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Clinical Aspects of Hypophosphatasia: An Update

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Clinical Reviews in Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Hypophosphatasia (HPP) is a heterogeneous rare inborn error of bone and mineral metabolism caused by mutations in the ALPL gene encoding the isoenzyme, tissue-nonspecific alkaline phosphatase (TNAP). These mutations result in a decreased level of TNAP activity and increased levels of its substrates, including inorganic pyrophosphate, pyridoxal-5′-phosphate and phosphoethanolamine. Clinical presentations are highly variable, ranging from stillbirth and absence of mineralization in severe disease to mild dental problems or osteopenia in adulthood. Further clinical symptoms include defective bone mineralization with bone deformities, recurrent fractures, chronic non-bacterial osteomyelitis, craniosynostosis, neonatal seizures, nephrocalcinosis, muscular hypotonia, failure to thrive and dental abnormalities with premature exfoliation of teeth and caries. Prognosis is very poor in severe perinatal forms with most patients dying from pulmonary complications of their skeletal disease but patients with mild phenotypes (adult form or Odonto-HPP) usually do not have a limitation in their life expectancy. Although TNAP is a ubiquitous enzyme, mostly known for its crucial role during mineralization of bone and teeth, its exact biological role in different human organs is still unclear, and the pathophysiology of symptoms due to TNAP deficiency in HPP are not understood in detail. Since inflammation and tissue destruction of the musculoskeletal system may occur in HPP, TNAP may also play an important role in controlling inflammatory processes. Recent investigations provide evidence that TNAP is also essentially involved in the development of the central nervous system and might contribute to multiple functions of the human brain. HPP can be diagnosed on clinical, biochemical and radiological criteria, and genetic testing confirms the diagnosis and is useful for genetic counseling. Since clinical symptoms are highly variable, patients should be followed up by a multidisciplinary team having experience in HPP treatment. Up to now, no curative treatment of HPP is available. Therefore, symptomatic treatment in particular with regard to pain, seizures and other metabolic phenomena is most important. However, recently, enzyme replacement therapy with a bone-targeted recombinant human TNAP molecule has been reported to improve bone mineralization, respiratory function and physical activity in severely affected infants with HPP, and further clinical trials are ongoing. Hopefully, this and other new therapeutic strategies may improve the prognosis and quality of life of patients with HPP and may contribute to our understanding of bone metabolism in general.

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Disclosures

Conflict of interest

CH received a scholarship from the Interdisciplinary Centre for Clinical Research IZKF Würzburg, Germany, and BM is supported by Bundesministerium für Bildung und Forschung BMBF, Berlin, Germany. JL and CH received a study grant from Alexion Pharma (Cheshire, Connecticut, U.S.) for a phase-two study on Asfotase alpha treatment for severe forms of HPP. F Jakob has received honoraria for lectures and advice from Eli Lilly, Amgen, Novartis, MSD, Nycomed, Servier and Roche; has received unrestricted research grants from Novartis and is involved in clinical studies related to osteoporosis drugs initiated by Eli Lilly, Amgen, Servier and Novartis.

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This article does not contain any studies with human or animal subjects performed by the any of the authors.

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Authors and Affiliations

  1. Children’s Hospital, University of Würzburg, Josef-Schneider-Str. 2, 97090, Würzburg, Germany

    C. Hofmann & J. Liese

  2. Children’s Hospital, Vivantes Hospital in Friedrichshain, Berlin, Germany

    H. J. Girschick

  3. Orthopedic Department, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany

    B. Mentrup, S. Graser, L. Seefried & F. Jakob

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  1. C. Hofmann
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Correspondence to C. Hofmann.

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Hofmann, C., Girschick, H.J., Mentrup, B. et al. Clinical Aspects of Hypophosphatasia: An Update. Clinic Rev Bone Miner Metab 11, 60–70 (2013). https://doi.org/10.1007/s12018-013-9139-0

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