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Disease definition and prevalence

Hypophosphatasia (HPP) is a rare, lifelong, and progressive metabolic disease caused by deficient activity of the enzyme tissue non-specific alkaline phosphatase (ALP). Low ALP in HPP is due to autosomal dominant or recessive inheritance of loss-of-function mutations in the ALPL gene. HPP affects people of all ages with a broad spectrum of clinical manifestations, high disease burden, and substantial negative impact on quality of life. Manifestations include impaired bone mineralization, muscle weakness, neurologic symptoms, fatigue, and musculoskeletal pain — manifestations that underscore the systemic nature of the disease and that may occur at any age and result in cumulative morbidity.^1-6

Based on data in the US from 2016 to 2023, the prevalence of diagnosed HPP across all ages was about 3:100,000 population, with ~79% of prevalent patients aged ≥18 years.⁷ However, the true incidence and prevalence of HPP across all ages remains uncertain due to underdiagnosis, with variable expressivity, penetrance, and clinical presentation.

Diagnosis of HPP

Persistently low age- and sex-adjusted serum alkaline phosphatase (ALP) activity (ie, at least 2 measurements), in conjunction with relevant clinical manifestations, and other criteria, according to International Working Group diagnostic criteria, and after exclusion of other causes of low ALP, supports a diagnosis of HPP in most cases.^6,8-10,11-16 Additional biochemical assessments, including analysis of ALP substrates, support the diagnosis of HPP but are not required.¹⁵ Pyridoxal 5'-phosphate (PLP) and phosphoethanolamine (PEA) concentrations are often elevated in patients with HPP. PLP (vitamin B6) is the most sensitive ALP substrate marker for HPP, although it may not be elevated in all patients.^{10,13,14,17,18} Inorganic pyrophosphate (PPi) levels may also be increased in plasma and urine; however, PPi assessment is not routinely available and is currently limited to research settings.^13,18-20

Genetic testing for ALPL variants may be helpful in confirming a diagnosis (although not mandatory), and family mapping may identify previously undiagnosed cases.^10,18,21 More than 450 disease-causing variants in the ALPL gene have been identified.^13,22-29

Integral to the diagnostic evaluation are the considerations listed below, with the key diagnostic indicator being low age- and sex-adjusted serum ALP activity level.^6,30

• Clinical and laboratory findings
• Skeletal and non-skeletal manifestations (neurological, renal, respiratory, muscular, rheumatologic)
• Dental manifestations
• Family history of siblings or parents with HPP

It is important to note that normal ranges for serum ALP activity are higher in infants, children, and adolescents than they are in adults.^31,32 In general, ALP <40 IU/L in adults or <160 IU/L in children should prompt evaluation for a pattern of persistently low ALP levels, the hallmark of HPP. These values serve as general guidelines to prompt further investigation; however, evaluation should always be based on persistently low readings relative to the specific age- and sex-adjusted reference ranges of the performing laboratory.³²

Clinical manifestations

Historically, characterization of HPP manifestations has focused on skeletal features, particularly rickets (in children), osteomalacia, dental abnormalities, tooth loss, recurrent fractures/pseudofractures, and bone deformity.^2-4 Furthermore, a growing body of evidence indicates that HPP is also characterized by several nonskeletal features that are tied to deficient ALP activity and its consequences. These include muscle weakness, fatigue, neurologic symptoms, pain (musculoskeletal and neuropathic), impaired renal function, impaired mobility, etc. Impaired calcium and phosphate metabolism may also occur, particularly in younger children.^2,3,33 In adults, disease burden is similar whether the patients have overt skeletal manifestations or predominantly non-skeletal manifestations (eg, muscle weakness and/or musculoskeletal pain).³⁴

In the natural history of the disease, mortality was reported to be 50‐100% within the first year of life in neonates and infants with early-onset, life-threatening HPP (prior to 6 months of age).^35-37 Data from a noninterventional, retrospective chart review study of 48 neonates and infants with life-threatening HPP estimated 75% mortality at 5 years of age.³⁸

Beyond early-onset HPP, HPP has the potential to cause significant morbidity and disability in patients of any age.^3,4,39,40 Disease burden in adults is associated with a significant negative impact on the health-related quality of life and the ability to carry out activities of daily living, and this can be observed regardless of whether patients have 2 or more ALPL variants.^40,41

The tables below provide a tool to assist in gathering information about the clinical signs and symptoms of HPP, but should not replace professional judgement or clinical decision making.¹⁵

Radiographic findings

In children with open growth plates, signs of rickets are visible on plain radiographs. Physeal widening may be seen along with irregularity of the provisional zone of calcification, as well as metaphyseal flaring with areas of radiolucency adjacent to areas of osteosclerosis. In infants and young children with HPP, bone demineralization can progress rapidly. For example, bones that are visible but deformed at birth may show rapid loss of skeletal mineral and severe rachitic changes within the first several months of life. Cupping and fraying of the metaphyses of long bones, widened growth plates, and spotty demineralization of the epiphyses can be seen.^42,43 A radiolucent “tongue” shape is commonly seen projecting from the epiphysis into the metaphysis of long bones.^42,43 Premature bony fusion of all cranial sutures (craniosynostosis) can occur, and can give the skull a “beaten-copper” appearance on radiographs.^6,43 Other radiographic indicators include rachitic ribs and bone fractures.³⁸

In adults, recurrent and/or poorly healing fractures or pseudofractures (especially atypical femoral fractures, femoral pseudofractures, metatarsal fractures/pseudofractures) are characteristic and can be more common than in children.^12,14,16,44 Pseudofractures are atraumatic radiolucencies resulting from compromised bone mineralization and are often associated with poor clinical outcomes. Pseudofractures may progress to a complete fracture.⁴⁵ Radiographic chondrocalcinosis and documented pyrophosphate arthropathy have also been observed.^46,47

Differential diagnosis

Misdiagnosis of HPP can be common and may lead to ineffective management that can compound the clinical picture and worsen HPP.^{9,34,40,48,49} It is important to keep in mind that patients with HPP typically do not have low BMD.⁵⁰ In fact, it may be normal or elevated, and increased lumbar spine BMD appears to be associated with severely compromised mineralization and increased risk for HPP-related fractures.⁴⁴

Differences in laboratory parameters are important when considering a differential diagnosis. Importantly, a low age- and sex-adjusted ALP activity level can assist in differentiating HPP from other skeletal-related disorders.^{6,9-12,14,15,32}

Unlike patients with most forms of rickets or osteomalacia, patients with HPP have low ALP activity, not elevated ALP.^2,3,9,33 In addition, patients with HPP do not have low serum calcium level and parathyroid hormone (PTH) levels are typically normal.⁹ However, some HPP patients may exhibit hypercalcemia with an accordingly low serum PTH level and low serum PTH levels may be evident when there is only hypercalciuria.^36,43

References

1. Salles J. Hypophosphatasia: biological and clinical aspects, avenues for therapy. Clin Biochem Rev. 2020; 41: 13-27.

2. Högler W, Linglart A, Petryk A et al. Growth and disease burden in children with hypophosphatasia. Endocr Connect. 2023; 12: e220240.

3. Dahir KM, Seefried L, Kishnani PS et al. Clinical profiles of treated and untreated adults with hypophosphatasia in the Global HPP Registry. Orphanet Journal of Rare Disease. 2022; 17: 277.

4. Rush ET, Moseley S, Petryk A. Burden of disease in pediatric patients with hypophosphatasia: results from the HPP Impact Patient Survey and the HPP Outcomes Study Telephone interview. Orphanet J Rare Dis. 2019; 14: 201.

5. Szabo SM, Tomazos IC, Petryk A et al. Frequency and age at occurrence of clinical manifestations of disease in patients with hypophosphatasia: a systematic literature review. Orphanet J Rare Dis. 2019; 14: 85.

6. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013; 10 Suppl 2: 380-388.

7. Fang S, Petryk AM, Yang F et al. Diagnosed Prevalence of Hypophosphatasia: A Retrospective Analysis of Electronic Health Records in the United States. Poster presented at ASBMR 2025 Annual Meeting; September 5-8, 2025; Seattle, WA.

8. Vieira LHR, Peixoto KC, Flösi CL et al. Active search of adult patients with persistently low serum alkaline phosphatase levels for the diagnosis of hypophosphatasia. Arch Endocrinol Metab. 2021; 65: 289-294.

9. Khan AA, Brandi ML, Rush ET et al. Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults. Osteoporos Int. 2024; 35: 431-438.

10. Khan AA, Josse R, Kannu P et al. Hypophosphatasia: Canadian update on diagnosis and management. Osteoporos Int. 2019; 30: 1713-1722.

11. Bishop N, Munns CF, Ozono K. Transformative therapy in hypophosphatasia. Arch Dis Child. 2016; 101: 514-515.

12. Brandi ML, Khan AA, Rush ET et al. The challenge of hypophosphatasia diagnosis in adults: results from the HPP International Working Group Literature Surveillance. Osteoporos Int. 2024; 35: 439-449.

13. Baroncelli GI, Carlucci G, Freri E et al. The diagnosis of hypophosphatasia in children as a multidisciplinary effort: an expert opinion. J Endocrinol Invest. 2024; 47: 739-747.

14. Desborough R, Nicklin P, Gossiel F et al. Clinical and biochemical characteristics of adults with hypophosphatasia attending a metabolic bone clinic. Bone. 2021; 144: 115795.

15. Kishnani PS, Rush ET, Arundel P et al. Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa. Mol Genet Metab. 2017; 122: 4-17.

16. Rush E, Brandi ML, Khan A et al. Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the HPP International Working Group. Osteroporos Int. 2024; 35: 1-10.

17. Whyte MP, Mahuren JD, Vrabel LA, Coburn SP. Markedly increased circulating pyridoxal-5’-phosphate levels in hypophosphatasia. Alkaline phosphatase acts in vitamin B6 metabolismia. J Clin Invest. 1985; 76: 752-756.

18. Simmons JH. Best practices in: recognizing and diagnosing hypophosphatasia. Clin Endocrinol News. 2013; 1-13.

19. Russell RG, Bisaz S, Donath A, Morgan DB, Fleisch H. Inorganic pyrophosphate in plasma in normal persons and in patients with hypophosphatasia, osteogenesis imperfecta, and other disorders of bone. J Clin Invest. 1971; 50: 961-969.

20. Russell RG. Excretion of inorganic pyrophosphate in hypophosphatasia. Lancet. 1965; 286: 461-464.

21. Taillandier A, Domingues C, De Cazanove C et al. Molecular diagnosis of hypophosphatasia and differential diagnosis by targeted Next Generation Sequencing. Mol Genet Metab. 2015; 116: 215-220.

22. Farman MR, Rehder C, Malli T et al. The global ALPL gene variant classification project: dedicated to deciphering variants. Bone. 2024; 178: 116947.

23. Huggins E, Ong R, Rockman-Greenberg C et al. Multigenerational case examples of hypophosphatasia: challenges in genetic counseling and disease management. Mol Genet Metab Rep. 2020; 25: 100661.

24. Eastman JR, Bixler D. Clinical, laboratory, and genetic investigations of hypophosphatasia: support for autosomal dominant inheritance with homozygous lethality. J Craniofac Genet Dev Biol. 1983; 3: 213-234.

25. Henthorn PS, Raducha M, Fedde KN, Lafferty M, Whyte MP. Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia. Proc Natl Acad Sci U S A. 1992; 89: 9924-9928.

26. Moore CA, Ward JC, Rivas ML, Magill L, Whyte MP. Infantile hypophosphatasia: autosomal recessive transmission to two related sibships. Am J Med Genet. 1990; 36: 15-22.

27. Mumm S, Jones J, Finnegan P, Henthorn PS, Podgornik MN, Whyte MP. Denaturing gradient gel electrophoresis analysis of the tissue nonspecific alkaline phosphatase isoenzyme gene in hypophosphatasia. Mol Genet Metab. 2002; 75: 143-153.

28. Mornet E. Molecular genetics of hypophosphatasia and phenotype-genotype correlations. Subcell Biochem. 2015; Chapter 2: 25-43.

29. Mornet E, Taillandier A, Domingues C et al. Hypophosphatasia: a genetic-based nosology and new insights in genotype-phenotype correlation. Eur J Hum Genet. 2021; 29: 289-299.

30. Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann NY Acad Sci. 2010; 1192: 190-200.

31. ARUP Laboratories. Alkaline Phosphatase Isoenzymes, Serum or Plasma. Accessed September 27, 2023. https://ltd.aruplab.com/Tests/Pub/0021020.

32. Adeli K, Higgins V, Trajcevski K, White-Al Habeeb N. The Canadian laboratory initative on pediatric reference intervals: a CALIPER white paper. Crit Rev Clin Lab Sci. 2017; 54: 358-413.

33. Martos-Moreno GA, Rockman-Greenberg C, Ozono K et al. Clinical profiles of children with hypophosphatasia prior to treatment with enzyme replacement therapy: an observational analysis from the Global HPP Registry. Horm Res Paediatr. 2024; 97: 233-242.

34. Dahir KM, Kishnani PS, Martos-Moreno GA et al. Impact of muscular symptoms and/or pain on disease characteristics, disability, and quality of life in adult patients with hypophosphatasia: a cross-sectional analysis from the Global HPP Registry. Front Endocrino. 2023;14: 1138599.

35. Fraser D. Hypophosphatasia. Am J Med. 1957; 22: 730-746.

36. Whyte MP. Hypophosphatasia. In: Thakker R, Whyte MP, Eisman J, Igarashi T, eds. Genetics of Bone Biology and Skeletal Disease. Elsevier Inc, 2013: 337-360.

37. Leung EC, Mhanni AA, Reed M et al. Outcome of perinatal hypophosphatasia in manitoba mennonites: a retrospective cohort analysis. JIMD Rep. 2013; 11: 73-78.

38. Whyte MP, Leung E, Wilcox WR et al. Natural history of perinatal and infantile hypophosphatasia: a retrospective study. J Pediatr. 2019; 209: 116-124.e114.

39. Högler W, Langman C, Gomes da Silva H et al. Diagnostic delay is common among patients with hypophosphatasia: initial findings from a longitudinal, prospective, global registry. BMC Musculoskelet Disord. 2019; 20: 80.

40. Seefried L, Dahir K, Petryk A et al. Burden of illness in adults with hypophosphatasia: data from the Global Hypophophatasia Patient Registry. J Bone Miner Res. 2020; 35: 2171-2178.

41. Kishnani PS, Seefried L, Dahir KM et al. Disease burden by ALPL variant number in patients with non-life-threatening hypophosphatasia in the Global HPP Registry. J Med Genet. 2025; 62: 249-257.

42. Whyte MP. Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. Endocr Rev. 1994; 15: 439-461.

43. Whyte MP. Hypophosphatasia. In: Glorieux F, Pettifor J, Juppner H, eds. Pediatric Bone. Elsevier, 2012: 771-794.

44. Genest F, Claußen L, Rak D, Seefried L. Bone mineral density and fracture risk in adult patients with hypophosphatasia. Osteroporos Int. 2021; 32: 377-385.

45. Seefried L, Rak D, Genest F. Grading pseudofractures-the “breach-beak-bump-bridge” approach. Calcif Tissue Int. 2025; 116: 62.

46. Berkseth KE, Tebben PJ, Drake MT et al. Clinical spectrum of hypophosphatasia diagnosed in adults. Bone. 2013; 54: 21-27.

47. Schmidt T, Mussawy H, Rolvien T et al. Clinical, radiographic and biochemical characteristics of adult hypophosphatasia. Osteoporos Int. 2017; 28: 2653-2662.

48. Braunstein NA. Multiple fractures, pain, and severe disability in a patient with adult-onset hypophosphatasia. Bone Rep. 2016; 4: 1-4.

49. Rauf MA, Kotecha J, Moss K. Reducing diagnostic delay in hypophosphatasia: a case series of 14 patients presenting to general rheumatology. Osteoporos Int. 2023; 34: 1647-1652.

50. Weber TJ, Sawyer EK, Moseley S, Odrljin T, Kishnani PS. Burden of disease in adult patients with hypophosphatasia: results from two patient-reported surveys. Metabolism. 2016; 65: 1522-1530.

51. Mornet E, Nunes ME. Gene Reviews^® Hypophosphatasia. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1150/.

52. Whyte MP. Atypical femoral fractures, bisphosphonates, and adult hypophosphatasia. J Bone Miner Res. 2009; 24: 1132-1134.

53. Di Rocco F, Rothenbuhler A, Cormier Daire V et al. Craniosynostosis and metabolic bone disorder. A review. Neurochirurgie. 2019; 65: 258-263

54. Silva I, Castelao W, Mateus M et al. Childhood hypophosphatasia with myopathy: clinical report with recent update. Acta Reumatol Port. 2012; 37: 92-96.

55. Mornet E, Beck C, Bloch-Zupan A et al. Clinical utility gene card for: hypophosphatasia. Eur J Hum Genet. 2011; 19.

56. Watanabe H, Umeda M, Seki T et al. Clinical and laboratory studies of severe periodontal disease in an adolescent associated with hypophosphatasia. A case report. J Periodontol. 1993; 64: 174-180.

57. Girschick HJ, Mornet E, Beer M et al. Chronic multifocal non-bacterial osteomyelitis in hypophosphatasia mimicking malignancy. BMC Pediatr. 2007; 7: 3.

58. Nikkel SM. Skeletal dysplasias: what every bone health clinician needs to know. Curr Osteoporos Rep. 2017; 15: 419-424.

59. Stokes VJ, Nielsen MF, Hannan FM et al. Hypercalcemic disorders in children. J Bone Miner Res. 2017; 32: 2157-2170.

60. Whyte MP, Wenkert D, McAlister WH et al. Chronic recurrent multifocal osteomyelitis mimicked in childhood hypophosphatasia. J Bone Miner Res. 2009; 24: 1493-1505.

61. Rush ET. Childhood hypophosphatasia: to treat or not to treat. Orphanet J Rare Dis. 2018; 13: 116.

62. O’Duffy JD. Hypophosphatasia associated with calcium pyrophosphate dihydrate deposits in cartilage. Report of a case. Arthritis Rheum. 1970; 13: 381-388.

63. Martins L, de Almeida AB, Dos Santos EJL et al. A novel combination of biallelic ALPL mutations associated with adult hypophosphatasia: a phenotype-genotype association and computational analysis study. Bone. 2019; 125: 128-139.

64. Rauch F, Bardai G, Rockman-Greenberg C. ALPL mutations in adults with rheumatologic disorders and low serum alkaline phosphatase activity. J Bone Miner Metab. 2019; 37: 893-899.

65. Sutton RAL, Mumm S, Coburn SP et al. “Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res. 2012; 27: 987-994.

66. McKiernan FE, Berg RL, Fuehrer J. Clinical and radiographic findings in adults with persistent hypophosphatasemia. J Bone Miner Res. 2014; 29: 1651-1660.

67. Riancho JA. Diagnostic approach to patients with low serum alkaline phosphatase. Calcif Tissue Int. 2023;112(3):289-296

68. Whyte MP. Hypophosphatasia: nature’s window on alkaline phosphatase function in humans. In: Bilezikian JP, Raisz LG, Martin TJ, eds. Principles of Bone Biology. San Diego, CA: Elsevier, 2008: 1573-1598.

69. Lum G. Significance of low serum alkaline phosphatase activity in a predominantly adult male population. Clin Chem. 1995; 41: 515-518.

70. Viapiana O, Gatti D, Dalle Grave R et al. Marked increases in bone mineral density and biochemical markers of bone turnover in patients with anorexia nervosa gaining weight. Bone. 2007; 40: 1073-1077.

71. Kondo T, Tasaka T, Tomioka N et al. Low neutrophil alkaline phosphatase score is a new aspect of calreticulin-mutated myeloproliferative neoplasms. Springerplus. 2016; 5:1146.

72. Shipman KE, Holt AD, Gama R. Interpreting an isolated raised serum alkaline phosphatase level in an asymptomatic patient. BMJ. 2013; 346:f976.

73. Mohn A, De Leonibus C, de Giorgis T et al. Hypophosphatasia in a child with widened anterior fontanelle: lessons learned from late diagnosis and incorrect treatment. Acta Paediatr. 2011; 100: e43-e46.

74. Bloch-Zupan A. Hypophosphatasia: diagnosis and clinical signs - a dental surgeon perspective. Int J Paediatr Dent. 2016; 26: 426-438.

75. Roth KS, Chan JCM, Rosenbloom a et al. Hypophosphatemic Rickets. Available at: https://emedicine.medscape.com/article/922305-overview.

76. Santos F, Fuente R, Mejia N et al. Hypophosphatemia and growth. Pediatr Nephrol. 2013; 28: 595-603

77. Baroncelli GI, Toschi B, Bertelloni S. Hypophosphatemic rickets. Curr Opin Endocrinol Diabetes Obes. 2012; 19: 460-467.

The information on this page is intended as educational information for healthcare professionals. It does not replace a healthcare professional’s judgement or clinical diagnosis.