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Avoid preventable morbidities and premature mortality1-3

Early and accurate diagnosis is essential to avoiding preventable morbidities and premature mortality.1-3

Delayed diagnosis can contribute to or compound life-threatening or debilitating manifestations1,4-6

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

In infants, even a delay of months can be life-threatening1,5

Misdiagnosis can lead to ineffective management that can compound clinical consequences1,2,4,7

Prevent misdiagnosis

Accurately diagnose hypophosphatasia with a routine laboratory test.4,7,8

High-dose vitamin D, calcium supplements, or bisphosphonates have been shown to exacerbate symptoms of hypophosphatasia1,2,7

Common misdiagnoses

Avoid common misdiagnoses

Hypophosphatasia is often misdiagnosed because its signs and symptoms can overlap with those of other disorders.4,7

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 resemble1-2:

Nutritional rickets
X-linked hypophosphatemic rickets
Osteogenesis imperfecta
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 resemble4,7:


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 as4,7:

Periodontal disease
Prevent misdiagnosis—accurately diagnose hypophosphatasia with a routine laboratory test.4,7,8

Case studies

Time to accurate diagnosis is a critical factor

Delayed diagnosis can contribute to or compound life-threatening or debilitating manifestations. Time of delay may vary from months to years, as detailed in these case reports.

11-month-old male

An 11-month-old male diagnosed with nutritional rickets and treated with increasing calcium and vitamin D supplementation; alkaline phosphatase was not assessed and symptoms worsened dramatically with inappropriate treatment. The patient was diagnosed with hypophosphatasia after a 5-month delay.1

9-year-old female

A 9-year-old female with a history of repetitive fractures and bone pain, dental abnormalities, and premature loss of some teeth; she was not diagnosed until she was 15 years old and presented with back pain and vertebral fracture. Lab tests showed low alkaline phosphatase level and ALPL mutation confirming a diagnosis of hypophosphatasia.9

50-year-old female

A 50-year-old female with bilateral femur stress fractures was treated with calcium, vitamin D, and risedronate for 2.5 years, then diagnosed with hypophosphatasia. She experienced symptoms consistent with hypophosphatasia during childhood, including premature tooth loss and seizures.11
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. 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. 2013;10(suppl 2):380-388. 5. 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. 6. 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. 7. Mornet E, Nunes ME. Hypophosphatasia. In: Pagon RA, Bird TD, Dolan CR, Stephen K, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993. Published November 20, 2007. Updated August 5, 2010. Accessed March 31, 2014. 8.Lab Tests Online. ALP. Washington DC: American Association for Clinical Chemistry; 2001. Updated October 29, 2015. Accessed April 6, 2016. 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, Morbath H, Richl P, et al. How can calcium pyrophosphate crystals induce inflammation in hypophosphatasia or chronic inflammatory joint diseases? Rheumatol Int. 2009;29(3): 229038. 11. Doshi KB, Hamrahian AH, Licata AA. Teriparatide treatment in adult hypophosphatasia in a patient exposed to bisphosphonate: a case report. Clin Cases Miner Bone Metab. 2009;6(3):266-269.