene. In this report, we present a family with heterozygous parents (maternal p.(Glu191Lys), paternal p.(Gly334Asp) mutations in the ALPL gene) and four children (one genotypically normal, one heterozygous carrier and two compound heterozygous) showing an unexpected high phenotypic variability. One of the compound heterozygous showed clinical symptoms of the mild childhood form mainly affecting the teeth. The other one was more seriously affected with severe failure to thrive, delayed motor development, need for oxygen supply and profound mineralization deficit compatible with an infantile form of HPP. Functional in vitro studies identified p.(Glu191Lys) as mild (68%, no dominant-negative effect) and p.(Gly334Asp) as severely affected allele (1.2%, dominant-negative effect). In vitro simulation of the children's genetic status showed a residual AP activity of 29%, while the biochemical AP activity in the serum was comparably reduced in both children (22 and 36 U/l). This family report indicates that mapping ALPL mutations within the gene does not necessarily help to predict the clinical severity of the phenotype. Therefore, results of prenatal diagnostics have to be interpreted with caution and prenatal genetic diagnosis and counseling for HPP should be provided within an experienced multidisciplinary team. Research about other confounding factors is urgently needed.
authors.affiliation: Pediatric Rheumatology and Osteology, Children's Hospital, University of Würzburg, Würzburg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Hofmann
authors.affiliation: Children's Hospital, Vivantes Hospital im Friedrichshain, Berlin, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Girschick
authors.affiliation: Unité de pathologie cellulaire et génétique EA2493, University of Versailles Saint Quentin en Yvelines, and Unité de Génétique Constitutionnelle, Centre Hospitalier de Versailles, Le Chesnay, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Mornet
authors.affiliation: Orthopedic Department, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Schneider
authors.affiliation: Orthopedic Department, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Jakob
authors.affiliation: Orthopedic Department, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Mentrup
mesh_terms: D000293:Adolescent; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D005260:Female; D056726:Genetic Association Studies; D005817:Genetic Counseling; D014644:Genetic Variation; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D007014:Hypophosphatasia / Q000175:diagnosis* / Q000235:genetics*; D007223:Infant; D009154:Mutation; D010641:Phenotype; D011296:Prenatal Diagnosis
chemical_list: C548267:ALPL protein, human; D000469:Alkaline Phosphatase