Endocrine Abstracts

JOINT3147

Background: Hypophosphatasia (HPP), an inherited metabolic disorder caused by ALPL gene mutations, manifests through deficient tissue-nonspecific alkaline phosphatase (TNSALP) activity, leading to skeletal complications and systemic morbidity. Persistent low serum alkaline phosphatase (ALP) activity is a hallmark biochemical feature, yet its non-specificity and overlap with other conditions often delay diagnosis. With the advent of enzyme replacement therapy, establishing a pediatric-specific diagnostic framework is imperative to prevent life-threatening sequelae and avoid mismanagement.

Methods: Based on the lower limit of the ALP reference interval for age-and gender-specific ranges in children, as outlined in the ‘Health Industry Standards of the People’s Republic of China’, we included children and adolescents with persistently low ALP activity in this study. These participants underwent whole-exome sequencing (WES) and plasma pyridoxal-5′-phosphate (PLP) measurement. By analyzing the genetic mutation positivity rate in the low ALP population, we calculated the cutoff value for PLP using ROC curve analysis. Clinical phenotype data were collected to clarify the characteristics of hypophosphatasia (HPP) in the Chinese population and to explore the genotype-phenotype correlation.

Results: Among 94, 467 analyzed samples, 246 subjects had persistently low ALP activity. ALPL variants were detected in 76 of 246 individuals (30. 9%) by WES. ROC curve analysis identified a PLP cutoff value of 21. 3 ng/mL (sensitivity 74. 6%, specificity 84. 4%). When PLP ≥ 21. 3 ng/mL, the positive predictive values for ALP mutation was 62. 4% (58/93). Further analysis revealed that PLP (AUC = 0. 819, P < 0. 05) was a better predictor of ALPL gene positivity than ALP (AUC = 0. 784, P < 0. 05). The carrier frequency of ALPL heterozygous mutations was approximately 1/500 to 1/133, missense mutations accounted for 80. 7% of ALPL mutations, with the most common being p. Arg136His (10. 8%). Not all carriers exhibited clinical symptoms, genotype-phenotype correlation study showed that 100%, 88% and 77% of carriers with severe dominant negative effect (DNE) mutation, severe haploinsufficiency (HI) mutation and moderate HI mutation of ALPL gene had clinical symptoms. The proportion of severe DNE mutation carriers with 1 or 2 symptoms was the highest, 60% and 40%, respectively. p. Arg136His were recognized in patients with fractures and epilepsy.

Conclusion: Our study identified PLP as a cost-effective screening biomarker for HPP in children and as a reliable biomarker for predicting ALPL mutations. We found that the carrier frequency of p. Arg136His is relatively high in the Chinese population. These findings also provide valuable insights into the genetic and phenotypic characteristics of HPP in the Chinese population.