Review

. 2024 Jan;35(1):1-10.

doi: 10.1007/s00198-023-06843-2. Epub 2023 Nov 20.

Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the HPP International Working Group

Eric Rush^{1

2

3}, Maria Luisa Brandi^{4

5}, Aliya Khan⁶, Dalal S Ali⁶, Hatim Al-Alwani⁶, Khulod Almonaei⁶, Farah Alsarraf⁶, Severine Bacrot⁷, Kathryn M Dahir⁸, Karel Dandurand⁹, Chad Deal¹⁰, Serge Livio Ferrari¹¹, Francesca Giusti⁵, Gordon Guyatt¹², Erin Hatcher¹³, Steven W Ing¹⁴, Muhammad Kassim Javaid¹⁵, Sarah Khan¹⁶, Roland Kocijan¹⁷, E Michael Lewiecki¹⁸, Agnes Linglart¹⁹, Iman M'Hiri¹⁶, Francesca Marini⁴, Mark E Nunes²⁰, Cheryl Rockman-Greenberg²¹, Christian Roux^{22

23}, Lothar Seefried²⁴, Susan R Starling²⁵, Leanne Ward²⁶, Liang Yao¹², Romina Brignardello-Petersen¹², Jill H Simmons⁸

Affiliations

¹ Division of Clinical Genetics, Children's Mercy Kansas City, 2401 Gillham Road, Kansas City, MO, USA. etrush@cmh.edu.
² Department of Pediatrics, University of Missouri - Kansas City School of Medicine, 2401 Gillham Road, Kansas City, MO, USA. etrush@cmh.edu.
³ Division of Endocrinology, Metabolism, Osteoporosis, and Genetics, Department of Internal Medicine, University of Kansas School of Medicine, Kansas City, KS, USA. etrush@cmh.edu.
⁴ F.I.R.M.O. Italian Foundation for the Research on Bone Diseases, Florence, Italy.
⁵ Donatello Bone Clinic, Villa Donatello Hospital, Florence, Italy.
⁶ Division of Endocrinology and Metabolism, McMaster University, Hamilton, Canada.
⁷ Department of Genetics, Centre Hospitalier de Versailles, Hôpital André Mignot, Versailles, France.
⁸ Division of Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ Department of Medicine, Endocrinology and Metabolism, Université de Sherbrooke, Sherbrooke, QC, Canada.
¹⁰ Center for Osteoporosis and Metabolic Bone Disease, Department of Rheumatology, The Cleveland Clinic Foundation, Cleveland, OH, USA.
¹¹ Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
¹² Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada.
¹³ Neuromuscular Clinic, McMaster University Medical Centre, Hamilton Health Sciences, Hamilton, Canada.
¹⁴ Division of Endocrinology, Diabetes, & Metabolism, Ohio State University Wexner Medical Center, Columbus, USA.
¹⁵ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
¹⁶ Bone Research and Education Centre, Oakville, ON, Canada.
¹⁷ 1st Medical Department, Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA, Trauma Centre Meidling, Hanusch Hospital, 1140, Vienna, Austria.
¹⁸ New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA.
¹⁹ APHP, Bicêtre Paris-Sud, University Paris Sud, Paris-Saclay, Le Kremlin Bicêtre, Paris, France.
²⁰ Division of Medical Genetics and Metabolism, Valley Children's HealthCare, Madera, CA, USA.
²¹ Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada.
²² Rheumatology Department, Hospital Pasteur 2 CHU, 06000, Nice, France.
²³ Inserm, CNRS, iBV, Université Côte d'Azur, 06000, Nice, France.
²⁴ Musculoskeletal Center Wuerzburg, University of Wuerzburg, Wuerzburg, Germany.
²⁵ Division of Clinical Genetics, Children's Mercy Kansas City, 2401 Gillham Road, Kansas City, MO, USA.
²⁶ Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada.

PMID: 37982855
PMCID: PMC10786745
DOI: 10.1007/s00198-023-06843-2

Review

Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the HPP International Working Group

Eric Rush et al. Osteoporos Int. 2024 Jan.

. 2024 Jan;35(1):1-10.

doi: 10.1007/s00198-023-06843-2. Epub 2023 Nov 20.

Authors

Affiliations

¹ Division of Clinical Genetics, Children's Mercy Kansas City, 2401 Gillham Road, Kansas City, MO, USA. etrush@cmh.edu.
² Department of Pediatrics, University of Missouri - Kansas City School of Medicine, 2401 Gillham Road, Kansas City, MO, USA. etrush@cmh.edu.
³ Division of Endocrinology, Metabolism, Osteoporosis, and Genetics, Department of Internal Medicine, University of Kansas School of Medicine, Kansas City, KS, USA. etrush@cmh.edu.
⁴ F.I.R.M.O. Italian Foundation for the Research on Bone Diseases, Florence, Italy.
⁵ Donatello Bone Clinic, Villa Donatello Hospital, Florence, Italy.
⁶ Division of Endocrinology and Metabolism, McMaster University, Hamilton, Canada.
⁷ Department of Genetics, Centre Hospitalier de Versailles, Hôpital André Mignot, Versailles, France.
⁸ Division of Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ Department of Medicine, Endocrinology and Metabolism, Université de Sherbrooke, Sherbrooke, QC, Canada.
¹⁰ Center for Osteoporosis and Metabolic Bone Disease, Department of Rheumatology, The Cleveland Clinic Foundation, Cleveland, OH, USA.
¹¹ Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
¹² Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada.
¹³ Neuromuscular Clinic, McMaster University Medical Centre, Hamilton Health Sciences, Hamilton, Canada.
¹⁴ Division of Endocrinology, Diabetes, & Metabolism, Ohio State University Wexner Medical Center, Columbus, USA.
¹⁵ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
¹⁶ Bone Research and Education Centre, Oakville, ON, Canada.
¹⁷ 1st Medical Department, Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA, Trauma Centre Meidling, Hanusch Hospital, 1140, Vienna, Austria.
¹⁸ New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA.
¹⁹ APHP, Bicêtre Paris-Sud, University Paris Sud, Paris-Saclay, Le Kremlin Bicêtre, Paris, France.
²⁰ Division of Medical Genetics and Metabolism, Valley Children's HealthCare, Madera, CA, USA.
²¹ Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada.
²² Rheumatology Department, Hospital Pasteur 2 CHU, 06000, Nice, France.
²³ Inserm, CNRS, iBV, Université Côte d'Azur, 06000, Nice, France.
²⁴ Musculoskeletal Center Wuerzburg, University of Wuerzburg, Wuerzburg, Germany.
²⁵ Division of Clinical Genetics, Children's Mercy Kansas City, 2401 Gillham Road, Kansas City, MO, USA.
²⁶ Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada.

PMID: 37982855
PMCID: PMC10786745
DOI: 10.1007/s00198-023-06843-2

Abstract

Hypophosphatasia (HPP) is a rare inborn error of metabolism that presents variably in both age of onset and severity. HPP is caused by pathogenic variants in the ALPL gene, resulting in low activity of tissue nonspecific alkaline phosphatase (TNSALP). Patients with HPP tend have a similar pattern of elevation of natural substrates that can be used to aid in diagnosis. No formal diagnostic guidelines currently exist for the diagnosis of this condition in children, adolescents, or adults. The International HPP Working Group is a comprised of a multidisciplinary team of experts from Europe and North America who have expertise in the diagnosis and management of patients with HPP. This group reviewed 93 papers through a Medline, Medline In-Process, and Embase search for the terms "HPP" and "hypophosphatasia" between 2005 and 2020 and that explicitly address either the diagnosis of HPP in children, clinical manifestations of HPP in children, or both. Two reviewers independently evaluated each full-text publication for eligibility and studies were included if they were narrative reviews or case series/reports that concerned diagnosis of pediatric HPP or included clinical aspects of patients diagnosed with HPP. This review focused on 15 initial clinical manifestations that were selected by a group of clinical experts.The highest agreement in included literature was for pathogenic or likely pathogenic ALPL variant, elevation of natural substrates, and early loss of primary teeth. The highest prevalence was similar, including these same three parameters and including decreased bone mineral density. Additional parameters had less agreement and were less prevalent. These were organized into three major and six minor criteria, with diagnosis of HPP being made when two major or one major and two minor criteria are present.

Keywords: ALPL; Alkaline phosphatase; HPP diagnosis in children; hypophosphatasia; osteomalacia; rickets.

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Conflict of interest statement

ETR has consulted for, received honoraria from, and has research supported by Alexion Pharmaceuticals, AstraZeneca Rare Disease

MLB has received honoraria from Amgen, Bruno Farmaceutici, Calcilytix, Kyowa Kirin, UCB, grants and/or speaker for Abiogen, Alexion, Amgen, Bruno Farmaceutici, Echolight, Eli Lilly, Kyowa Kirin, SPA, Theramex, UCB, Consultant for Aboca, Alexion, Amolyt, Bruno Farmaceutici, Calcilytix, Kyowa Kirin, UCB

AAK has received research grants from Alexion, Amgen, Ascendis, Chugai, Radius, Takeda, Ultragenyx and is on the advisory board for Amgen, Amolyt and Takeda

SB has received advisory board participation from Alexion

KMD has received research grants and honoraria from Alexion

CD serves as an investigator, consultant, and speaker for Amgen; investigator for Radius; speaker for Alexion

SWI has received grant funding, ad hoc advisory board participation from Alexion Pharmaceuticals

MKJ has received honoria and grants from UCB, Amgen, Kyowa Kirin, Sanofi, Besin Healthcare, Abbvie

RK is a speaker and has received research funding from Alexion, AstraZeneca Rare Disease

AL is a consultant for and has received research funding and honoraria from Alexion

MEN serves as a non-paid consultant (fee equivalent donated to 501(c)3 patient advocacy groups) for Alexion

CR has received research grants and honoraria from Alexion, Kyowa Kirin, and Regeneron

CRG is a member of the Scientific Advisory Board of the HPP Global Patient Registry sponsored by Alexion Astra-Zeneca Rare Disease. She has had received honoraria for participation on this Board and has also received honoraria for select Alexion-sponsored presentations.

LS has received honoraria and grants from Alexion, Amgen, Chiesi, KyowaKirin, Novartis, Theramex, UCB

JHS serves as an Investigator and consultant for Alexion

SRS has received honoraria from, and has research supported by Alexion Pharmaceuticals, AstraZeneca Rare Disease

LMW serves as a consultant to Alexion

EML serves as an investigator, consultant, and speaker for Amgen; investigator for Radius; speaker for Alexion

DSA, HA, KA, FA, KD, SLF, FG, GG, EH, SK, IM, FM, LY, RBP declare no conflict of interest.

Figures

See this image and copyright information in PMC

References

1. Mornet E (2017) Genetics of hypophosphatasia. Arch Pediat 24(5S2):5S51–5S56. 10.1016/S0929-693X(18)30014-9 - PubMed
1. Khan AA, Josse R, Kannu P, et al. Hypophosphatasia: Canadian update on diagnosis and management. Osteoporos Int. 2019;30(9):1713–1722. doi: 10.1007/s00198-019-04921-y. - DOI - PubMed
1. Hofmann C, Girschick HJ, Mentrup B, et al. Clinical aspects of hypophosphatasia: an update. Clin Rev Bone Min Metabol. 2013;11(2):60–70. doi: 10.1007/s12018-013-9139-0. - DOI
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1. Whyte MP. Hypophosphatasia-aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016;12(4):233–246. doi: 10.1038/nrendo.2016.14. - DOI - PubMed

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Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the HPP International Working Group

Affiliations

Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the HPP International Working Group

Authors

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Abstract

Conflict of interest statement

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