Integrated Genetic and Biochemical Approach to Patients with Bone Disorders Exhibiting Low Alkaline Phosphatase

Hypophosphatasia (HPP) is a rare metabolic disorder caused by loss-of-function ALPL variants and characterized by heterogeneous skeletal and extra-skeletal manifestations. Although recent diagnostic criteria include ALPL variants, the diagnosis can be made based solely on clinical features. In adult-onset HPP, however, symptoms are often mild or nonspecific, including musculoskeletal symptoms and fatigue, making it difficult to differentiate from other conditions. This retrospective, cross-sectional study aimed to integrate genetic and biochemical data to enhance the clinical interpretation of low alkaline phosphatase (ALP) in patients with bone disorders. Among 865 consecutive adults visiting a bone-specialized outpatient department, patients with persistent hypophosphatasemia underwent ALPL sequencing. Clinical and biochemical characteristics were compared among three groups: biallelic or monoallelic variants with dominant-negative effect (DNE), monoallelic variants without DNE, and variant-negative individuals. Fifty-six patients (6.5%) showed persistent hypophosphatasemia. Two (0.2%) were compound heterozygotes, and 29 (3.4%) carried monoallelic variants without DNE. Clinical symptoms and secondary causes of hypophosphatasemia were similar between monoallelic without DNE and variant-negative patients, whereas serum ALP, urinary phosphoethanolamine (PEA), and plasma inorganic pyrophosphate (PPi) differed significantly. A model using thresholds of ALP < 35 IU/L, urinary PEA > 91 µmol/gCr, and plasma PPi > 1.96 µmol/L demonstrated high diagnostic performance for identifying patients with monoallelic variants without DNE. This study elucidated the complex clinical spectrum of patients with low ALP. Although clinical manifestations were comparable between monoallelic individuals without DNE and variant-negative individuals, distinct biochemical profiles were observed. Integrating genetic nosology into current diagnostic criteria may refine clinical decision-making.