McCune-Albright syndrome MAS is a rare mosaic disorder caused by post-zygotic GNAS activating mutations. MAS is characterized by fibrous dysplasia (FD) of the skeleton, café-au-lait skin macules, and hyperfunctioning endocrinopathies such as precocious puberty, thyroid disease, growth hormone excess, and FGF23-mediated phosphate wasting. Mosaicism leads to marked clinical heterogeneity and complicates molecular diagnosis. We retrospectively analyzed clinical and genotyping data of patients referred for suspected or clinically diagnosed MAS in a single French center (2014-2025). GNAS R201C and R201H mutations were detected by digital droplet PCR using peripheral blood as first-line samples, with additional testing of circulating cell-free, saliva, or tissue when indicated. We included 405 patients, from which 89 (22%) carried a GNAS mutation (52 R201C, 37 R201H). No significant clinical differences were observed between R201C and R201H. Among 578 analyzed samples, mutation detection varied by sample type, with the highest rates in tissue. Mutant allele frequency (MAF) in blood DNA was higher in patients with polyostotic than in FD (p = 0.0055), but was not associated with the overall MAS-related lesion number. No correlation was found between MAF and age at diagnosis. MAS shows substantial clinical and molecular heterogeneity without clear genotype-phenotype differences between R201 variants. Mutation detection strongly depends on sample type, reflecting disease mosaicism. A multimodal diagnostic strategy and larger collaborative cohorts are needed to optimize molecular diagnosis and refine genotype-phenotype correlations in MAS patients.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy of the adrenal glands, characterized by a high potential for local invasion and metastasis. In pediatric patients, it often presents as a localized tumor with either benign or intermediate malignant potential. While ACC is considered rare in children, early diagnosis and intervention are critical for improving outcomes. This case report presents three children diagnosed with intermediate-potential malignant ACC, diagnosed at an early stage, and successfully treated with complete surgical resection. The first case involves a 2-month-old female neonate presenting with signs of Cushingoid syndrome and a 5.5 cm left-sided stage II ACC. The second case describes a 3-year-old male who exhibited peripheral signs of precocious puberty with a 7 cm androgen-secreting right-sided stage II ACC. The third case involves a 2.5-year-old boy who presented with a hypertensive crisis-related seizure, adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome, and peripheral precocious puberty due to a 3.5 cm right adrenal stage I ACC. All three patients underwent successful complete resection of their respective tumors, with no signs of locoregional invasion or distant metastasis. Postoperatively, there was a complete resolution of the endocrine manifestations, such as Cushingoid features and precocious puberty. All three children underwent successful complete tumor resection, resolution of the endocrine findings and no recurrences after up to 4 years of follow-up. This case report highlights the diverse clinical presentations of pediatric ACC, showcasing the various hormonal profiles and symptoms associated with the disease. It emphasizes the critical importance of early detection and complete surgical resection in improving patient outcomes. Although pediatric ACC is a rare and aggressive disease, these cases demonstrate that with appropriate intervention, favorable outcomes can be achieved, even in cases with intermediate malignant potential.

Recent studies have revealed de novo or germline-derived GNAS-Gsα variants with constitutive ligand-independent gain-of-function (GOF) effects on specific G-protein-coupled receptor signalings in patients with nephrogenic syndrome of inappropriate antidiuresis (NSIAD), osteolytic bone disorder with metaphyseal dysplasia, and peripheral precocious puberty. We encountered a Japanese girl with NSIAD and osteolytic bone disorder with metaphyseal dysplasia. Whole genome sequencing identified a de novo ″likely pathogenic″ heterozygous GNAS-Gsα missense variant (NM_000516.7:c.163 A > G:p.(Thr55Ala)) which occurred on the paternally inherited allele. Luciferase assays for p.Thr55Ala showed ligand-independent GOF effects on AVPR2 and PTH1R signalings, and a ligand-dependent loss-of-function (LOF) effect on PTH1R signaling. Protein structural analysis for p.Thr55Ala indicated disruption of the hydrogen bond between p.Thr55 side chain and the α-phosphate group of the bound nucleotide in both GDP-bound inactive form and GTP-bound active form and resultantly reduced affinity of the variant-positive Gsα protein for both GDP and GTP, consistent with the ligand-independent GOF and ligand-dependent LOF effects. The results, in conjunction with the previous findings, indicate that GNAS-Gsα variants with constitutive GOF effects cause clinically distinctive congenital rare disorders including NSIAD and characteristic bone disorder.

Peripheral precocious puberty (PPP) is an endocrine disorder characterized by premature, autonomous gonadal or extragonadal sexual steroid secretion. Accounting for about 20% of cases of precocious puberty, PPP is usually caused by rare diseases, including congenital adrenal hyperplasias, hormone-secreting gonadal and adrenal tumours, and McCune-Albright Syndrome (MAS). MAS is a rare, genetic disorder, mainly characterized by bone dysplasia, skin hyperpigmentation, and endocrine, hyperfunctioning disorders, including, as reported, PPP. Being a rare disease, PPP management in MAS patients is currently anecdotically reported, and no systematic approach is granted. A four years and two months boy was admitted in our department due to precocious pubarche and recent growth acceleration. At physical examination, he showed cafè-au-lait skin macules on thorax, abdomen, and posterior neck, and at hormonal evaluation he showed evidence of PPP, confirmed at both baseline and stimulated gonadotropin and testosterone levels. Due to the clinical features, he was diagnosed with MAS, that was further confirmed by the evidence of bone skull and testicular lesions; a thyroid lesion was also reported, but its relationship with MAS was questioned. He therefore started combined treatment with androgen receptor blocker bicalutamide and aromatase inhibitor anastrazole, that were able to significantly reduce growth acceleration and to stop pubertal progression. He safely continued combined treatment for three years, showing good efficacy on growth and pubertal outcome. Combined treatment with bicalutamide and anastrozole is a safe and effective long-term therapeutic approach to PPP in MAS boys, although evidences on its use are scarce; therefore, wider studies including larger populations deriving from different centres should be performed to obtain general consensus.

Precocious puberty (PP) in girls is defined as the appearance of clinical signs of puberty before the age of eight. While central precocious puberty (CPP) is commonly idiopathic, peripheral precocious puberty (PPP) can be linked to estrogen-producing ovarian cysts or tumors. This study presents a rare case of ovarian serous cystadenoma mimicking polycystic ovarian morphology (PCOM) in a prepubertal girl, contributing to persistent hormonal disturbances and symptoms of PP. The objective is to highlight the diagnostic challenges and management strategies for such cases. A retrospective case review was performed, detailing the clinical course, diagnostic imaging, laboratory findings, treatment decisions, and histopathological results. A literature review was conducted using the EMBASE and MEDLINE databases to compare this case with previously reported instances of ovarian cystadenoma associated with precocious puberty. A 15-year-old girl presented with persistent ovarian cysts and PP symptoms first noted at the age of 5. Initial imaging revealed enlarged ovaries with a polycystic appearance. Despite treatment with a GnRH analog, hormonal abnormalities persisted, with increasing estrogen and androgen levels. MRI demonstrated progressive ovarian enlargement with cystic transformation. Surgical intervention was performed at age 15, and histopathological examination confirmed serous cystadenoma. Following surgery, hormonal levels normalized, and clinical symptoms resolved. This case illustrates an unusual presentation of ovarian serous cystadenoma mimicking PCOM and contributing to persistent precocious puberty. Given the diagnostic challenge, a multidisciplinary approach involving endocrinologists and gynecologists is essential. Early recognition, close monitoring, and appropriate surgical intervention are crucial to managing such rare cases effectively.