Diagnostic Yield of Laboratory-Based Screening for Hypophosphatasia Among Chinese Children With Low Alkaline Phosphatase.

Abstract

Context: Hypophosphatasia (HPP) is a rare metabolic bone disease caused by pathogenic variants in ALPL gene. Due to its marked phenotypic heterogeneity, milder pediatric forms are frequently underdiagnosed, and systematic, laboratory-based screening strategies remain poorly defined.

Objective: To establish a routine laboratory-based screening algorithm in a tertiary pediatric setting, characterize the ALPL genetic landscape in Chinese children, and delineate the milder clinical and neurobehavioral manifestations of HPP.

Methods: We screened the laboratory records of 178,778 pediatric subjects at the Children's Hospital of Soochow University from September 2023 through August 2025 by means of daily surveillance. Individuals with persistently low serum alkaline phosphatase (ALP) levels (<2.5th percentile for age and sex) underwent ALPL next-generation sequencing and serum pyridoxal 5'-phosphate (PLP) measurement by UPLC-MS/MS. In vitro tissue-nonspecific ALP (TNSALP) functional assays were performed to adjudicate variants of uncertain significance (VUS).

Results: Among 339 enrolled subjects, 73 clinically relevant ALPL variants were identified in 114 individuals, including 16 pathogenic and 30 likely pathogenic variants. Functional assays supported the reclassification of three VUS as likely pathogenic on the basis of significantly reduced TNSALP activity. Integrated clinical and genetic assessment confirmed HPP in 32 subjects and identified 25 suspected cases and 57 asymptomatic carriers. The predominant clinical features were dental abnormalities and impaired linear growth. Although classic severe complications were uncommon, neurobehavioral manifestations, including attention-deficit/hyperactivity disorder and tic disorders, were observed, broadening the recognized pediatric phenotype.

Conclusion: A routine laboratory-based low-ALP screening algorithm can effectively identify previously unrecognized HPP in a pediatric population. Our findings demonstrate a high prevalence of mild HPP in Chinese children, highlight neurobehavioral manifestations, and provide a clinical framework for earlier diagnosis and timely intervention.