Genotype-phenotype correlations in pseudohypoparathyroidism type 1a patients: a systemic review

Abstract

Background Pseudohypoparathyroidism type 1a (PHP1a) is a rare endocrine disease caused by partial defects of the α subunit of the stimulatory 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%). TSH 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 round face (P = 0.001) and subcutaneous ossifications (P < 0.001) than those with loss-of-function (nonsense, frameshift, splicing site variants and large deletions) variants. Conclusions This study revealed the correlation between loss-of-function RVs with round face and subcutaneous ossifications in PHP 1a patients. Further exploration on genotype phenotype correlations through more standardized and prospective studies with long-term follow-up is necessary.