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SUN-709 Applying the Hypophosphatasia Diagnostic Criteria in a Patient Cohort at the Penn Bone Center

Year: 2025
Type: article
Abstract: Disclosure: J. Ocampo Mascaro: None. K. Todder: None. S. Kallish: Sanofi, Ipsen, Amicus, Idorsia, Incyte. M. Al Mukaddam: Ipsen, Incyte. Hypophosphatasia (HPP) is a genetic disorder characterized by decreased activity of the enzyme tissue non-specific alkaline phosphatase (ALP), which leads to impaired bone and teeth mineralization. It has a very broad clinical spectrum, ranging from severe forms in patients with perinatal/infantile disease to mild non-specific cases in some adults. There is significant variability within age groups as well. The diagnosis of HPP was based on clinical judgement and only recently an international task force published proposed diagnostic criteria in 20231. These criteria include 4 major (pathogenic/likely pathogenic variant, elevation of natural substrates, recurrent metatarsal fractures, and atypical femoral fracture) and 5 minor (poorly-healing fractures, chronic musculoskeletal pain, early atraumatic teeth loss, chondrocalcinosis, and nephrocalcinosis). Criteria are met if patients have 2 major or 1 major + 2 minor criteria. To assess the performance of these diagnostic criteria in clinical practice, we applied them in a retrospective cohort of 35 adult patients (ages 22-74 years) with HPP (diagnosis based on presentation and physician’s clinical judgement) at the Penn Bone Center, located at a large US-based academic hospital. Out of 35 patients, 19 met diagnostic criteria (54%). Molecular testing results in our cohort were as follows: 26 had an ALPL variant in genetic testing (12 pathogenic, 5 likely pathogenic, and 9 variants of uncertain significance), 3 were negative, and 6 did not undergo testing yet. ALP values ranged from 11 to 39 U/L (N: 38-126). The percentages of patients that met major criteria were as follows: pathogenic/likely pathogenic variant (49%), elevation of natural substrates (69%), recurrent metatarsal fractures (9%), and atypical femoral fracture (3%). For minor criteria the percentages were: poorly-healing fractures (9%), chronic musculoskeletal pain (54%), early atraumatic teeth loss (14%), chondrocalcinosis (11%), and nephrocalcinosis (3%). Six patients within the cohort had previous or current treatment with asfotase alfa, and FDA-approved enzyme replacement therapy used in adult patients if one of the presenting symptoms was before age 18 years. Out of these six patients, only two met diagnostic criteria. Both patients were related and experienced symptomatic improvement while on therapy. Continued iteration of these diagnostic criteria is needed to account for the significant clinical variability seen in HPP. Factors such as disease progression with time are currently unaccounted for. Adopting a score system similar to those used in diagnosis of rheumatologic disease could be considered in the future. 1 Khan AA, et al. Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults. Osteoporos Int. 2024 Mar;35(3):431-438. Presentation: Sunday, July 13, 2025
DOI: 10.1210/jendso/bvaf149.662
Language: English
Field: Medicine
Open Access status: gold
Estimated APC paid: $3,255
OpenAlex ID: W7093324756
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