Intrafamilial phenotypic distinction of hypophosphatasia with identical tissue nonspecific alkaline phosphatase gene mut
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Intrafamilial phenotypic distinction of hypophosphatasia with identical tissue nonspecific alkaline phosphatase gene mutation: a family report Masaru Kato1 · Toshiyuki Hattori2 · Tomohiro Shimizu3 · Keita Ninagawa1 · Rimi Izumihara1 · Hiroshi Nomoto1 · Kazuhide Tanimura2 · Tatsuya Atsumi1 Received: 18 April 2020 / Accepted: 30 July 2020 © The Japanese Society Bone and Mineral Research and Springer Japan KK, part of Springer Nature 2020
Abstract Hypophosphatasia (HPP) is caused by mutations in the tissue nonspecific alkaline phosphatase (TNSALP) gene in an autosomal recessive or dominant manner and characterized by defective mineralization of bone and low serum ALP levels. In this report, we present a family with HPP mother (case 1) and HPP child (case 2) who have identical TNSALP gene mutation (c.1015G>A p.Gly339Arg heterozygous mutation) but distinct clinical phenotypes. Whereas case 1 appeared to be asymptomatic despite extremely low levels of serum ALP, case 2 had several HPP-related symptoms, such as tooth loss, fractures, short stature, with slightly decreased ALP levels. Upon the diagnosis of HPP, case 1 discontinued denosumab, which was used to treat her rheumatoid arthritis, concerning the risk of atypical femoral fractures. The clinical course of this family was suggestive in a genotype–phenotype imbalance in HPP, the underdiagnosis of HPP in adults, and the risk of atypical femoral fractures using bone resorption inhibitors. Keywords Hypophosphatasia · TNSALP gene · Denosumab · Family report
Introduction Hypophosphatasia (HPP) is caused by mutations in the tissue nonspecific alkaline phosphatase (TNSALP) gene and characterized by defective mineralization of bone and low serum ALP levels. HPP can result from either autosomal recessive or autosomal dominant inheritance. Due to its rarity as well as the varieties of its severity, the clinical characteristics of HPP, particularly those of adult cases, remains to be fully determined. Adult HPP is typically diagnosed based on musculoskeletal pain, bone fractures, * Masaru Kato [email protected] 1
Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N15W7, Kita‑Ku, Sapporo 060‑8638, Japan
2
Hokkaido Medical Center for Rheumatic Diseases, Sapporo, Japan
3
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
dental abnormalities, and/or a childhood history of premature deciduous tooth loss [1, 2]. Since pain and fractures are nonspecific clinical features, there are cases who need to be differentiated from rheumatic diseases such as osteoporosis, rheumatoid arthritis (RA), spondyloarthritis, and fibromyalgia. The data regarding the correlation between HPP phenotype and TNSALP genotype also remain insufficient. Some genotype–phenotype correlations are seen in the perinatal lethal type of HPP, whereas different clinical features are associated with the same gene mutation in t
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