Disorders caused by GNAS gene variants, including pseudohypoparathyroidism (PHP) types 1a, 1b and 1c, and pseudo-pseudohypoparathyroidism (PPHP), present with complex imprinting and phenotypic variability. The gene's parent-of-origin expression pattern results in diverse clinical manifestations. We report a three-generation family harboring a heterozygous missense variant in GNAS (c.305 C > T, p.Ala102Val), classified as "likely pathogenic". The proband, a 29-year-old primigravida, and her mother displayed phenotypic features of Albright hereditary osteodystrophy (AHO) including short stature, brachydactyly, round face, and obesity. The proband was diagnosed with primary hypothyroidism at age 25. During pregnancy, her hormonal profile resembled PPHP rather than PHP 1a, with normocalcemia and elevated parathyroid hormone (PTH), potentially masked by pregnancy physiology. Her mother's phenotype was consistent with PPHP and exhibited elevated PTH due to vitamin D deficiency. The proband delivered a male neonate with normal birth parameters, but was later found to carry the familial GNAS variant. The neonate developed features of AHO, elevated PTH, and transient hypothyroidism, consistent with PHP 1a. Hormonal and calcium homeostasis remained stable with supplementation. This is, to the best of our knowledge, the first reported case of a three-generation family with a GNAS variant demonstrating an evolving phenotype during pregnancy and early life. Pregnancy-related physiological changes may counteract typical hormone resistance, complicating diagnosis. Our findings emphasize the importance of genetic counseling and longitudinal follow-up in GNAS-related disorders, particularly during reproductive planning and early infancy.

Pseudohypoparathyroidism (PHP) was first described as a syndrome characterized by PTH resistance combined with skeletal abnormalities known as Albright's hereditary osteodystrophy (AHO). Studies have since focused on genetic or epigenetic alterations underlying PHP and related disorders. The α-subunit of the stimulatory G protein (Gsα) mediates the signaling of G protein-coupled receptors that stimulate cAMP generation. The Gsα-cAMP cascade is pivotal for human skeletal growth, as evidenced by pathogenic mutations converging on this signaling pathway in a spectrum of skeletal dysplasias that overlap with AHO. The gene encoding Gsα, GNAS, is subject to genomic imprinting, an epigenetic mechanism governing allele-specific gene expression through differential methylation. Parental allele contribution to Gsα expression differs among tissues. While Gsα is biallelically transcribed in most tissues, including bone and cartilage, the paternal Gsα allele is suppressed in a limited number of cells/tissues, including the proximal renal tubule, where PTH exerts critical actions. Therefore, Gsα mutations cause distinct clinical manifestations according to the affected parental allele. While maternal mutations result in PHP type 1A, which consists of PTH resistance and AHO, paternal mutations lead to pseudo-pseudohypoparathyroidism (PPHP), that is, AHO without hormone resistance. Epigenetic alterations of GNAS cause PHP type 1B (PHP1B), defined by PTH resistance in the absence of AHO. Thus, genomic imprinting plays a key role in the phenotypes associated with GNAS alterations. Investigations on the genetic cause of PHP1B have identified crucial imprinting control regions of GNAS, whose functions were elucidated only recently using human embryonic stem cells to model imprinting regulatory mechanisms in the early embryo. We herein review the current understanding of the genetic and epigenetic basis of PHP and related disorders, focusing on their skeletal manifestations. Pseudohypoparathyroidism (PHP) is characterized by PTH resistance with skeletal and developmental abnormalities. Pseudohypoparathyroidism results from genetic or epigenetic alterations affecting the GNAS gene. GNAS encodes the stimulatory G protein α-subunit, a signaling mediator essential for human skeletal growth. GNAS undergoes genomic imprinting, that is, transcriptional regulation occurs differently on each parental allele. This epigenetic mechanism plays a key role in the phenotypes of PHP and related disorders. Recent studies have elucidated the molecular basis of GNAS imprinting, revealing the mechanisms that operate during early embryonic stages. Such advances enabled a logical approach to the molecular diagnosis of PHP.

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.

Background/Objectives: Pseudohypoparathyroidism (PHP) is a group of genetic disorders characterized by end-organ resistance to multiple hormones, short stature, brachydactyly, subcutaneous ossifications, obesity, and developmental delays. The tissue specific imprinting of GNAS in the hypothalamus may lead to different eating behavior phenotypes in maternally inherited (PHP1A, PHP1B) vs. paternally inherited (PPHP) variants. In this exploratory study, we aimed to evaluate differences in eating behaviors in a cohort of patients with PHP1A, PPHP and PHP1B. Methods: Assessments included caregiver-reported measures (hyperphagia questionnaire, children's eating behavior questionnaire, child feeding questionnaire) and self-reported measures (three factor eating behavior questionnaire). Results: A total of 58 patients with PHP1A, 13 patients with PPHP and 10 patients with PHP1B contributed data, along with 124 obese pediatric controls. An increased risk of obesity was found in PHP1A vs. PPHP (adult body mass index (BMI) 39.8 ± 8.7 vs. 30.2 ± 7.4 kg/m2, p = 0.03). Parents reported significantly earlier onset of interest in food in children with PHP1A (2.0 ± 2.3 years) and PHP1B (1.1 ± 1.3 years) compared with controls (5.2 ± 3.2 years, p < 0.001). Measures of hyperphagia, satiety and other feeding behaviors were all similar to controls. The highest hyperphagia questionnaire scores were seen prior to adolescence. In a multi-year, longitudinal assessment of 11 pediatric patients with PHP1A, hyperphagia scores were stable and 25% showed an improvement in symptoms. Conclusion: Patients with PHP1A/1B may have hyperphagia symptoms from a young age but they do not worsen over time. Patients may overeat when allowed access to food, but do not usually have disruptive food seeking behaviors. Early diagnosis can give clinicians the opportunity to provide anticipatory diagnosis on the increased risk of obesity in PHP1A/1B and need for scheduled meals and controlled portions. Further studies with larger cohorts are needed to confirm these findings.

We assessed pediatric patients with clinically diagnosed pseudohypoparathyroidism (PHP), pseudopseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH) for genetic and epigenetic defects in GNAS and characterized their clinical features. We enrolled a total of 87 patients in our study, 70 patients underwent genetic analysis. We compared the clinical manifestations according to the previously reported inactivating PTH/PTHrP signaling disorder (iPPSD) classification combined with conventional clinical classification. We identified pathogenic variants within exons 1-13 of GNAS in 31 patients (iPPSD2), with the majority presenting as PHP1A, and 2 cases each of PPHP and POH. GNAS imprinting defects were found in 39 patients (iPPSD3), with the clinical types including 11 cases of PHP1A and 28 cases of PHP1B. Sluggish height growth and hypocalcemia-related symptoms were common presenting complaints in PHP1A, while hypocalcemia-related symptoms were typical in PHP1B. Both iPPSD2 and iPPSD3 patients had variable manifestations of Albright hereditary osteodystrophy (AHO), but heterotopic ossification was limited to iPPSD2. We compared the clinical characteristics of these iPPSD2 patients presented as PHP1A in different cohorts. The AHO phenotypes varied among the 4 cohorts. Three PHP1A patients were treated with recombinant human growth hormone and showed improved height and growth rates. Our findings suggest that molecular screening can be highly specific in patients with parathyroid hormone resistance. Furthermore, we found significant overlap in the clinical features between patients with iPPSD2 and iPPSD3, suggesting that a combination of molecular genetic diagnosis and clinical evaluation may be the better approach for fully understanding GNAS inactivation defects disorders.