BACKGROUND Pseudohypoparathyroidism type 1a (PHP1a) is a rare endocrine disease caused by partial defects of the α subunit of the stimulatory Guanosin triphosphate (GTP) binding protein (Gsα) resulting from maternal GNAS gene variation. The clinical manifestations are related to PTH resistance (hypocalcemia, hyperphosphatemia, and elevated serum intact PTH) in the presence or absence of multihormone resistance, and Albright's hereditary osteodystrophy (AHO). OBJECTIVES To summarize the molecular genetics results and clinical characteristics as well as to explore the correlations between them. METHODS Articles pertaining to PHP1a until May, 31, 2021 were reviewed and 527 patients with genetic diagnosis were included in the data analysis. The clinical characteristics and molecular genetics results of these patients were analyzed and compared to explore the correlations between them. RESULTS A total of 258 GNAS rare variants (RVs) were identified in 527 patients. The RVs were most commonly found in exons 1 and 7 (17.6% each), with frameshift (36.8%), and missense (31.3%) being the main types of RVs. The median age of onset was 5.0 years old. The most common clinical manifestations were elevation of PTH (86.7%) and AHO (87.5%). Thyroid stimulating hormone resistance was the most common hormone resistance (75.5%) other than PTH resistance. Patients with missense and in-frame RVs had lower incidence rates of the round face (P = .001) and subcutaneous ossifications (P < .001) than those with loss-of-function (non-sense, frameshift, splicing site variants, and large deletions) variants. CONCLUSIONS This study revealed the correlation between loss-of-function RVs with round faces and subcutaneous ossifications in PHP 1a patients. Further exploration of genotype-phenotype correlations through more standardized and prospective studies with long-term follow-up is necessary.

中文翻译：

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1a 型假性甲状旁腺功能减退症患者的基因型-表型相关性：系统评价。

背景 1a 型假性甲状旁腺功能减退症 (PHP1a) 是一种罕见的内分泌疾病，由母体 GNAS 基因变异导致刺激性鸟苷三磷酸 (GTP) 结合蛋白 (Gsα) 的 α 亚基部分缺陷所致。临床表现与存在或不存在多激素抵抗的 PTH 抵抗（低钙血症、高磷血症和血清完整 PTH 升高）以及奥尔布赖特遗传性骨营养不良（AHO）有关。目的总结分子遗传学结果和临床特征并探讨它们之间的相关性。方法回顾截至2021年5月31日有关PHP1a的文章，并纳入527例基因诊断患者进行数据分析。对这些患者的临床特征和分子遗传学结果进行分析比较，探讨其之间的相关性。结果 在 527 名患者中总共鉴定出 258 个 GNAS 罕见变异 (RV)。RV 最常见于外显子 1 和 7（各 17.6%），其中移码（36.8%）和错义（31.3%）是 RV 的主要类型。中位发病年龄为 5.0 岁。最常见的临床表现是PTH（86.7%）和AHO（87.5%）升高。促甲状腺激素抵抗是除 PTH 抵抗之外最常见的激素抵抗（75.5%）。与功能丧失（无义、移码、剪接位点变异、和大量删除）变体。结论 这项研究揭示了 PHP 1a 患者圆脸 RV 功能丧失与皮下骨化之间的相关性。有必要通过更标准化、前瞻性的研究和长期随访来进一步探索基因型-表型相关性。