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

Abstract

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.

Conflict of interest statement

Authors’ information

Not applicable.

Ethics approval and consent to participate

The study protocol was approved by the institutional review board (or local equivalent) of participating study sites and is being conducted in accordance with International Conference on Harmonisation Good Clinical Practice Guidelines and the Declaration of Helsinki. All patients and/or their parent/legal guardians provided written informed consent and approval to release medical records before participation.

Consent for publication

Not applicable.

Competing interests

All authors are members of the Scientific Advisory Board responsible for oversight of the HPP Registry.

CL, WH, AL, KO, and CRG are clinical study investigators and have received consultancy fees, and/or institutional research funding, and/or grant support, and/or travel support from Alexion Pharmaceuticals, Inc. At the time of the study, WH was affiliated with University of Birmingham, Birmingham, UK.

LS is a clinical study investigator and has received consultancy fees and research grants to his institution from Alexion Pharmaceuticals, Inc.

SF and AP are employees of and may own stock/options in Alexion Pharmaceuticals, Inc., which sponsored the study.

HG was an employee of and may own stock/options in Alexion Pharmaceuticals, Inc., which sponsored the study.

PSK is a clinical study investigator and has received consultancy fees and travel support from Alexion Pharmaceuticals, Inc. for consulting and participation on advisory boards.

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Figures

Fig. 1

Age category at time of diagnosis of HPP (n = 201). HPP hypophosphatasia

Fig. 2

Age at earliest reported manifestation vs. age at diagnosis of HPP (a: children; c: adults) and diagnostic delay by age at earliest reported manifestation of HPP (b: children; d: adults). Patients with reported age at first reported manifestation occurring after their age at diagnosis were excluded from the analysis of diagnostic delay. Negative values for age indicate a date that occurred during pregnancy. HPP hypophosphatasia

Fig. 3

Treatments affecting bone mineralization reported in medical histories for children and adults enrolled in the HPP Registry. HPP hypophosphatasia; PTH parathyroid hormone

Fig. 4

Frequency of ALPL pathogenic variants. Pathogenic variants were categorized using the definitions from Sequence Ontology [40]. Figure reports the percentages of the total number of pathogenic variants reported (n = 218). aOther includes structural variant (n = 2), synonymous variant (n = 2), and missense variant/splice region variant (n = 1)