Department of Rheumatology, La Paz University Hospital, IdiPAZ, Paseo de la Castellana, 261, 28046, Madrid, Spain.
Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain.
Orphanet J Rare Dis. 2020 Feb 17;15(1):51. doi: 10.1186/s13023-020-1315-y.
Hypophosphatasia (HPP) is an inborn error of metabolism characterized by low levels of serum alkaline phosphatase (ALP). Scarce evidence exists about features that should signal the potential association between hypophosphatasaemia and HPP in adults. The aim of this study is to estimate the prevalence of ALPL variants in subjects with persistent hypophosphatasaemia and determine the associated clinical and laboratory features. For this cross-sectional study, laboratory records of 386,353 subjects were screened by measurement of ALP activity. A total of 85 (0.18%) subjects with persistent hypophosphatasaemia (≥2 serum alkaline phosphatase-ALP-measurements ≤35 IU/L and none > 45 IU/L) were included (secondary causes previously discarded). ALPL genetic testing and a systematized questionnaire to retrieve demographic, clinical and laboratory data were performed. Descriptive analysis and logistic regression models were employed to identify the clinical and laboratory characteristics associated with ALPL variants.
Forty subjects (47%) had a variant(s) in ALPL. With regard to clinical characteristics, the presence of an ALPL variant was significantly associated only with musculoskeletal pain (OR: 7.6; 95% IC: 1.9-30.9). Nevertheless, a trend to present more dental abnormalities (OR: 3.6; 95% IC: 0.9-13.4) was observed. Metatarsal stress fractures were also more frequent (4 vs 0; p < 0.05) in this group. Regarding laboratory features, median ALP levels were lower in subjects with ALPL variants (26 vs 29 IU/L; p < 0.005). Interestingly, the threshold of ALP levels < 25 IU/L showed a specificity, positive predictive value and positive likelihood ratio of 97.8, 94.4% and 19.8 to detect a positive ALPL test, respectively.
In subjects with persistent hypophosphatasaemia -secondary causes excluded- one out of two presented ALPL variants. Musculoskeletal pain and ALP levels < 25 IU/L are associated with this variant(s). In this scenario, ALP levels < 25 IU/L seem to be very useful to identify individuals with the presence of an ALPL variant.
低磷酸酶血症（HPP）是一种代谢性遗传病，其特征为血清碱性磷酸酶（ALP）水平降低。目前关于成人低磷酸血症与 HPP 之间潜在关联的特征证据较少。本研究旨在评估持续性低磷酸血症患者中 ALPL 变异的发生率，并确定相关的临床和实验室特征。
本研究为一项横断面研究，通过测量 ALP 活性筛选了 386353 名受试者的实验室记录。共纳入 85 名（0.18%）持续性低磷酸血症（≥2 次血清碱性磷酸酶-ALP 测量值≤35IU/L，且均无>45IU/L）患者（已排除次要原因）。进行 ALPL 基因检测和系统问卷调查，以获取人口统计学、临床和实验室数据。采用描述性分析和逻辑回归模型来确定与 ALPL 变异相关的临床和实验室特征。
40 名（47%）患者存在 ALPL 变异。就临床特征而言，ALPL 变异的存在与肌肉骨骼疼痛显著相关（OR：7.6；95%CI：1.9-30.9）。然而，观察到存在更多牙齿异常的趋势（OR：3.6；95%CI：0.9-13.4）。该组中跖骨应力性骨折也更为常见（4 例比 0 例；p<0.05）。就实验室特征而言，ALPL 变异患者的 ALP 水平中位数较低（26 比 29IU/L；p<0.005）。有趣的是，ALP 水平<25IU/L 的阈值检测 ALPL 阳性的特异性、阳性预测值和阳性似然比分别为 97.8%、94.4%和 19.8。
在排除继发性原因的持续性低磷酸血症患者中，每两名患者中就有一名存在 ALPL 变异。肌肉骨骼疼痛和 ALP 水平<25IU/L 与该变异相关。在此情况下，ALP 水平<25IU/L 似乎非常有助于识别存在 ALPL 变异的个体。
