Montero-Lopez Rodrigo, Farman Mariam R, Högler Florian, Saraff Vrinda, Högler Wolfgang
Centre for Growth and Osteology, Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz, Austria,
Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz, Austria.
Horm Res Paediatr. 2024 Aug 5:1-10. doi: 10.1159/000540692.
Hypophosphatasia (HPP) is a rare genetic disorder caused by loss-of-function variants in the ALPL gene, leading to deficient tissue-nonspecific alkaline phosphatase (ALP) activity. This results in a distinctive biochemical profile marked by low serum 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 of HPP relies on identifying the characteristic biochemical signature (low ALP, high PLP), concomitant with skeletal (osteomalacia, rickets, pseudofracture) or extraskeletal (muscle weakness, musculoskeletal pain, dental) manifestations. Current diagnostic frameworks lack uniformity, highlighting the imperative for a standardized diagnostic approach. Molecular genetic testing plays a pivotal role in making the diagnosis of HPP, but difficulties persist in diagnosing milder cases and correlating genotypes with phenotypes. 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.
Mild forms of HPP and asymptomatic carriers of pathogenic ALPL variants pose substantial diagnosis and management challenges. Developing consensus-driven guidelines is crucial to enhance clinical outcomes and patient care.
低磷酸酯酶症（HPP）是一种罕见的遗传性疾病，由ALPL基因的功能丧失变异引起，导致组织非特异性碱性磷酸酶（ALP）活性不足。这导致了一种独特的生化特征，表现为血清ALP水平低和磷酸吡哆醛（PLP）升高。HPP的临床谱范围从围产期致死到无症状病例，带来了重大的诊断和治疗挑战。
HPP 的诊断依赖于识别特征性的生化特征（低 ALP、高 PLP），同时伴有骨骼（骨软化症、佝偻病、假性骨折）或骨骼外（肌肉无力、肌肉骨骼疼痛、牙齿问题）表现。当前的诊断框架缺乏统一性，凸显了标准化诊断方法的必要性。分子基因检测在 HPP 的诊断中起着关键作用，但在诊断较轻病例以及将基因型与表型相关联方面仍存在困难。全面的多学科护理不可或缺，酶替代疗法（ERT）在严重病例中已证明有效，而对于较轻表现则需要更细致的管理方法。克服 ERT 启动、治疗反应评估、剂量滴定和长期监测方面的挑战需要进一步完善管理指南。
轻度形式的 HPP 和致病性 ALPL 变异无症状携带者带来了重大的诊断和管理挑战。制定基于共识的指南对于改善临床结果和患者护理至关重要。
