Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
F.I.R.M.O. Italian Foundation for the Research on Bone Diseases, Florence, Italy.
J Clin Endocrinol Metab. 2022 Apr 19;107(5):e2087-e2094. doi: 10.1210/clinem/dgab914.
Hypophosphatasia (HPP) is a rare metabolic disorder caused by deficiency of alkaline phosphatase (ALP) enzyme activity, leading to defective mineralization, due to pathogenic variants of the ALPL gene, encoding the tissue nonspecific alkaline phosphatase (TNSALP) enzyme. Inheritance can be autosomal recessive or autosomal dominant. An abnormal ALPL genetic test enables accurate diagnosis, avoiding the administration of contraindicated antiresorptive drugs that, in patients with HPP, substantially increase the risk of atypical femur fractures (AFFs) and worsen the fracture healing process that is usually already compromised in these patients.
Performing ALPL genetic testing to identify rare variants in suspected adult patients with HPP. Comparing frequencies of ALPL common variants in individuals with biochemical and/or clinical signs suggestive of adult HPP and non-HPP controls, and among different clinical subgroups of patients with a clinical suspicion of adult HPP.
Patients with suspected adult HPP were retrospectively selected for the genetic testing of the ALPL gene. Patients included were from 3 main European Bone Units (Florence, Naples, and Geneva); 106 patients with biochemical and/or clinical signs suggestive of a mild form of HPP were included.
Genetic testing led to the identification of a heterozygote rare variant in 2.8% of cases who were initially referred as suspected osteoporosis. The analysis of frequencies of ALPL common variants showed a high prevalence (30.8%) of homozygosity in subjects who developed an AFF, in association with normal serum total ALP activity.
The results suggest homozygosity of common ALPL variants as a possible genetic mark of risk for these fractures.
低磷酸酯酶症（HPP）是一种罕见的代谢疾病，由碱性磷酸酶（ALP）酶活性缺乏引起，由于 ALPL 基因的致病变体，导致组织非特异性碱性磷酸酶（TNSALP）酶的缺陷性矿化。遗传方式可为常染色体隐性或常染色体显性。异常的 ALPL 基因检测可实现准确诊断，避免使用禁忌的抗吸收药物，这些药物在 HPP 患者中会大大增加非典型股骨骨折（AFF）的风险，并使这些患者通常已经受损的骨折愈合过程恶化。
对疑似成人 HPP 患者进行 ALPL 基因检测，以鉴定罕见变异。比较具有生化和/或临床迹象提示成人 HPP 和非 HPP 对照个体中 ALPL 常见变异的频率，以及在具有成人 HPP 临床怀疑的不同临床亚组患者中。
回顾性选择疑似成人 HPP 患者进行 ALPL 基因检测。纳入的患者来自 3 个主要的欧洲骨骼单位（佛罗伦萨、那不勒斯和日内瓦）；纳入了 106 名具有生化和/或临床迹象提示轻度 HPP 的患者。
遗传检测在最初被转诊为疑似骨质疏松症的患者中发现了 2.8%的杂合罕见变异。对 ALPL 常见变异频率的分析表明，发生 AFF 的患者中存在高度的同型合子（30.8%），同时血清总 ALP 活性正常。
结果表明，常见 ALPL 变异的同型合子可能是这些骨折的遗传风险标志。
