Hypophosphatasia (HPP) is a rare inborn error of metabolism due to a decreased activity of tissue nonspecific alkaline phosphatase (TNSALP). As the onset and severity of HPP are heterogenous, it can be challenging to determine the pathogenicity of detected rare ALPL variants in symptomatic patients. We aimed to characterize patients with rare ALPL variants to propose which patients can be diagnosed with adult HPP. We included 72 patients with (1) clinical symptoms of adult HPP or positive family history and (2) low TNSALP activity and/or high pyridoxal 5′-phosphate (PLP) levels, who underwent ALPL gene sequencing. The patients were analyzed and divided into three groups depending on ALPL variant pathogenicity according to the classification of the American College of Medical Genetics and Genomics (ACMG). Reported pathogenic (n = 34 patients), rare (n = 17) and common (n = 21) ALPL variants only were found. Muscular complaints were the most frequent symptoms (> 80%), followed by bone affection (> 50%). Tooth involvement was significantly more common in patients with pathogenic or rare ALPL variants. Seven rare variants could be classified as likely pathogenic (ACMG class 4) of which five have not yet been described. Inconclusive genetic findings and less specific symptoms make diagnosis difficult in cases where adult HPP is not obvious. As not every pathogenic or rare ALPL variant leads to a manifestation of HPP, only patients with bone complications and at least one additional complication concerning teeth, muscle, central nervous and mental system, repeated low TNSALP activity and high PLP levels should be diagnosed as adult HPP if rare ALPL gene variants of ACMG class 4 or higher support the diagnosis.

低磷酸酯酶症 (HPP) 是一种罕见的先天性代谢缺陷，由于组织非特异性碱性磷酸酶 (TNSALP) 的活性降低。由于 HPP 的发病和严重程度是异质的，因此在有症状的患者中确定检测到的罕见ALPL变异的致病性可能具有挑战性。我们旨在表征具有罕见ALPL变异的患者，以提出哪些患者可以诊断为成人 HPP。我们纳入了 72 名具有 (1) 成人 HPP 临床症状或阳性家族史和 (2) TNSALP 活性低和/或吡哆醛 5'-磷酸 (PLP) 水平高的患者，他们接受了ALPL基因测序。对患者进行分析并根据ALPL分为三组根据美国医学遗传学和基因组学学会 (ACMG) 的分类，变异致病性。仅发现了报告的致病性（n  = 34 名患者）、罕见（n  = 17）和常见（n  = 21）ALPL变异。肌肉不适是最常见的症状（> 80%），其次是骨病（> 50%）。在具有致病性或罕见ALPL变异的患者中，牙齿受累明显更常见。七种罕见变异可被归类为可能致病（ACMG 4 类），其中五种尚未被描述。在成人 HPP 不明显的情况下，不确定的遗传发现和不太具体的症状使诊断变得困难。由于并非所有致病性或罕见的ALPL变异导致 HPP 的表现，只有具有骨骼并发症和至少一种额外的牙齿、肌肉、中枢神经和精神系统并发症、反复低 TNSALP 活性和高 PLP 水平的患者才能诊断为成人 HPP，如果罕见的ALPL基因变异ACMG 4 级或更高级别支持诊断。