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Background The  GNAS  gene on chromosome 20q13.3, encodes the alpha-subunit of the stimulatory G protein, which is expressed in most tissues and regulated through reciprocal genomic imprinting. Disorders of  GNAS  inactivation produce several different clinical phenotypes including pseudohypoparathyroidism (PHP), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). The clinical and biochemical characteristics overlap of PHP subtypes and other related disorders presents challenges for differential diagnosis. Methods We enrolled a total of 11 Chinese children with PHP in our study and analyzed their clinical characteristics, laboratory results, and genetic mutations. Results Among these 11 patients, nine of them (9/11) presented with resistance to parathyroid hormone (PTH); and nine (9/11) presented with an Albright′s hereditary osteodystrophy (AHO) phenotype.  GNAS  abnormalities were detected in all 11 patients, including nine cases with  GNAS  gene variations and two cases with  GNAS  methylation defects. These  GNAS  variations included an intronic mutation (c.212 + 3_212 + 6delAAGT), three missense mutations (c.314C &gt; T, c.308 T &gt; C, c.1123G &gt; T), two deletion mutations (c.565_568delGACT*2, c.74delA), and two splicing mutations (c.721 + 1G &gt; A, c.432 + 1G &gt; A). Three of these mutations, namely, c.314C &gt; T, c.1123G &gt; T, and c.721 + 1G &gt; A, were found to be novel. This data was then used to assign a  GNAS  subtype to each of these patients with six cases diagnosed as PHP1a, two cases as PHP1b, one as PPHP, and two as POH. Conclusions Evaluating patients with PTH resistance and AHO phenotype improved the genetic diagnosis of  GNAS  mutations significantly. In addition, our results suggest that when  GNAS  gene sequencing is negative,  GNAS  methylation study should be performed. Early genetic detection is required for the differential diagnosis of  GNAS  disorders and is critical to the clinician’s ability to distinguish between heterotopic ossification in the POH and AHO phenotype.

Evaluating the variety of GNAS inactivation disorders and their clinical manifestations in 11 Chinese children