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Low alkaline phosphatase (ALP) can differentiate hypophosphatasia (HPP)

Early and accurate diagnosis is essential to avoiding preventable morbidities and premature mortality.1-3
Detection of low alkaline phosphatase activity in patients with clinical manifestations of hypophosphatasia can lead to an accurate diagnosis.4,5
Low alkaline phosphatase can be identified with a readily available, routine laboratory test4-6
Alkaline phosphatase activity should be age-adjusted and is laboratory-specific5

Prominent clinical symptoms of hypophosphatasia

Clinical manifestations and low alkaline phosphatase activity can confirm a diagnosis of hypophosphatasia.4,5

Low alkaline phosphatase is the biochemical hallmark of hypophosphatasia.4,7 When clinical manifestations of hypophosphatasia are present, checking for low alkaline phosphatase activity can confirm a diagnosis.4,5
In patients with a family history of hypophosphatasia, testing for low alkaline phosphatase at the first presentation of clinical symptoms may be appropriate.4,5

Diagnostic considerations of Hypophosphatasia
Prominent clinical symptoms
DENTAL4,5,8-12
Premature or nontraumatic tooth loss with the root intact
Skeletal4,13-21
Severe hypomineralization, skeletal deformities, craniosynostosis, rachitic chest, rickets, bowing, short stature, osteomalacia, bone pain, frequent fractures
Muscular/rheumatologic4,9,18,22,23
Muscle weakness, hypotonia, muscular/joint pain, waddling gait, difficulty walking

Symptoms may also include

Respiratory24-26

Respiratory insufficiency, respiratory failure

Neurologic14,25

Vitamin B6-responsive seizures, increased intracranial pressure

Renal1,4,27,28

Hypercalciuria, nephrocalcinosis, renal damage

Growth/development4,15,16,22

Failure to thrive, delayed or missed motor milestone, short stature

High index of suspicion for HYPOPHOSPHATASIA

Evaluate results of age- and gender-adjusted alkaline phosphatase activity

Low alkaline phosphatase activity (age-and gender-adjusted)5
If confirmation is needed, test for elevated PLP (vitamin B6) or urinary PEA.5,25,29,30,a,b,c

aIf alkaline phosphatase activity is low, elevated serum PLP (vitamin B6) is a highly sensitive indicator of hypophosphatasia.5
bHigh urinary PEA is a diagnostic marker of hypophosphatasia, but its relation to disease pathology is not fully understood.30,31

cPPi is not a commercially available lab test.4

The information is intended as educational information for healthcare professionals. It does not replace a healthcare professional's judgment or clinical diagnosis.

Diagnosing hypophosphatasia with a routine laboratory test.4-6

Diagnosing hypophosphatasia

See how low alkaline phosphatase can differentiate hypophosphatasia from other metabolic disorders.1,4,5

Low alkaline phosphatase

Learn how low alkaline phosphatase in hypophosphatasia ruins bones, bodies, and lives.4,9,22,24,25,27,28

Avoid misdiagnoses

Hypophosphatasia is often misdiagnosed because the signs and symptoms can overlap with those of other disorders.4,5

Low alkaline phosphatase is the biological hallmark of hypophosphatasia4,7

Growth and development profoundly affect the normal interval for alkaline phosphatase31,32
Assess your patient’s alkaline phosphatase
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References: 1. 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. 2. Sutton RAL, Mumm S, Coburn SP, Ericson KL, Whyte MP. “Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res. 2012;27(5):987-994. 3. Cundy T, Michigami T, Tachikawa K, Dray M, Collins J. Phenotypic change in a patient with hypophosphatasia with the onset of renal failure. Paper presented at: 40th Annual Congress of the European Calcified Tissue Society (ECTS); May 18-21, 2013; Lisbon, Portugal. 4. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. Berkseth 2013/ p23, fig1b 2013;10(suppl 2):380-388. 5. Mornet E, Nunes ME. Hypophosphatasia. In: Pagon RA, Bird TD, Dolan CR, Stephen K, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993. http://www.ncbi.nlm.nih.gov/books/NBK1150/. Published November 20, 2007. Updated Aedugust 5, 2010. Accessed March 31, 2014. 6. Lab Tests Online: ALP. Accessed April 6,2016. Last updated October 29, 2015. Available from: https://labtestsonline.org/understanding/analytes/alp/tab/test/ 7. Whyte M. Hypophosphatasia: nature’s window on alkaline phosphatase function in humans. In: Bilezikian JP RL, Martin TJ, editor. Principles of Bone Biology. 3 ed. San Diego, CA: Academic Press; 2008. p. 1573-98. 8. 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. http://www.ojrd.com/content/4/1/6. Published February 21, 2009. Accessed March 31, 2014. 9. 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. 10. Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci. 2010;1192:190-200. 11. van den Bos T, Handoko G, Niehof A, et al. Cementum and dentin in hypophosphatasia. J Dent Res. 2005;84(11):1021-1025. 12. Mornet E. Hypophosphatasia. Best Pract Res Clin Rheumatol. 2008;22(1):113-127. 13. Whyte MP, Greenberg CR, Salman N, et al. Engl J Med. 2012;366(10):904-913. 14. Collmann H, Mornet E, Gattenlöhner S, Beck C, Girschick H. Neurosurgical aspects of childhood hypophosphatasia. Childs Nerv Syst. 2009;25(2):217-223. 15. 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. 16. 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. 17. 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. 18. Data on file, Alexion Pharmaceuticals. 19. 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. 20. 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. 21. 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. 22. Seshia SS, Derbyshire G, Haworth JC, Hoogstraten J. Myopathy with hypophosphatasia. Arch Dis Child. 1990;65(1):130-131. 23. Chuck AJ, Pattrick MG, Hamilton E, Wilson R, Doherty M. Crystal deposition in hypophosphatasia: a reappraisal. Ann Rheum Dis. 1989 Jul;48(7):571-6. 24. Baumgartner-Sigl S, Haberlandt E, Mumm S, et al. Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. Bone. 2007;40(6):1655-1661. 25. Balasubramaniam S, Bowling F, Carpenter K, et al. Perinatal hypophosphatasia presenting as neonatal epileptic encephalopathy with abnormal neurotransmitter metabolism secondary to reduced co-factor pyridoxal-5′-phosphate availability. J Inherit Metab Dis. 2010;33(3):25-33. 26. Silver MM, Vilos GA. Pulmonary hypoplasia in neonatal hypophosphatasia. Pediatr Pathol. 1988;8(5):483-493. 27. 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. 28. Eade AWT, Swannell AJ, Williamson N. Pyrophosphate arthropathy in hypophosphatasia. Ann Rheum Dis. 1981;40(2):164-170. 29. Whyte MP. Hypophosphatasia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 4. 8th ed. New York, NY: McGraw-Hill; 2001:5313-5329. 30. Whyte MP, Mahuren JD, Vrabel LA, Coburn SP. Markedly increased circulating pyridoxal-5’-phosphate levels in hypophosphatasia. J Clin Invest. 1985;76(2):752-756. 31. Colantonio DA, Kyriakopoulou L, Chan MK, et al. Closing the gaps in pediatric laboratory reference intervals: a CALIPER database of 40 biochemical markers in a healthy and multiethnic population of children. Clin Chem. 2012 May;58(5):854-68. 32. Turan S, Topcu B, Gokce I, et al. Serum alkaline phosphatase levels in healthy children and evaluation of alkaline phosphatase z-scores in different types of rickets. J Clin Res Pediatr Endocrinol. 2011;3(1):7-11.