Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Internal Medicine Neurology Oncology Pediatrics Respiratory Medicine Surgery
Congress Coverage
2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting

Keynote Webinar | Spotlight on Diet and Diabetes

Watch on-demand

An expert-led symposium exploring the prevention and management of type 2 diabetes through dietary interventions. 
ADVANCED SEARCH
Log in
Top
Osteoporosis International

Open Access 20-11-2023 | Review

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

Authors: Aliya A. Khan, Maria Luisa Brandi, Eric T. Rush, Dalal S. Ali, Hatim Al-Alwani, Khulod Almonaei, Farah Alsarraf, Severine Bacrot, Kathryn M. Dahir, Karel Dandurand, Chad Deal, Serge Livio Ferrari, Francesca Giusti, Gordon Guyatt, Erin Hatcher, Steven W. Ing, Muhammad Kassim Javaid, Sarah Khan, Roland Kocijan, Agnes Linglart, Iman M’Hiri, Francesca Marini, Mark E. Nunes, Cheryl Rockman-Greenberg, Christian Roux, Lothar Seefried, Jill H. Simmons, Susan R. Starling, Leanne M. Ward, Liang Yao, Romina Brignardello-Petersen, E. Michael Lewiecki

Published in: Osteoporosis International

Login to get access

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.
Literature
1.
Khan AA et al (2019) Hypophosphatasia: Canadian update on diagnosis and management. Osteoporos Int 30(9):1713–1722 PubMedCrossRef
2.
Bianchi ML et al (2020) Hypophosphatasia in adolescents and adults: overview of diagnosis and treatment. Osteoporos Int 31(8):1445–1460 PubMedCrossRef
3.
Whyte MP (2016) Hypophosphatasia — aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 12(4):233–246 PubMedCrossRef
4.
Rockman-Greenberg C (2013) Hypophosphatasia. Pediatr Endocrinol Rev 10(Suppl 2):380–388 PubMed
5.
Seefried L et al (2020) Burden of illness in adults with hypophosphatasia: data from the Global Hypophosphatasia Patient Registry. J Bone Miner Res 35(11):2171–2178 PubMedCrossRef
6.
Whyte MP (2009) Atypical femoral fractures, bisphosphonates, and adult hypophosphatasia. J Bone Miner Res 24(6):1132–1134 PubMedCrossRef
7.
Bishop N (2015) Clinical management of hypophosphatasia. Clin Cases Mineral Bone Metab : the official journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases 12(2):170–173
8.
Jemmerson R, Low MG (1987) Phosphatidylinositol anchor of HeLa cell alkaline phosphatase. Biochemistry 26(18):5703–5709 PubMedCrossRef
9.
Seetharam B, Tiruppathi C, Alpers DH (1987) Hydrophobic interactions of brush border alkaline phosphatases: the role of phosphatidyl inositol. Arch Biochem Biophys 253(1):189–198 PubMedCrossRef
10.
Le Du MH, Millan JL (2002) Structural evidence of functional divergence in human alkaline phosphatases. J Biol Chem 277(51):49808–49814 PubMedCrossRef
11.
Orimo H (2010) The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J Nippon Med Sch 77(1):4–12 PubMedCrossRef
12.
Fedde KN, Whyte MP (1990) Alkaline phosphatase (tissue-nonspecific isoenzyme) is a phosphoethanolamine and pyridoxal-5’-phosphate ectophosphatase: normal and hypophosphatasia fibroblast study. Am J Hum Genet 47(5):767–775 PubMedPubMedCentral
13.
Fedde KN et al (1999) Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia. J Bone Miner Res 14(12):2015–2026 PubMedCrossRef
14.
Lei W et al (2013) Alkaline phosphatases contribute to uterine receptivity, implantation, decidualization, and defense against bacterial endotoxin in hamsters. Reproduction 146(5):419–432 PubMedPubMedCentralCrossRef
15.
Narisawa S, Yadav MC, Millán JL (2013) In vivo overexpression of tissue-nonspecific alkaline phosphatase increases skeletal mineralization and affects the phosphorylation status of osteopontin. J Bone Miner Res 28(7):1587–1598 PubMedCrossRef
16.
Millán JL (2013) The role of phosphatases in the initiation of skeletal mineralization. Calcif Tissue Int 93(4):299–306 PubMedCrossRef
17.
Fleisch H, Russell RG, Straumann F (1966) Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. Nature 212(5065):901–903 PubMedCrossRef
18.
Sutton RA et al (2012) “Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res 27(5):987–994 PubMedCrossRef
19.
20.
Wong YW, Low MG (1994) Biosynthesis of glycosylphosphatidylinositol-anchored human placental alkaline phosphatase: evidence for a phospholipase C-sensitive precursor and its post-attachment conversion into a phospholipase C-resistant form. Biochemical journal 301(1):205–209 PubMedPubMedCentralCrossRef
21.
Nosjean O et al (1997) Human tissue non-specific alkaline phosphatases: sugar-moiety-induced enzymic and antigenic modulations and genetic aspects. Biochemical journal 321(2):297–303 PubMedPubMedCentralCrossRef
22.
23.
Hofmann C et al (2013) Compound heterozygosity of two functional null mutations in the ALPL gene associated with deleterious neurological outcome in an infant with hypophosphatasia. Bone 55(1):150–157 PubMedCrossRef
24.
25.
Whyte MP et al (2015) Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients. Bone 75:229–239 PubMedCrossRef
26.
Bowen RA et al (2010) Impact of blood collection devices on clinical chemistry assays. Clin Biochem 43(1–2):4–25 PubMedCrossRef
27.
Mohri M, Rezapoor H (2009) Effects of heparin, citrate, and EDTA on plasma biochemistry of sheep: comparison with serum. Res Vet Sci 86(1):111–114 PubMedCrossRef
28.
Eastell R et al (2011) Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J Bone Miner Res 26(3):530–537 PubMedCrossRef
29.
Kruse K et al (1989) Biochemical markers of bone turnover, intact serum parathyroid horn and renal calcium excretion in patients with pseudohypoparathyroidism and hypoparathyroidism before and during vitamin D treatment. Eur J Pediatr 148(6):535–539 PubMedCrossRef
30.
31.
Lum G (1995) Significance of low serum alkaline phosphatase activity in a predominantly adult male population. Clin Chem 41(4):515–518 PubMedCrossRef
32.
Osella G et al (1997) Serum markers of bone and collagen turnover in patients with Cushing’ s syndrome and in subjects with adrenal incidentalomas. J Clin Endocrinol Metab 82(10):3303–3307 PubMed
33.
Bardin T (1992) Renal osteodystrophy, disorders of vitamin D metabolism, and hypophosphatasia. Curr Opin Rheumatol 4(3):389–393 PubMedCrossRef
34.
35.
Lund T et al (2010) Multiple myeloma: changes in serum C-terminal telopeptide of collagen type I and bone-specific alkaline phosphatase can be used in daily practice to detect imminent osteolysis*. Eur J Haematol 84(5):412–420 PubMedPubMedCentralCrossRef
36.
Shaver WA, Bhatt H, Combes B (1986) Low serum alkaline phosphatase activity in Wilson’ s disease. Hepatology 6(5):859–863 PubMedCrossRef
37.
Korman JD et al (2008) Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology 48(4):1167–1174 PubMedCrossRef
38.
Yücel D, Dalva K (1992) Effect of in vitro hemolysis on 25 common biochemical tests. Clin Chem 38(4):575–577 PubMedCrossRef
39.
Shapiro JR, Lewiecki EM (2017) Hypophosphatasia in adults: clinical assessment and treatment considerations. J Bone Miner Res 32(10):1977–1980 PubMedCrossRef
40.
Linglart A, Salles JP (2017) Hypophosphatasia: the contribution of imaging. Arch Pediatr 24(5S2):5S74-5S79 PubMedCrossRef
41.
Mannes I et al (2022) Imaging patterns in pediatric hypophosphatasia. Pediatr Radiol 52(5):998–1006 PubMedCrossRef
42.
43.
Taillandier A et al (2015) Molecular diagnosis of hypophosphatasia and differential diagnosis by targeted Next Generation Sequencing. Mol Genet Metab 116(3):215–220 PubMedPubMedCentralCrossRef
44.
Payne RB (1998) Renal tubular reabsorption of phosphate (TmP/GFR): indications and interpretation. Annal Clin Biochem: international journal of laboratory medicine 35(2):201–206 CrossRef
45.
46.
Shapiro JR, Brennen F-S (2014) Chapter 55 - Osteogenesis imperfecta: maintenance of adult bone health. In: Shapiro JR et al (eds) Osteogenesis imperfecta. Academic Press, San Diego, pp 509–518 CrossRef
47.
48.
Mohn A et al (2011) Hypophosphatasia in a child with widened anterior fontanelle: lessons learned from late diagnosis and incorrect treatment. Acta Paediatr 100(7):e43–e46 PubMedCrossRef
49.
Nield LS et al (2006) Rickets: not a disease of the past. Am Fam Physician 74(4):619–626 PubMed
50.
Carpenter TO et al (2011) A clinician’s guide to X-linked hypophosphatemia. J Bone Miner Res 26(7):1381–1388 PubMedCrossRef
51.
Reynolds RD et al (1991) Extremely low serum pyridoxal 5′-phosphate in children with familial hypophosphatemic rickets. Am J Clin Nutr 53(3):698–701 PubMedCrossRef
52.
Tournis ST et al (2005) Co-existence of X-linked hypophosphatemic rickets (XLH) and primary hyperparathyroidism: case report and review of the literature. J Musculoskelet Neuronal Interact 5(2):150–154 PubMed
53.
Kramer K et al (2021) Dental defects in the primary dentition associated with hypophosphatasia from biallelic ALPL mutations. Bone 143:115732 PubMedCrossRef
Metadata
Title
Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults
Authors
Aliya A. Khan
Maria Luisa Brandi
Eric T. Rush
Dalal S. Ali
Hatim Al-Alwani
Khulod Almonaei
Farah Alsarraf
Severine Bacrot
Kathryn M. Dahir
Karel Dandurand
Chad Deal
Serge Livio Ferrari
Francesca Giusti
Gordon Guyatt
Erin Hatcher
Steven W. Ing
Muhammad Kassim Javaid
Sarah Khan
Roland Kocijan
Agnes Linglart
Iman M’Hiri
Francesca Marini
Mark E. Nunes
Cheryl Rockman-Greenberg
Christian Roux
Lothar Seefried
Jill H. Simmons
Susan R. Starling
Leanne M. Ward
Liang Yao
Romina Brignardello-Petersen
E. Michael Lewiecki
Publication date
20-11-2023
Publisher
Springer London
Published in
Osteoporosis International
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-023-06844-1