Challenges in Hypophosphatasia: Suspicion, Diagnosis, Genetics, Management, and Follow-Up

Abstract

Hypophosphatasia (HPP) is a rare genetic disorder caused by loss-of-function variants in the ALPL gene, leading to deficient tissue-nonspecific alkaline phosphatase activity. This results in a distinctive biochemical profile marked by low serum alkaline phosphatase (ALP) levels and elevated pyridoxal-5-phosphate (PLP). The clinical spectrum of HPP ranges from perinatal lethality to asymptomatic cases, presenting significant diagnostic and therapeutic challenges. Diagnosis primarily hinges upon identifying the characteristic biochemical signature (low ALP, high PLP), concomitant with skeletal (osteomalacia, rickets, pseudofracture) or extraskeletal (muscle weakness, muskuloskeletal pain, dental) manifestations. Current diagnostic frameworks lack uniformity, highlighting the imperative for a standardized diagnostic approach. Molecular genetic testing plays a pivotal role in the diagnosis. However, challenges persist in establishing robust diagnoses in the milder disease spectrum and understanding genotype-phenotype correlations. Comprehensive multidisciplinary care is indispensable, with enzyme replacement therapy (ERT) proving efficacious in severe cases and more nuanced management approaches for milder presentations. Overcoming challenges in ERT initiation, treatment response assessment, dose titrations, and long-term surveillance necessitates further refinement of management guidelines. This review explores the complexities of identifying, diagnosing, genetically confirming, managing, and monitoring individuals with less overt symptomatic presentations of HPP, providing valuable insights into current clinical management paradigms.