Hypophosphatasia: Nonlethal Disease with Prenatal Skeletal Presentation and Severe Short Stature

Presentation Number: LB MON 44
Date of Presentation: April 3rd, 2017

Malvina Del Valle Signorino*1, Silvia Edith Martin2, Liliana Silvano3, Gabriela Sobrero1, Volker Boettcher4, Catarina Pereira5 and Mirta Beatriz Miras1
1Hospital de Niños de la Santisima Trinidad, Cordoba, Argentina, 2Hospital de Niños de la Santísima Trinidad. Córdoba, Argentina, 3Hospital de Niños de la Santísima Trinidad. Córdoba, Córdoba, Argentina, 4CENTOGENE AG. The Rare Disease Company, 65824 Schwalbach am Taunus, GERMANY, 5CENTOGENE AG. The Rare Disease Company, Germany., Germany


Background: Hypophosphatasia (HPP) is a rare inherited disorder caused by deactivating mutations within the gene of the tissue non-specific alkaline phosphatase (TNSALP).

HPP skeletal disease in utero was thought to predict a lethal outcome. However, several reports empathized a Benign Prenatal form (BP-HPP) with a mild postnatal course.

Although more than 300 mutations have been analyzed to explain the wide range of severity of the disease, the variability of clinical behavior is discussed. We described a girl with prenatal bowing of the long bones suggestive of a severe dysplasia. The molecular analyses confirmed the diagnosis of BP-HPP caused by mutations in TNSALP gene, one of which has not been described in humans.

Clinical case: The girl was a product of non-consanguineous healthy parents. Screening US in the second gestational trimester showed femoral and humeral shortness and bowing. She was born at term, birth weight: 2,650 g (-1.2 SDS), length: 44 cm (-2.7 SDS). Radiographs at 4 months of CA showed severe symmetrical bowing and shortening of the long tubular bones, flared front end of ribs and vertebrae defect in the ossification. At 2 yrs of CA she showed height: 71.5 cm (-4.6 SDS), Weight: 6,760 g (-3.4 SDS), hypotony, delayed psychomotor development, pectus carinatum, bilateral limb bowing, and clubfoots. Normal serum levels of calcium and phosphorus, low ALP: 44 UI/L with elevated level of B6 vitamin: 25.3 ng/ml (HPLC). Rx scan showed signs of rickets, chest deformity, lower limbs with symmetrical bowing and shortening with metaphyseal widening, less deformity of tibiae and fibulae and bowdler [M1] spurs of the radius. At the age of 3.6 yrs, she showed height: 81.2 cm (-4.38 SDS), with less limb bowing with disappearance of the radius spurs and premature exfoliation of one teeth with intact roots. Genomic DNA from peripheral blood leukocytes confirmed a compound heterozygous mutations in the TNSALP gene: in exon 6, c.542C>T (p.Ser181Leu) and in exon 12, c.1400T>C (p.Met467Thr).The first variant has been described as pathogenic in heterozygosis in a patient with Infantile HPP(1) The other mutation previously not described was reported as pathogenic in the specific database, with a frequency of 0.0000085 in the total population. The molecular analysis of the parents revealed that the mother was carrier of variant c.542C> T and the father the c.1400T>C

Conclusions: In addition to the reported, the phenotype in this patient would be explained by the existence of both mutations, one of which was not described. Other additional epigenetic factors could explain the clinical behavior observed in this case.References (1) Lia-Baldini A, Muller F, Taillandier A, Gibrat J, Mouchard M, Robin B, Simon-Bouy B, Serre J, Aylsworth A, Bieth E, Delanote S, Freisinger P, Hu J, Krohn H, Nunes M, Mornet E. A Molecular Approach to Dominance in Hypophosphatasia. Hum Genet 2001 109:99–108



Nothing to Disclose: MDVS, SEM, LS, GS, VB, CP, MBM