Six cases of ectopic cutaneous ossification associated with GNAS gene variants.

Abstract

The GNAS gene gives rise to stimulatory G protein Gs-alpha (Gsα), a pivotal transducer of hormonal signalling pathways. Variants inherited maternally lead to reduced Gsα activity in certain tissues, resulting in resistance to multiple hormones and manifesting clinically as pseudohypoparathyroidism (PHP). In contrast, paternal transmission is linked to pseudopseudohypoparathyroidism (PPHP), which is characterized by extensive ectopic cutaneous ossification but lacks endocrine resistance. Thus, the phenotypic spectrum arising from GNAS gene variants is profoundly influenced by the parent-of-origin effect. Objectives: To analyse the clinical characteristics and GNAS gene variants of six patients with ectopic cutaneous ossification. We retrospectively analysed six patients with GNAS-related ectopic cutaneous ossification, with evaluation of clinical features, laboratory results, histopathology, and genetic testing data. Six patients presented with cutaneous ossification and Albright hereditary osteodystrophy (AHO) phenotype associated with GNAS gene variants. The identified variants comprised a splicing mutation (c.718+1G>A), two nonsense mutations (c.91C>T and c.103C>T), and three frameshift mutations (c.518_521del, c.565_568del, and c.522_523del). Notably, the frameshift variant c.522_523del has not been previously reported in the literature. Five patients were diagnosed with PHP, one with PPHP. This study expands the mutational spectrum of GNAS by identifying a novel variant and highlights the phenotypic heterogeneity of GNAS-associated disorders. Early molecular diagnosis, integrated with clinical evaluation, is essential for timely intervention, mitigating disease progression, and enhancing the overall quality of life in affected children.