A case of lethal hypophosphatasia providing new insights into the perinatal benign form of hypophosphatasia and expression of the ALPL gene

Brun-Heath, Isabelle; Chabrol, E; Fox, Maurice S.; Drexler, Kathryn; Petit, Christine; Taillandier, A.; Mazancourt, Philippe de; Serre, J. L.; Mornet, Étienne

doi:10.1111/j.1399-0004.2007.00902.x

Cited by 14 publications

(7 citation statements)

References 27 publications

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“…AR inheritance of TNSALP mutations in a fetus with in utero skeletal manifestations of HPP has been considered by some to predict a lethal outcome 9, 10, 55. However, our literature review of 24 BP‐HPP patients and our 17 additional BP‐HPP patients show that most (64%) carry two defective TNSALP alleles.…”

Section: Discussionmentioning

confidence: 85%

Hypophosphatasia: Nonlethal disease despite skeletal presentation in utero (17 new cases and literature review)

Wenkert

McAlister

Coburn

et al. 2011

Journal of Bone and Mineral Research

130

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Hypophosphatasia (HPP) is caused by deactivating mutation(s) within the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Patients manifest rickets or osteomalacia and dental disease ranging from absence of skeletal mineralization in utero to only loss of adult dentition. Until recently, HPP skeletal disease in utero was thought to always predict a lethal outcome. However, several reports beginning in 1999 emphasized a benign prenatal form of HPP (BP-HPP) where skeletal disease detected in utero had a mild postnatal course. Here we describe prenatal and postnatal findings of 17 additional BP-HPP patients among our 178 pediatric HPP patients. Their findings are compared with those of their siblings with HPP, carrier parents, and others with identical TNSALP mutations. New information concerning 7 previously published BP-HPP patients accompanies a review of the HPP literature. Among our 17 BP-HPP patients, prenatal ultrasound showed normal chest or abdominal circumferences where recorded. Sometimes, poor skeletal mineralization, fetal crowding, and third-trimester improvement were observed. Postnatally, extremity bowing further improved (13 patients). BP-HPP severity postnatally spanned the ''infantile'' to ''odonto'' HPP phenotypes, resembling our patients who harbored identical TNSALP mutation(s). Eight had autosomal dominant (AD) and 9 had autosomal recessive (AR) BP-HPP. Fourteen of our 15 mothers were HPP carriers or affected. Of the 41 cumulative BP-HPP patients (24 literature cases meriting a BP-HPP diagnosis since 1996 plus our 17 patients), 63% had AR BP-HPP. Maternally transmitted HPP involved 11 of the 13 total AD BP-HPP probands ( p ¼ 0.01), supporting a maternal in utero effect on the baby. Fetal crowding, normal fetal mineralization and chest size, and TNSALP heterozygosity seem to identify BP-HPP. However, bowed fetal long bones with AR HPP, specific TNSALP mutations, or poor skeletal mineralization before the third trimester do not reliably diagnose HPP lethality. ß

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Section: Discussionmentioning

confidence: 85%

Hypophosphatasia: Nonlethal disease despite skeletal presentation in utero (17 new cases and literature review)

Wenkert

McAlister

Coburn

et al. 2011

Journal of Bone and Mineral Research

130

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“…The six clinical types of HPP are: (1) perinatal lethal which is apparent at birth; (2) infantile from 1-6 months; (3) childhood type from the age of 6 months-18 years; (4) odonto type, which is characterized by the premature loss of deciduous teeth by 5 years without apparent bone symptoms; and (5) adult. Interestingly, some patients with prenatal onset, namely the prenatal benign type have ameliorated spontaneous skeletal defects and survive (Ozono et al 1996;Brun-Heath et al 2008;Wenkert et al 2011). The perinatal lethal type usually has poor prognosis because of a profound reduction of bone mineralization; half of patients with the infantile type and all patients with the childhood type survive but experience premature loss of deciduous teeth as well as delayed walking and waddling, which reflect the degree of the skeletal disease (Whyte 2001(Whyte , 2010Mornet 2008).…”

Section: Introductionmentioning

confidence: 97%

Neurological Symptoms of Hypophosphatasia

Taketani¹

2015

Subcellular Biochemistry

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Hypophosphatasia (HPP) is a bone metabolic disorder caused by mutations in the liver/bone/kidney alkaline phosphatase gene (ALPL), which encodes tissue-nonspecific alkaline phosphatase (TNAP). This disease is characterized by disrupted bone and tooth mineralization, and reduced serum AP activity. Along with bone and tooth symptoms, many neurological symptoms, seizure, encephalopathy, intracranial hypertension, mental retardation, deafness, and growth hormone deficiency (GHD), are frequently found in HPP patients. Seizure occurs in severe HPP types soon after birth, and responds to pyridoxine, but is an indicator of lethal prognosis. Encephalopathy rarely presents in severe HPP types, but has severe sequelae. Intracranial hypertension complicated in mild HPP types develops after the age of 1 year and sometimes need neurosurgical intervention. Mental retardation, deafness and GHD are more frequently found in Japanese HPP patients. Mental retardation occurs in all HPP types. Deafness in perinatal lethal type is both conductive and sensorineural. GHD develops in all but perinatal lethal type and the diagnosis tends to delay. The pathogenesis of these neural features of HPP might be due to impairment of both vitamin B6 metabolism and central nervous system development by ALPL mutations.

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“…Depending on the type of mutation and the mode of inheritance, the disease is highly variable in its clinical expression and can be classified into six major forms (perinatal lethal, prenatal benign, infantile, childhood, adult, and odontohypophosphatasia) [10]. Given the severe skeletal hypomineralization, the perinatal form either results in stillbirth or in early postnatal lethality [11,12]. The clinical course of the infantile form starts in the first 6 months of life and is characterized by rickets, craniosynostosis, nephrocalcinosis, and premature death [13].…”

Section: Introductionmentioning

confidence: 99%

Skeletal mineralization defects in adult hypophosphatasia—a clinical and histological analysis

et al. 2011

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A case of lethal hypophosphatasia providing new insights into the perinatal benign form of hypophosphatasia and expression of the ALPL gene

Cited by 14 publications

References 27 publications

Hypophosphatasia: Nonlethal disease despite skeletal presentation in utero (17 new cases and literature review)

Hypophosphatasia: Nonlethal disease despite skeletal presentation in utero (17 new cases and literature review)

Neurological Symptoms of Hypophosphatasia

Skeletal mineralization defects in adult hypophosphatasia—a clinical and histological analysis

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