Surgical correction of femoral deformities in polyostotic fibrous dysplasia (PFD) or McCune-Albright syndrome (MAS), such as coxa vara or shepherd's crook deformity, is a challenge.

Guanine nucleotide-binding protein/α-subunit (GNAS) mutations are involved in fibrous dysplasia (FD) pathogenesis. Here, we analyzed GNAS mutations in FD which were performed by pyrosequencing DNA isolated from formalin-fixed paraffin-embedded (FFPE) tissue. The mutation detection rate was determined in FD specimens with and without decalcification. GNAS mutation was identified in 28 cases out of 87 FDs (32.18%) [p.R201C (N = 14) and p.R201H (N = 14)]. GNAS mutation was more likely to occur in polyostotic FD (7/28, 25.0%); FD without GNAS mutation was mostly monostotic form (56/59, 94.9%, P = 0.011). The G > A (R201H) mutation was more frequent in polyostotic FD (6/14 patients, 42.9%) than the C > T (R201C) mutation (1/14, 7.1%) (P = 0.077). We divided the FD cases into two subgroups: tissue specimens that were not decalcified (N = 35, 40.2%), and tissue specimens that were decalcified (N = 52, 59.8%). GNAS mutation was more frequently identified in FD specimens that were not subjected to decalcification (23/35, 65.7%) than in FD specimens that were decalcified (5/52, 9.6%) (P = 0.001). In conclusion, mutation analysis of GNAS by pyrosequencing has diagnostic value in FFPE tissue of patients with FD, especially in specimens that were not decalcified. The R201H substitution mutation of GNAS may be involved in the pathogenesis of polyostotic FD.

Fibrous dysplasia of bone (FD) is a rare congenital bone disease, characterized by a fibrous component in the bone marrow. Periostin has been extensively researched because of its implication in various fibrotic or inflammatory diseases. Periostin may be associated with the burden or the severity of FD. The case control PERIOSDYS study aimed at assessing serum periostin levels in FD patients. Sixty four patients with monostotic or polyostotic disease were included, in order to evaluate whether the concentrations were greater in patients than in 128 healthy age, BMI and sex-matched controls and if they were more elevated in patients with the more severe phenotypes. We found that periostin levels were greater in patients with FD compared to controls (mean = 1085 vs 958 pmol/l, p = 0.026), especially in those with a history of fracture (mean = 1475 vs 966 pmol/l, p = 0.0005), polyostotic forms (mean = 1214 vs 955 pmol/l, p = 0.004) or McCune-Albright syndrome (mean = 1585 vs 1023 pmol/l, p = 0.0048). In contrast, high pain levels were not associated with periostin levels (mean = 1137 vs 1036 pmol/l, p = 0.445). Furthermore, patients undergoing bisphosphonate therapy had significantly lower levels than treatment naïve patients (mean = 953 vs 1370 pmol/l, p = 0.002). In conclusion, periostin may be a biochemical marker indicative of the most severe forms of FD and could be used to monitor patients treated with bisphosphonates.

Fibrous dysplasia (FD) is a rare bone disorder that can involve any part of the skeleton, leading to bone pain, deformities, and fractures. Treatment with intravenous bisphosphonates has been used with variable results. Therefore, we aimed to evaluate the effects of zoledronic acid (ZA) therapy in patients with monostotic or polyostotic FD.

McCune-Albright Syndrome (MAS; OMIM # 174800) is a rare, sporadic disease caused by a post-zygotic, activating mutation in the guanine-nucleotide binding protein α-subunit (GNAS1) gene. MAS is characterized by the clinical triad of polyostotic fibrous dysplasia of bone, café-au-lait skin pigmentation and peripheral precocious puberty. However, clinical presentation is highly variable depending on mosaic tissue distribution of mutant-bearing cells. Precocious puberty is the most common endocrine manifestation of MAS and is often the presenting, and sometimes the only, clinical sign of MAS. Due to the very low prevalence of MAS, data on course of precocious puberty, effectiveness of treatments and gonadal function during post-pubertal period are lacking. Our knowledge on this issue derives essentially from case reports and small cohorts of patients. The aim of this review is to report all available literature data on clinical aspects, therapeutic management and outcomes of precocious puberty in children with MAS. A systematic research was carried out through MEDLINE via PubMed, EMBASE, Web of Science, Semantic Scholar, Cochrane Library.

Somatic gain-of-function mutations of GNAS cause a spectrum of clinical phenotypes, ranging from McCune-Albright syndrome (MAS) to isolated disease of bone, endocrine glands, and more rarely, other organs. In MAS, a syndrome classically characterized by polyostotic fibrous dysplasia (FD), café-au-lait (CAL) skin spots, and precocious puberty, the heterogenity of organ involvement, age of onset, and clinical severity of the disease are thought to reflect the variable size and the random distribution of the mutated cell clone arising from the postzygotic mutation. We report a case of neonatal MAS with hypercortisolism and cholestatic hepatobiliary dysfunction in which bone changes indirectly emanating from the disease genotype, and distinct from FD, led to a fatal outcome. Pulmonary embolism of marrow and bone fragments secondary to rib fractures was the immediate cause of death. Ribs, and all other skeletal segments, were free of changes of typical FD and fractures appeared to be the result of a mild-to-moderate degree of osteopenia. The mutated allele was abundant in the adrenal glands and liver, but not in skin, muscle, and fractured ribs, where it could only be demonstrated using a much more sensitive PNA hybridization probe-based FRET (Förster resonance energy transfer) technique. Histologically, bilateral adrenal hyperplasia and cholestatic disease matched the abundant disease genotype in the adrenals and liver. Based on this case and other sporadic reports, it appears that gain-of-function mutations of GNAS underlie a unique syndromic profile in neonates characterized by CAL skin spots, hypercortisolism, hyperthyroidism, hepatic and cardiac dysfunction, and an absence (or latency) of FD, often with a lethal outcome. Taken together, our and previous cases highlight the phenotypic severity and the diagnostic and therapeutic challenges of MAS in neonates. Furthermore, our case specifically points out how secondary bone changes, unrelated to the direct impact of the mutation, may contribute to the unfavorable outcome of very early-onset MAS.