Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China.
Eur J Endocrinol. 2023 Nov 8;189(5):S103-S111. doi: 10.1093/ejendo/lvad142.
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).
To summarize the molecular genetics results and clinical characteristics as well as to explore the correlations between them.
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.
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.
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.
假性甲状旁腺功能减退症 1 型（PHP1a）是一种罕见的内分泌疾病，由母源性 GNAS 基因突变导致刺激鸟苷三磷酸（GTP）结合蛋白（Gsα）的α亚单位部分缺陷引起。临床表现为伴有或不伴有多种激素抵抗的 PTH 抵抗（低钙血症、高磷血症和血清完整 PTH 升高）和 Albright 遗传性骨营养不良（AHO）。
总结分子遗传学结果和临床特征，并探讨两者之间的相关性。
检索截至 2021 年 5 月 31 日的关于 PHP1a 的文献，纳入 527 例基因诊断患者进行数据分析。分析这些患者的临床特征和分子遗传学结果，并进行比较，以探讨两者之间的相关性。
在 527 例患者中发现了 258 个 GNAS 罕见变异（RV）。RV 最常见于外显子 1 和 7（各占 17.6%），主要类型为移码（36.8%）和错义（31.3%）。发病中位年龄为 5.0 岁。最常见的临床表现为 PTH 升高（86.7%）和 AHO（87.5%）。除 PTH 抵抗外，甲状腺刺激激素抵抗是最常见的激素抵抗（75.5%）。错义 RV 和无功能 RV 患者的圆脸发生率（P =.001）和皮下骨化发生率（P <.001）低于失功能 RV（无义、移码、剪接位点变异和大片段缺失）患者。
本研究揭示了 PHP1a 患者失功能 RV 与圆脸和皮下骨化之间的相关性。需要通过更多具有长期随访的标准化和前瞻性研究进一步探讨基因型-表型相关性。
