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  3. Diagnosing HPP
  4. Consequences of misdiagnosis

Diagnosis of hypophosphatasia (HPP) is often missed or delayed.1,2

Early and accurate diagnosis is essential to avoiding preventable morbidities and premature mortality.3-5

Delayed diagnosis can contribute to or compound life-threatening or debilitating manifestations1,3,6,7

Patients with hypophosphatasia (HPP) have experienced diagnostic delays from months to years.

In infants, even a delay of months can be life-threatening3,6

Misdiagnosis can lead to ineffective management that can compound clinical consequences1-4

Prevent misdiagnosis

Accurately diagnose hypophosphatasia with a routine laboratory test.1,2,8

High-dose vitamin D, calcium supplements, or bisphosphonates have been shown to exacerbate symptoms of hypophosphatasia2-4

Hypophosphatasia is often misdiagnosed because its signs and symptoms can overlap with those of other disorders.1,2

Common misdiagnoses may include the following1,2

9-year-old patient with HPP
Image adapted from Moulin et al.9
The skeletal manifestations of hypophosphatasia, including rachitic, poorly mineralized, or easily-fractured bones can resemble3,4:

Nutritional rickets
X-linked hypophosphatemic rickets
Osteogenesis imperfecta
Osteomalacia
Osteopenia/osteoporosis
Chondrodysplasia with bone-mineralization defects

13-year-old patient with HPP
Image adapted from Beck et al.10 Rheumatologic and muscular manifestations, such as joint and muscle pain or weakness, can resemble1,2:

Osteoarthritis/arthritis
Hypophosphatemia

Left: Incisor from patient with hypophosphatasia with root intact.
Right: Incisor with root absorbed.
Image courtesy of Research Center, Shriners Hospitals for Children – St. Louis. Tooth loss observed in hypophosphatasia may be misdiagnosed as1,2:

Periodontal disease
Prevent misdiagnosis—accurately diagnose hypophosphatasia with a routine laboratory test.1,2,8

Low alkaline phosphatase (ALP) can differentiate hypophosphatasia from nutritional rickets and other metabolic disorders.1-3,11

Misdiagnosis and delayed diagnosis can lead to ineffective management that can compound clinical consequences.1,2,4,13

High-dose vitamin D, calcium supplements, or bisphosphonates have been shown to exacerbate the symptoms of hypophosphatasia2,4,13

As diagnosis is often delayed, critical evaluation of patient history, including dental history, can provide a comprehensive clinical picture of the patient.1

Learn More

Early and accurate diagnosis of hypophosphatasia is critical to avoid preventable morbidities and premature death.3,4,16

Learn more about the consequences of missed or delayed diagnosis.

View Patient Case Studies
Patient and family experiences with hypophosphatasia

"The biggest struggle for me is the energy and keeping my pain at a place where I can still function."

"I first learned of hypophosphatasia when Abigail was diagnosed at 7 months old."

"I was born with it, struggled a lot through birth and my teen years."

"He gave me a blood test, and sure enough, my alkaline phosphatase was very low."

"We kept telling them . . . it’s not a nutrition issue, it’s something else."

"She looks like everything’s fine, when underneath there’s so many issues…"

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References:
  1. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013;10(suppl 2):380-388.
  2. 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.
  3. 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.
  4. 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.
  5. Cundy T, Michigami T, Tachikawa K, Dray M, Collins J. Phenotypic change in a patient with hypophosphatasia with the onset of renal failure. 40th Annual Congress of the European Calcified Tissue Society (ECTS); May 18-21, 2013; Lisbon, Portugal.
  6. 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.
  7. Whyte MP, Greenberg CR, Salman NJ, et al. N Engl J Med. 2012;366(10):904-913.
  8. Lab Tests Online. ALP. Washington DC: American Association for Clinical Chemistry; 2001. https://labtestsonline.org/understanding/analytes/alp/tab/test/. Updated March 22, 2017. Accessed October 26, 2017.
  9. Moulin P, Vaysse F, Bieth E, et al. Hypophosphatasia may lead to bone fragility: don’t miss it. Eur J Pediatr. 2009;168(7):783-788.
  10. 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.
  11. Nield LS, Mahajan P, Joshi A, Kamat D. Rickets: not a disease of the past. Am Fam Physician. 2006;74(4):619-626.
  12. Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A clinician's guide to X-linked hypophosphatemia. J Bone Miner Res. 2011;26(7):1381-1388.
  13. 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.
  14. Reynolds RD, Lorenc RS, Wieczorek E, Pronicka E. Extremely low serum pyridoxal 5'-phosphate in children with familial hypophosphatemic rickets. Am J Clin Nutr. 1991;53(3):698-701.
  15. Tournis ST, Giannikou PV, Paspati IN, Katsalira EA, Voskaki IC, Lyritis GP. Co-existence of X-linked hypophosphatemic rickets (XLH) and primary hyperparathyroidism: case report and review of the literature. J Musculoskelet Neuronal Interact. 2005;5(2):150-154.
  16. Cundy T, Michigami T, Tachikawa K, et al. Reversible deterioration in hypophosphatasia caused by renal failure with bisphosphonate treatment. J Bone Miner Res. 2015;30(9):1726-1737.