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Intrafamilial phenotypic distinction of hypophosphatasia with identical tissue nonspecific alkaline phosphatase gene mutation: a family report

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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.

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Authors and Affiliations

  1. Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N15W7, Kita-Ku, Sapporo, 060-8638, Japan

    Masaru Kato, Keita Ninagawa, Rimi Izumihara, Hiroshi Nomoto & Tatsuya Atsumi

  2. Hokkaido Medical Center for Rheumatic Diseases, Sapporo, Japan

    Toshiyuki Hattori & Kazuhide Tanimura

  3. Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

    Tomohiro Shimizu

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  1. Masaru Kato
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  2. Toshiyuki Hattori
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  3. Tomohiro Shimizu
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  4. Keita Ninagawa
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  5. Rimi Izumihara
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  6. Hiroshi Nomoto
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  7. Kazuhide Tanimura
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  8. Tatsuya Atsumi
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Correspondence to Masaru Kato.

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Conflicts of interest

Masaru Kato has received research grants from AbbVie, Actelion, and GlaxoSmithKline and speaking fees from Eli Lilly. Tatsuya Atsumi has received research grants from Astellas, Takeda, Mitsubishi Tanabe, Chugai, Daiichi-Sankyo, Otsuka, Pfize, Alexion, Bayer, Otsuka, Chugai, Takeda, Eisai, Bristol-Myers Squibb, Daiichi Sankyo, Mitsubishi Tanabe and AsahiKasei, consultant fees from Ono, Sanofi, Daiichi Sankyo and Pfizer and speaking fees from Mitsubishi Tanabe, Chugai, Astellas, Takeda, Pfizer, Daiichi Sankyo, Bristol-Myers Squibb and Eli Lilly. Other authors have nothing to declare.

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Kato, M., Hattori, T., Shimizu, T. et al. Intrafamilial phenotypic distinction of hypophosphatasia with identical tissue nonspecific alkaline phosphatase gene mutation: a family report. J Bone Miner Metab 38, 903–907 (2020). https://doi.org/10.1007/s00774-020-01137-7

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  • DOI: https://doi.org/10.1007/s00774-020-01137-7

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