ESPE2024 Poster Category 2 Late Breaking (107 abstracts)
Clinical Evaluation and Molecular Analysis of Genetic and Epigenetic Inactivation Defects in GNAS in children: A multicenter experience in China
Xiaoqin Xu 1 , Yingxiao Shen 1 , Wei Yang 2 , Haiyan Wei 2 , Ting Chen 3 , Linqi Chen 3 , Zhihua Wang 4 , Hui Yao 5 , Jianpin Zhang 6 , Ruimin Chen 7 , Yan Sun 8 , Levine MA 9 , Ke Huang 1 , Guanpin Dong 1 , Junfen Fu 1 & Wei Wu 1
1Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou, China. 2Department of Endocrinology, Genetics and Metabolism, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou, China. 3Department of Endocrinology, Genetics and Metabolism, Children's Hospital of Soochow University, Suzhou, China. 4Department of Endocrinology, Xi'an Children's Hospital, Xi'an, China. 5Department of Endocrinology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 6Department of Pediatrics, Ningbo Women & Children's Hospital, Ningbo, China. 7Department of Endocrinology, Fuzhou Children's Hospital of Fujian Medical University, Fuzhou, China. 8Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China. 9Division of Endocrinology and Diabetes, Center for Bone Health, The Children's Hospital of Philadelphia, Philadelphia, USA
This study aim ed to screen pediatric patients with clinically diagnosed pseudohypoparathyroidism (PHP), pseudopseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH) for genetic and epigenetic defects in GNAS and to assess their clinical features. A total 87 patients from 8 medical centers in China were included in this study, and 70 patients underwent analysis of GNAS by next-generation sequencing and methylation-specific multiple ligation-dependent probe amplification to identify causative defects. Inactivating PTH/PTHrP signalling disorder (iPPSD) system was used to distinguish patients with GNAS variants from those with imprinting defects. We found GNAS imprinting defects in 39 patients (iSSPD3) and pathogenic variants within exons 1-13 of GNAS in 31 patients (iSSPD2). Sluggish statural growth and hypocalcemia-related symptoms were common presenting complaints in iSSPD2 patients, while hypocalcemia-related symptoms were typical of iSSPD3 patients in our cohort. Both iSSPD2 and iSSPD3 patients had variable manifestations of Albright hereditary osteodystrophy, but heterotopic ossification was limited to iSSPD2. We compared the clinical characteristics of these PHP1A patients in different cohorts. Our cohort and the Korean cohort had younger diagnostic ages than the Spanish cohort. The Albright hereditary osteodystrophy phenotypes varied among the four cohorts. Three PHP1A patients were treated with recombinant human growth hormone and showed improved height and growth rates (8.2 to 9.2 cm per year). Our findings suggest that genetic screening for PHP1A and PHP1B can be highly specific (100%) in patients with parathyroid hormone resistance, but the sensitivity of screening is variable. Furthermore, we found a great degree of overlap in the clinical features of PHP1A and PHP1B, indicating that molecular analysis is critical for the proper diagnosis and management of GNAS disorders.
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