Evaluation of Low Alkaline Phosphatase Levels in Clinical Practice: Implications for Diagnosing Hypophosphatasia

Persistent low serum alkaline phosphatase (ALP) levels are crucial in identifying genetic disorders such as hypophosphatasia (HPP). This study investigates the causes of low ALP levels in children, aiming to evaluate the demographic and clinical characteristics of those diagnosed with HPP.We evaluated 2243 children and adolescents, ranging from 0 to 19 years old between September 2019 and July 2024, who exhibited at least two ALP levels below the age- and gender-specific lower limit.In the patient group, 95.4% (2140 patients) exhibited transient low ALP levels, while 4.6% (103 patients) showed persistently low levels. In the persistent group, eleven additional medical conditions were identified, excluding HPP, with calorie depletion (anorexia, malnutrition) being the most common cause. The study identified 16 HPP patients (10 females, 6 males) with high phenotypic variability even within the same variants, comprising 0.71% of the whole group. Genetic testing identified 13 pathogenic/likely pathogenic ALPL gene variants (10 heterozygous, 3 homozygous), two of which were novel. Among HPP patients, 56.2% presented with HPP-related symptoms, most commonly short stature. We found a significant negative correlation between total ALP and serum pyridoxal phosphate (PLP) levels (Rho = - 0.55, p = 0.039), but no correlation with urine phosphoethanolamine.Persistently low ALP levels are a vital clinical indicator for a wide range of disorders, especially HPP. This study expands the phenotypic and genotypic profiles of HPP while improving our understanding of the disease in children. Increasing disease awareness, particularly for milder forms, is essential to avoid delayed diagnosis.