Vol.:(0123456789) 1 3 Osteoporosis International https://doi.org/10.1007/s00198-023-06859-8 REVIEW The challenge of hypophosphatasia diagnosis in adults: results from the HPP International Working Group Literature Surveillance Maria Luisa Brandi 1,2  · Aliya A. Khan 3  · Eric T. Rush 4,5  · Dalal S. Ali 3  · Hatim Al‑Alwani 3  · Khulod Almonaei 3  · Farah Alsarraf 3  · Severine Bacrot 6  · Kathryn M. Dahir 7  · Karel Dandurand 8  · Chad Deal 9  · Serge Livio Ferrari 10  · Francesca Giusti 2  · Gordon Guyatt 11  · Erin Hatcher 12  · Steven W. Ing 13  · Muhammad Kassim Javaid 14  · Sarah Khan 15  · Roland Kocijan 16  · E. Michael Lewiecki 17  · Agnes Linglart 18  · Iman M’Hiri 15  · Francesca Marini 1  · Mark E. Nunes 19  · Cheryl Rockman‑Greenberg 20  · Lothar Seefried 21  · Jill H. Simmons 7  · Susan R. Starling 4  · Leanne M. Ward 22  · Liang Yao 11  · Romina Brignardello‑Petersen 11  · Christian Roux 23,24 Received: 6 July 2023 / Accepted: 10 July 2023 © International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation 2023 Abstract Hypophosphatasia (HPP) is an inborn error of metabolism caused by reduced or absent activity of the tissue non-specific alkaline phosphatase (TNSALP) enzyme, resulting from pathogenic variants in the ALPL gene. Clinical presentation of HPP is highly variable, including lethal and severe forms in neonates and infants, a benign perinatal form, mild forms manifesting in adulthood, and odonto-HPP. Diagnosis of HPP remains a challenge in adults, as signs and symptoms may be mild and non-specific. Disease presentation varies widely; there are no universal signs or symptoms, and the disease often remains underdiagnosed or misdiagnosed, particularly by clinicians who are not familiar with this rare disorder. The absence of diagnosis or a delayed diagnosis may prevent optimal management for patients with this condition. Formal guidelines for the diagnosis of adults with HPP do not exist, complicating efforts for consistent diagnosis. To address this issue, the HPP International Working Group selected 119 papers that explicitly address the diagnosis of HPP in adults through a Medline, Medline In-Process, and Embase search for the terms “hypophosphatasia” and “HPP,” and evaluated the pooled prevalence of 17 diagnostic characteristics, initially selected by a group of HPP clinical experts, in eligible studies and in patients included in these studies. Six diagnostic findings showed a pooled prevalence value over 50% and were considered for inclusion as major diagnostic criteria. Based on these results and according to discussion and consideration among members of the Work- ing Group, we finally defined four major diagnostic criteria and five minor diagnostic criteria for HPP in adults. Authors suggested the integrated use of the identified major and minor diagnostic criteria, which either includes two major criteria, or one major criterion and two minor criteria, for the diagnosis of HPP in adults. Keywords Diagnostic parameters · HPP diagnosis in adults · Hypophosphatasia · Systematic review Introduction Hypophosphatasia (HPP) is a rare inborn error of metab- olism characterized by low alkaline phosphatase (ALP) activity that results from pathogenic variants in the ALPL gene, encoding the tissue non-specific alkaline phosphatase (TNSALP) enzyme [1]. The current HPP nosology is based upon the age of onset of symptoms, which can often be used as a rough surrogate for disease severity, such that neonates and infants typically present with several, potentially lethal disease, whereas adults typically present with milder signs and symptoms and may only present with dental complications without any evi- dence of skeletal or other organ involvement [2]. The overall prevalence of HPP in adults is yet unknown, partly due to lack of disease awareness, heterogeneous pres- entation, and signs and symptoms that, depending on the underlying ALPL mutation [3–6], can be mild and non-spe- cific and manifest later in life [2, 7–12]. Many adults who Maria Luisa Brandi, Aliya A. Khan, and Eric T. Rush share co-first authorship. Extended author information available on the last page of the article