Musculoskeletal pain and muscular weakness as the main symptoms of adult hypophosphatasia in a Spanish cohort: clinical characterization and identification of a new ALPL gene variant

Introduction: Hypophosphatasia (HPP) is a rare inherited disorder, caused by mutations in the alkaline phosphatase (ALPL) gene, which encodes for the tissue non-specific alkaline phosphatase (TNSALP) isoform of alkaline phosphatase (ALP). Adult HPP is one of the mild forms that presents with unspecific signs such as osteopenia, osteomalacia and muscle involvement. Our purpose was to identify and characterize possibly misdiagnosed adult HPP patients at a clinical and biochemical level.

Material and methods: At the laboratory of Miguel Servet University Hospital we retrospectively reviewed serum ALP levels in adults over a 48-month period. The clinical records of individuals with consistently low ALP levels were reviewed to exclude secondary causes. Those with persistent hypophosphatasemia were screened for symptoms of HPP. The study participants were evaluated at biochemical and genetic levels.

Results: We identified 705 ALP determinations (out of 384,000 processed) in 589 patients below the reference range (30 U/l). Only 21 patients with clinical signs and symptoms of HPP were selected for genetic testing. Finally, only 12 patients participated in the study, 83.3% of whom (10/12) harbored a pathogenic or likely pathogenic variant in a heterozygous state. The major symptoms of our cohort were the presence of musculoskeletal pain (100% of patients) and muscular weakness (83.3% patients).

Conclusion: Mild HPP patients presenting with diffuse symptoms such as musculoskeletal pain may be undiagnosed or misdiagnosed as osteoporosis patients by routine diagnosis. It is important to identify these individuals, to avoid inappropriate treatment with antiresorptive drugs.