Diagnostic delay is common among patients with hypophosphatasia: initial findings from a longitudinal, prospective, global registry

BMC Musculoskelet Disord. 2019 Feb 14;20(1):80. doi: 10.1186/s12891-019-2420-8.


Background: Hypophosphatasia (HPP) is a rare, systemic disease caused by mutation(s) within the ALPL gene encoding tissue-nonspecific alkaline phosphatase (ALP). HPP has a heterogeneous presentation, which coupled with its rarity, often leads to missed/delayed diagnosis and an incomplete understanding of its natural history. To better understand the epidemiology and clinical course of HPP, including timing of diagnosis after first reported manifestation, we present baseline data for patients enrolled in the Global HPP Registry.

Methods: Data were analyzed from patients with an HPP diagnosis confirmed by low serum ALP activity and/or an ALPL pathogenic variant, regardless of prior or current treatment, according to age at enrollment (children: < 18 y; adult: ≥18 y). All analyses were descriptive.

Results: Of 269 patients from 11 countries enrolled January 2015-September 2017, 121 (45.0%) were children and 148 (55.0%) were adults. The majority of children and adults were female (61.2 and 73.0%, respectively) and white (57.7 and 90.0%, respectively). Children had a median (min, max) age at earliest reported HPP manifestation of 7.2 months (- 2.3 mo, 16.0 y), which was > 12 months before diagnosis at age 20.4 months (- 0.2 mo, 16.0 y). In adults, the earliest reported manifestation occurred at a median (min, max) age of 37.6 years (0.2 y, 75.2 y), which preceded age at diagnosis (47.5 years [0.2 y, 75.2 y]) by ~ 10 years. Premature loss of deciduous teeth (48.2%, age ≥ 6 mo), bone deformity (32.5%), and failure to thrive (26.7%) were most commonly reported in the HPP-related disease history of children. Pain (74.5%), orthopedic procedures and therapies (44.6%), and recurrent and poorly healing fractures (36.5%) were most commonly reported in the HPP-related disease history of adults.

Conclusions: The Global HPP Registry represents the largest observational study of patients with HPP, capturing real world data. This analysis shows that diagnostic delay is common, reflecting limited awareness of HPP, and that HPP is associated with systemic manifestations across all ages. Many patients diagnosed in adulthood had HPP manifestations in childhood, highlighting the importance of taking thorough medical histories to ensure timely diagnosis.

Trial registration: Clinicaltrials.gov : NCT02306720 , December 2014; ENCePP.eu: EUPAS13526 , May 2016 (retrospectively registered).

Keywords: Alkaline phosphatase; Asfotase alfa; Hypophosphatasia; Natural history; Rare diseases.

Publication types

  • Multicenter Study
  • Observational Study

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Aged
  • Alkaline Phosphatase / genetics
  • Child
  • Child, Preschool
  • Delayed Diagnosis*
  • Europe / epidemiology
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Hypophosphatasia / diagnosis*
  • Hypophosphatasia / drug therapy
  • Hypophosphatasia / epidemiology
  • Hypophosphatasia / genetics
  • Infant
  • Japan / epidemiology
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Mutation
  • North America / epidemiology
  • Phenotype
  • Predictive Value of Tests
  • Prognosis
  • Prospective Studies
  • Registries
  • Time Factors
  • Young Adult


  • ALPL protein, human
  • Alkaline Phosphatase

Associated data

  • ClinicalTrials.gov/NCT02306720