Bone and Joint Pain

Developmental Delays

Muscle Weakness

PERPLEXING SYMPTOMS Pediatric patients with hypophosphatasia (HPP) may present with one or more of these key symptoms, or report them in their medical history1:• joint, bone, and muscle pain • muscle weakness • mobility issues or gait disturbance• early loss of baby teeth with root intact• developmental delaysFind other possible symptoms of HPP displayed on the back of this page.

See reverse for age- and sex-adjusted references ranges for ALP.

Connect Perplexing Symptoms With Low Alkaline Phosphatase (ALP)

PERSISTENTLY LOW ALP LEVELSThe key to diagnosing a rare metabolic bone disease in some patients is persistently low age- and sex-adjusted levels of ALP.2,3

Ordered ItemsComp. Metabolic Panel (14): Venipuncture

Comp. Metabolic Panel (14) Glucose, serum 100

BUN 16

Creatinine, serum 0.96

Sodium, serum 140

Potassium, serum 4.2

Chloride, serum 99

Carbon dioxide, total 23

Calcium, serum 10.1

Albumin, serum 3.8

Total protein 7.4

Bilirubin, total 0.5

AST (SGOT) 30

ALT (SGPT) 35

Alkaline phosphatase (ALP) 111 Low

TESTS RESULT FLAG

Learn more about using low ALP to make the connection at hypophosphatasia.com/hcp

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Patient image and patient lab values are hypothetical.

The diagnosis may point to hypophosphatasia (HPP) 4

ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase.

HPP Diagnosis2,5,6Perplexing Symptoms

Persistently Low ALP

(age- and sex-adjusted)2,3

Persistently Low ALP Age- and sex-adjusted ALP reference intervals must be used to correctly diagnose HPP, especially in childhood1,2

Perplexing SymptomsOne or more of these key signs and symptoms plus persistently low alkaline phosphatase (ALP) is sufficient to diagnose hypophosphatasia (HPP)2,5,6

NOTE: Graph adapted from the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) project. CALIPER samples from 1072 male and 1116 female participants (newborn to 18 years) were used to calculate age- and sex-specific reference intervals. No variation in ALP based on ethnic differences was observed.19

*Check with your lab for their appropriate age- and sex-adjusted reference range.

Age- and sex-adjusted ALP reference ranges (U/L)1-6*

Age

Adults*

ALP

activ

ity (U

/L)

90134

156 141 12789

59 40

273

518

369

460

280

12895

273

518

369

460

517

365

164120

0

100

200

300

400

500

600

0-14 d 15 d to< 1 y

1 to< 10 y

10 to< 13 y

13 to< 15 y

15 to< 17 y

17 to< 19 y

0-14 d 15 d to< 1 y

1 to< 10 y

10 to< 13 y

13 to< 15 y

15 to< 17 y

17 to< 19 y

MaleFemale

90134

156 141

62 54 48

Normal ALP Low ALP in Females and Males <19 years Low ALP in Adults

Age- and sex-adjusted ALP reference ranges (U/L)14-19

References: 1. Bishop N, Munns CF, Ozono K. Transformative therapy in hypophosphatasia. Arch Dis Child. 2016;101(6):514-515. 2. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013;10(suppl 2):380-388. 3. McKiernan FE, Berg RL, Fuehrer J. Clinical and radiographic findings in adults with persistent hypophosphatasemia. J Bone Miner Res. 2014;29(7):1651-1660. 4. Bianchi ML, Bishop NJ, Guañabens N, et al. Hypophosphatasia in adolescents and adults: overview of diagnosis and treatment. Osteoporos Int. 2020;31(8):1445–1460. 5. Mornet E, Nunes ME. Hypophosphatasia. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. University of Washington; 2007. Accessed September 9, 2021. https://www.ncbi.nlm.nih.gov/books/NBK1150/ 6. Whyte MP. Hypophosphatasia: nature’s window on alkaline phosphatase function in humans. In: Bilzikian JP, ed. Principles of Bone Biology. 3rd ed. Academic Press; 2008:1573-1598. 7. Whyte MP. Hypophosphatasia. In: Thakker RV, Whyte MP, Eisman JA, Igarashi T, eds. Genetics of Bone Biology and Skeletal Disease. Elsevier Inc; 2013:337-360. 8. Zankl A, Mornet E, Wong S. Specific ultrasonographic features of perinatal lethal hypophosphatasia. Am J Med Genet. 2008;146A(9):1200-1204. 9. 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. 10. 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):S25-S33. 11. Silver MM, Vilos GA, Milne KJ. Pulmonary hypoplasia in neonatal hyphophosphatasia. Pediatr Pathol. 1988;8(5):483-493. 12. Colazo JM, Hu JR, Dahir KM, Simmons JH. Neurological symptoms in hypophosphatasia. Osteoporos Int. 2019;30(2):469-480. 13. Fallon MD, Teitelbaum SL, Weinstein R, Goldfischer S, Brown DM, Whyte MP. Hypophosphatasia: clinicopathologic comparison of the infantile, childhood, and adult forms. Medicine (Baltimore). 1984;63(1):12-24. 14. Adeli K, Higgins V, Nieuwesteeg M, et al. Biochemical marker reference values across pediatric, adult, and geriatric ages: establishment of robust pediatric and adult reference intervals on the basis of the Canadian Health Measures Survey. Clin Chem. 2015;61(8):1049-1062. 15. Schuman G, Klauke R, Canalias F, et al. IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37°C. Part 9: reference procedure for the measurement of catalytic concentration of alkaline phosphatase International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Scientific Division, Committee on Reference Systems of Enzymes (C-RSE) (1)). Clin Chem Lab Med. 2011;49(9):1439-1446. 16. Quest Diagnostics. Alkaline phosphatase. Accessed September 9, 2021. https://testdirectory.questdiagnostics.com/test/test-detail/234/alkaline-phosphatase? cc=MASTER 17. LabCorp. Alkaline phosphatase. Accessed September 9, 2021. https://www.labcorp.com/tests/ 001107/alkaline-phosphatase# 18. ARUP Laboratories. Alkaline phosphatase isoenzymes, serum or plasma. Accessed September 9, 2021. https://ltd. aruplab.com/Tests/Pub/0021020 19. 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;58(5):854-868.

Not all signs and symptoms need to be present for a patient to be diagnosed with HPP4

Skeletal2,6-8

Bone/joint pain, fractures, rickets, osteomalacia,

pseudofractures, osteopenia, skeletal deformities

Development/Growth2,6

Missed milestones, failure to thrive,

bowing, short stature

Neurologic12

Fatigue, headache, sleep disturbances,

mood disorder, seizures

Respiratory2,6,9-11

Rachitic chest, pneumonia, pulmonary

insufficiency

Renal2,7,13

Hypercalcemia, hypercalciuria,

nephrocalcinosis

Muscular2

Muscle pain or weakness, waddling

gait, difficulty walking

Dental2

Premature tooth loss, abnormal dentition, periodontal disease