Review

. 2024 Mar;35(3):431-438.

doi: 10.1007/s00198-023-06844-1. Epub 2023 Nov 20.

Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults

Aliya A Khan^#¹, Maria Luisa Brandi^#^{2

3}, Eric T Rush^#^{4

5

6}, Dalal S Ali^#⁷, Hatim Al-Alwani⁷, Khulod Almonaei⁷, Farah Alsarraf⁷, Severine Bacrot⁸, Kathryn M Dahir⁹, Karel Dandurand¹⁰, Chad Deal¹¹, Serge Livio Ferrari¹², Francesca Giusti³, Gordon Guyatt¹³, Erin Hatcher¹⁴, Steven W Ing¹⁵, Muhammad Kassim Javaid¹⁶, Sarah Khan¹⁷, Roland Kocijan¹⁸, Agnes Linglart¹⁹, Iman M'Hiri¹⁷, Francesca Marini², Mark E Nunes²⁰, Cheryl Rockman-Greenberg²¹, Christian Roux^{22

23}, Lothar Seefried²⁴, Jill H Simmons⁹, Susan R Starling⁴, Leanne M Ward²⁵, Liang Yao¹³, Romina Brignardello-Petersen¹³, E Michael Lewiecki²⁶

Affiliations

¹ Division of Endocrinology and Metabolism, McMaster University, Hamilton, Canada. aliya@mcmaster.ca.
² F.I.R.M.O. Italian Foundation for the Research On Bone Diseases, Florence, Italy.
³ Donatello Bone Clinic, Villa Donatello Hospital, Florence, Italy.
⁴ Division of Clinical Genetics, Children's Mercy Kansas City, Kansas City, MO, USA.
⁵ Division of Endocrinology, Metabolism, Osteoporosis and Genetics, Department of Internal Medicine, University of Kansas School of Medicine, Kansas City, KS, USA.
⁶ Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.
⁷ Division of Endocrinology and Metabolism, McMaster University, Hamilton, Canada.
⁸ Department of Genetics, Centre Hospitalier de Versailles, Hôpital André Mignot, Versailles, France.
⁹ Division of Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁰ Department of Medicine, Endocrinology and Metabolism, Université de Sherbrooke, Sherbrooke, QC, Canada.
¹¹ Center for Osteoporosis and Metabolic Bone Disease, Department of Rheumatology, The Cleveland Clinic Foundation, Cleveland, OH, USA.
¹² Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
¹³ Department of Health Research Methods, Evidence and Impact at McMaster University, Hamilton, Canada.
¹⁴ Neuromuscular Clinic, McMaster University Medical Centre, Hamilton Health Sciences, Hamilton, Canada.
¹⁵ Division of Endocrinology, Diabetes & Metabolism, Ohio State University Wexner Medical Center, Columbus, OH, USA.
¹⁶ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
¹⁷ Bone Research and Education Centre, Oakville, ON, Canada.
¹⁸ Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA, Trauma Centre Meidling, 1St Medical Department Hanusch Hospital, 1140, Vienna, Austria.
¹⁹ APHP, Bicêtre Paris-Sud, UniversityParis 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 INSERM CRESS UMR 1153, Paris, France.
²³ Université Paris-Cité, Department of Rheumatology, APHP-Centre, Cochin Hospital, Paris, France.
²⁴ Musculoskeletal Center Wuerzburg, University of Würzburg, Würzburg, Germany.
²⁵ Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.
²⁶ New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA.

^# Contributed equally.

PMID: 37982857
PMCID: PMC10866785
DOI: 10.1007/s00198-023-06844-1

Review

Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults

Aliya A Khan et al. Osteoporos Int. 2024 Mar.

. 2024 Mar;35(3):431-438.

doi: 10.1007/s00198-023-06844-1. Epub 2023 Nov 20.

Authors

Affiliations

¹ Division of Endocrinology and Metabolism, McMaster University, Hamilton, Canada. aliya@mcmaster.ca.
² F.I.R.M.O. Italian Foundation for the Research On Bone Diseases, Florence, Italy.
³ Donatello Bone Clinic, Villa Donatello Hospital, Florence, Italy.
⁴ Division of Clinical Genetics, Children's Mercy Kansas City, Kansas City, MO, USA.
⁵ Division of Endocrinology, Metabolism, Osteoporosis and Genetics, Department of Internal Medicine, University of Kansas School of Medicine, Kansas City, KS, USA.
⁶ Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.
⁷ Division of Endocrinology and Metabolism, McMaster University, Hamilton, Canada.
⁸ Department of Genetics, Centre Hospitalier de Versailles, Hôpital André Mignot, Versailles, France.
⁹ Division of Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁰ Department of Medicine, Endocrinology and Metabolism, Université de Sherbrooke, Sherbrooke, QC, Canada.
¹¹ Center for Osteoporosis and Metabolic Bone Disease, Department of Rheumatology, The Cleveland Clinic Foundation, Cleveland, OH, USA.
¹² Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
¹³ Department of Health Research Methods, Evidence and Impact at McMaster University, Hamilton, Canada.
¹⁴ Neuromuscular Clinic, McMaster University Medical Centre, Hamilton Health Sciences, Hamilton, Canada.
¹⁵ Division of Endocrinology, Diabetes & Metabolism, Ohio State University Wexner Medical Center, Columbus, OH, USA.
¹⁶ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
¹⁷ Bone Research and Education Centre, Oakville, ON, Canada.
¹⁸ Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA, Trauma Centre Meidling, 1St Medical Department Hanusch Hospital, 1140, Vienna, Austria.
¹⁹ APHP, Bicêtre Paris-Sud, UniversityParis 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 INSERM CRESS UMR 1153, Paris, France.
²³ Université Paris-Cité, Department of Rheumatology, APHP-Centre, Cochin Hospital, Paris, France.
²⁴ Musculoskeletal Center Wuerzburg, University of Würzburg, Würzburg, Germany.
²⁵ Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.
²⁶ New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA.

^# Contributed equally.

PMID: 37982857
PMCID: PMC10866785
DOI: 10.1007/s00198-023-06844-1

Erratum in

Correction: Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults.
Khan AA, Brandi ML, Rush ET, Ali DS, Al-Alwani H, Almonaei K, Alsarraf F, Bacrot S, Dahir KM, Dandurand K, Deal C, Ferrari SL, Giusti F, Guyatt G, Hatcher E, Ing SW, Javaid MK, Khan S, Kocijan R, Linglart A, M'Hiri I, Marini F, Nunes ME, Rockman-Greenberg C, Roux C, Seefried L, Simmons JH, Starling SR, Ward LM, Yao L, Brignardello-Petersen R, Michael Lewiecki E. Khan AA, et al. Osteoporos Int. 2024 May;35(5):933-934. doi: 10.1007/s00198-024-07048-x. Osteoporos Int. 2024. PMID: 38498158 Free PMC article. No abstract available.

Abstract

Background: This manuscript provides a summary of the current evidence to support the criteria for diagnosing a child or adult with hypophosphatasia (HPP). The diagnosis of HPP is made on the basis of integrating clinical features, laboratory profile, radiographic features of the condition, and DNA analysis identifying the presence of a pathogenic variant of the tissue nonspecific alkaline phosphatase gene (ALPL). Often, the diagnosis of HPP is significantly delayed in both adults and children, and updated diagnostic criteria are required to keep pace with our evolving understanding regarding the relationship between ALPL genotype and associated HPP clinical features.

Methods: An International Working Group (IWG) on HPP was formed, comprised of a multidisciplinary team of experts from Europe and North America with expertise in the diagnosis and management of patients with HPP. Methodologists (Romina Brignardello-Petersen and Gordon Guyatt) and their team supported the IWG and conducted systematic reviews following the GRADE methodology, and this provided the basis for the recommendations.

Results: The IWG completed systematic reviews of the literature, including case reports and expert opinion papers describing the phenotype of patients with HPP. The published data are largely retrospective and include a relatively small number of patients with this rare condition. It is anticipated that further knowledge will lead to improvement in the quality of genotype-phenotype reporting in this condition.

Conclusion: Following consensus meetings, agreement was reached regarding the major and minor criteria that can assist in establishing a clinical diagnosis of HPP in adults and children.

Keywords: Diagnosis; Hypophosphatasia; Major criteria; Minor criteria.

PubMed Disclaimer

Conflict of interest statement

AAK has received research grants from Alexion, Amgen, Ascendis, Chugai, Radius, Takeda, and Ultragenyx and is on the advisory board for Amgen, Amolyt, and Takeda. MLB has received honoraria from Amgen, Bruno Farmaceutici, Calcilytix, Kyowa Kirin, and UCB; grants and/or speaker for Abiogen, Alexion, Amgen, Bruno Farmaceutici, Echolight, Eli Lilly, Kyowa Kirin, SPA, Theramex, and UCB; Consultant for Aboca, Alexion, Amolyt, Bruno Farmaceutici, Calcilytix, Kyowa Kirin, and UCB. ETR has consulted for, received honoraria from, and has research supported by Alexion Pharmaceuticals, AstraZeneca Rare Disease. 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 and ad hoc advisory board participation from Alexion Pharmaceuticals. MKJ has received honoria and grants from UCB, Amgen, Kyowa Kirin, Sanofi, Besin Healthcare, and 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. CRG is a member of the Scientific Advisory Board of the HPP Global Patient Registry sponsored by Alexion AstraZeneca Rare Disease. She has had received honoraria for participation on this Board and has also received honoraria for select Alexion-sponsored presentations.CR has received research grants and honoraria from Alexion, Kyowa Kirin, and Regeneron. LS has received honoraria and grants from Alexion, Amgen, Chiesi, KyowaKirin, Novartis, Theramex, and 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

**Fig. 1**
Features of HPP in the pediatric and adult patient population with some overlapping features between the two age groups

See this image and copyright information in PMC

References

1. Khan AA, 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. Bianchi ML, et al. Hypophosphatasia in adolescents and adults: overview of diagnosis and treatment. Osteoporos Int. 2020;31(8):1445–1460. doi: 10.1007/s00198-020-05345-9. - DOI - PubMed
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
1. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013;10(Suppl 2):380–388. - PubMed
1. Seefried L, et al. Burden of illness in adults with hypophosphatasia: data from the Global Hypophosphatasia Patient Registry. J Bone Miner Res. 2020;35(11):2171–2178. doi: 10.1002/jbmr.4130. - DOI - PubMed

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Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults

Affiliations

Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

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