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Manifestations of hypophosphatasia (HPP) may be hidden below the surface.1-3

Visible symptoms:

Bone, muscle, or joint pain1,4,5
Fracture6-8
Short stature1,9
Impaired mobility1,10

Potential hidden symptoms:

Skeletal demineralization2
Stress fractures11,12
Pseudofractures1,13
Osteomalacia13
Osteopenia/ osteoporosis1,14
Calcium pyrophosphate dihydrate (CPPD) deposition disease1,15,16
Limited ability to perform everyday activities10
Decreased quality of life17

Baseline assessment, along with medical and family histories, can uncover hidden manifestations of hypophosphatasia. 1-3,14

Patients may not be aware that current and past symptoms could be caused by hypophosphatasia.3

Select appropriate tests/assessments from the following (not all are required):

Possible hidden manifestations

Tests and assessments to consider

Skeletal

Skeletal deformities1

Stress fractures11,12

Pseudofractures1,13

Progressive demineralization / rickets / osteopenia / osteoporosis1,2,14

Osteomalacia13

History of fractures and / or skeletal surgeries 6-8

Hypomineralization1

Craniosynostosis1

Complete skeletal survey 2

Sequential radiographs 10

DXA10,14

History / record review

Pain and muscle weakness

Bone pain1

Muscle pain1,4

Joint pain5

Muscle weakness1,4,10

Hypotonia1

Standardized pain assessment tool (eg, BPI, NIPS)10,18

Medication use review (current / past / increasing use of analgesics) 10

HHD10,19

History/record review 10

Renal

Hypercalciuria1,20

Nephrocalcinosis1,21

Kidney stones10

Progressive renal impairment 2,22,23

Laboratory testing (eg, urinary calcium, serum creatinine) 1,10,14

Renal ultrasound10

History/record review 10

Dental

Premature tooth loss 1,24,25

Abnormal dentition1

Dental cavities14,26

Periodontal disease 27,28

Complete dental examination and history 1

Growth / development

Failure to thrive1

Short stature1,9

Missed motor milestones / delayed motor development1,4,29

Developmental assessment (eg, DDST) 10

History/record review

Physical function and quality of life

Impaired mobility1,10

Abnormal or waddling gait 1,4,10

Reduced ability to perform normal everyday activities10

Pain or unusual fatigue following gentle exercise or mild exertion 10,30,31

Impaired quality of life 17

Mobility assessment (eg, 6MWT, BOT-2) 10

Gait assessment32

Standardized, age-appropriate quality-of-life assessment tool (eg, SF-36, PedsQL, EuroQoL EQ-5D-5L) 33

Patient discussion10

Medicine use review (eg, antidepressants, anti-anxiety) 10

Abbreviations: 6MWT, 6-minute walk test; BOT-2, Bruininks-Oseretsky Test of Motor Proficiency; BPI, Brief Pain Inventory; DDST, Denver Developmental Screening Test; DXA, dual-energy X-ray absorptiometry; HHD, handheld dynamometry; NIPS, Neonatal Infant Pain Scale; PedsQL, Pediatric Quality of Life Inventory; SF-36, 36-item Short Form Health Survey.

A physical or occupational therapist can help evaluate and/or assist with the management of the patient’s physical function and disability.14,32

Detailed patient discussions are critical to uncovering the full daily impact of hypophosphatasia.

Patients may not realize the extent of their limitations or may not connect them to hypophosphatasia.

To uncover the full daily impact of hypophosphatasia, ask your patients about the following:

Choose an icon to learn more

  • Limited mobility
  • Pain and muscle weakness
  • Difficulty with everyday activities
  • Problems with work or school
  • Family or social challenges
Difficulty making friends or participating in activities with similarly aged peers 10
Depression or anxiety10

Clinical symptoms

Prominent clinical symptoms of hypophosphatasia

Regular follow-up evaluations are recommended, as symptoms may appear or worsen at any time.1,17,35,36
Comprehensive clinical assessment and patient history are necessary to evaluate the full impact of hypophosphatasia.1-3
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References:
  1. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013;10(suppl 2):380-388.
  2. Whyte MP. Hypophosphatasia. In: Thakker RV, Whyte MP, Eisman JA, Igarashi T, eds. Genetics of Bone Biology and Skeletal Disease. London, UK: Academic Press; 2013:337-360.
  3. Whyte MP, Greenberg CR, Kishnani PS, et al. Fracture burden in children and adults with hypophosphatasia. Poster presented at: 39th Annual Congress of the European Calcified Tissue Society (ECTS). May 19-23, 2012; Stockholm, Sweden.
  4. Seshia SS, Derbyshire G, Haworth JC, Hoogstraten J. Myopathy with hypophosphatasia. Arch Dis Child. 1990;65(1):130-131.
  5. Whyte MP, Madson KL, Munns CF, et al. A retrospective, multi-national, non-interventional, natural history study of the childhood form of hypophosphatasia [abstract LB-OR01]. Endocrine Society's 97th Annual Meeting and Expo website. https://endo.confex.com/endo/2015endo/webprogram/Paper22822.html. Accessed October 26, 2017.
  6. Coe JD, Murphy WA, Whyte MP. Management of femoral fractures and pseudofractures in adult hypophosphatasia. J Bone Joint Surg Am. 1986;68(7):981-990.
  7. Gagnon C, Sims NA, Mumm S, et al. Lack of sustained response to teriparatide in a patient with adult hypophosphatasia. J Clin Endocrinol Metab. 2010;95(3):1007-1012.
  8. Schalin-Jäntti C, Mornet E, Lamminen A, Välimäki MJ. Parathyroid hormone treatment improves pain and fracture healing in adult hypophosphatasia. J Clin Endocrinol Metab. 2010;95(12):5174-5179.
  9. Taketani T, Onigata K, Kobayashi H, Mushimoto Y, Fukuda S, Yamaguchi S. Clinical and genetic aspects of hypophosphatasia in Japanese patients. Arch Dis Child. 2014;99(3):211-215.
  10. Data on file, Alexion Pharmaceuticals.
  11. Whyte MP. Hypophosphatasia: nature’s window on alkaline phosphatase function in humans. In: Bilezikian JP, Raisz LG, Martin TJ, ed. Principles of Bone Biology. Vol 2. 3rd ed. San Diego, CA: Academic Press; 2008:1573-1598.
  12. Whyte MP, Mumm S, Deal C. Adult hypophosphatasia treated with teriparatide. J Clin Endocrinol Metab. 2007;92(4):1203-1208.
  13. Barvencik F, Beil FT, Gebauer M, et al. Skeletal mineralization defects in adult hypophosphatasia--a clinical and histological analysis. Osteoporos Int. 2011;22(10):2667-2675.
  14. Mornet E, Nunes ME. Hypophosphatasia. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993. http://www.ncbi.nlm.nih.gov/books/NBK1150/. Published November 20, 2007. Updated February 4, 2016. Accessed October 26, 2017.
  15. Chuck AJ, Pattrick MG, Hamilton E, Wilson R, Doherty M. Crystal deposition in hypophosphatasia: a reappraisal. Ann Rheum Dis. 1989;48(7):571-576.
  16. Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci. 2010;1192:190-200.
  17. Weber TJ, Sawyer EK, Moseley S, Odrljin T, Kishnani PS. Burden of disease in adult patients with hypophosphatasia: results from patient-reported outcome surveys. Poster presented at: Endocrine Society Annual Meeting; March 5-8, 2015; San Diego, CA.
  18. Breivik H, Borchgrevink PC, Allen SM, et al. Assessment of pain. Br J Anaesth. 2008;101(1):17-24.
  19. Hébert LJ, Maltais DB, Lepage C, Saulnier J, Crête M. Hand-held dynamometry isometric torque reference values for children and adolescents. Pediatr Phys Ther. 2015;27(4):414-423.
  20. Fallon MD, Teitelbaum SL, Weinstein RS, Goldfischer S, Brown DM, Whyte MP. Hypophosphatasia: clinicopathologic comparison of the infantile, childhood, and adult forms. Medicine. 1984;63(1):12-24.
  21. Mohn A, De Leonibus C, de Giorgis T, Mornet E, Chiarelli F. Hypophosphatasia in a child with widened anterior fontanelle: lessons learned from late diagnosis and incorrect treatment. Acta Paediatr. 2011;100(7):e43-e46.
  22. Eade AWT, Swannell AJ, Williamson N. Pyrophosphate arthropathy in hypophosphatasia. Ann Rheum Dis. 1981;40(2):164-170.
  23. Whyte MP, Leelawattana R, Reinus WR, Yang C, Mumm S, Novack DV. Acute severe hypercalcemia after traumatic fractures and immobilization in hypophosphatasia complicated by chronic renal failure. J Clin Endocrinol Metab. 2013;98(12):4606-4612.
  24. Reibel A, Maniére M-C, Clauss F, et al. Orodental phenotype and genotype findings in all subtypes of hypophosphatasia. Orphanet J Rare Dis. 2009;4:6.
  25. Whyte MP, Murphy WA, Fallon MD. Adult hypophosphatasia with chondrocalcinosis and arthropathy. Variable penetrance of hypophosphatasemia in a large Oklahoma kindred. Am J Med. 1982;72(4):631-641.
  26. Silva I, Castelão W, Mateus M, Branco JC. Childhood hypophosphatasia with myopathy: clinical report with recent update. Acta Rheumatol Port. 2012;37(1):92-96.
  27. Foster BL, Ramnitz MS, Gafni RI, et al. Rare bone diseases and their dental, oral, and craniofacial manifestations. J Dent Res. 2014;93(suppl 7):7S-19S.
  28. Watanabe H, Umeda M, Seki T, Ishikawa I. Clinical and laboratory studies of severe periodontal disease in an adolescent associated with hypophosphatasia. A case report. J Periodontol. 1993;64(3):174-180.
  29. Beck C, Morbach H, Wirth C, Beer M, Girschick HJ. Whole-body MRI in the childhood form of hypophosphatasia. Rheumatol Int. 2011;31(10):1315-1320.
  30. Girschick HJ, Seyberth HW, Huppertz HI. Treatment of childhood hypophosphatasia with nonsteroidal antiinflammatory drugs. Bone. 1999;25(5):603-607.
  31. Girschick HJ, Schneider P, Haubitz I, et al. Effective NSAID treatment indicates that hyperprostaglandinism is affecting the clinical severity of childhood hypophosphatasia. Orphanet J Rare Dis. 2006;1:24.
  32. Phillips D, Griffin D, Przybylski T, et al. Gait assessment in children with childhood hypophosphatasia: impairments in muscle strength and physical function. Poster presented at: Endocrine Society Annual Meeting; March 5-8, 2015; San Diego, CA.
  33. Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30(6):473-483.
  34. Binkley JM, Stratford PW, Lott SA, Riddle DL; North American Orthopaedic Rehabilitation Research Network. The Lower Extremity Functional Scale (LEFS): scale development, measurement properties, and clinical application. Physical Therapy. 1999;79(4):371-383.
  35. Caswell AM, Whyte MP, Russell RGG. Hypophosphatasia and the extracellular metabolism of inorganic pyrophosphate: clinical and laboratory aspects. Crit Rev Clin Lab Sci. 1991;28(3):175-232.
  36. Birtwell WM Jr, Riggs L, Peterson LF, Jones JD. Hypophosphatasia in an adult. Arch Intern Med. 1967;120(1):90-93.