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

Abstract

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 > T, c.308 T > C, c.1123G > T), two deletion mutations (c.565_568delGACT*2, c.74delA), and two splicing mutations (c.721 + 1G > A, c.432 + 1G > A). Three of these mutations, namely, c.314C > T, c.1123G > T, and c.721 + 1G > 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.

Keywords: Albright’s hereditary osteodystrophy; GNAS; Progressive osseous heteroplasia; Pseudohypoparathyroidism; Pseudopseudohypoparathyroidism.

Fig. 1

The clinical characteristics of patients with pseudohypoparathyroidism. a High density shadows in the subcutaneous soft tissue of both the wrist and right elbow were observed in patient 1.b Brachydactyly of the hand and feet digits was presented in patient 2. Shortening of the metacarpals and metatarsals was revealed by X-ray, involving F2-5 on the left, F3-5 on right, and T3-4 on both sides. c Brachydactyly of the hands and feet was noted in patient 3. Radiographs of patient 3 revealed shortening of the metacarpals and metatarsals, particularly F1-5 and T4 on both sides. Patient 3 also presented with subcutaneous calcifications across their back, and cranial CT revealed multiple bilateral calcifications involving the cerebral hemisphere. d Patient 6 presented with a rounded face, and her head MRI revealed basal ganglia calcification. e Patient 9 experienced deformity of thorax, and her chest radiograph revealed scoliosis. f Patient 10 suffered from subcutaneous calcifications in the left thigh with developing nodes in the left wrist, both shanks, the back, the abdomen, the auricula, and the inframandibular region. Radiograph revealed high density shadows in both lower limbs