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Activating Gs Mutations: Analysis of 113 Patients with Signs of McCune-Albright Syndrome—A European Collaborative Study

Service d’Hormonologie (S.L., F.P., C.S.), Hôpital Lapeyronie, Centre Hospitalier Universitaire (CHU) de Montpellier and Institut National de la Santé et de la Recherche Médicale, Montpellier, France 34295; and Unité d’Endocrinologie et Gynécologie Pédiatriques (F.P., C.S.), Service de Pédiatrie I, Hôpital Arnaud de Villeneuve, CHU de Montpellier, Montpellier, France 34295

Address all correspondence and requests for reprints to: Professor Charles Sultan, Unité d’Endocrinologie et Gynécologie Pédiatriques, Service de Pédiatrie I, Hôpital A. de Villeneuve, 34295 Montpellier, France. Email: chsultan{at}montp.inserm.fr.

McCune-Albright syndrome (MAS) is a sporadic disorder characterized by the classic triad of polyostotic fibrous dysplasia, café-au-lait skin pigmentation, and peripheral precocious puberty. It is due to postzygotic activating mutations of arginine 201 in the guanine-nucleotide-binding protein (G protein) -subunit (Gs), leading to a mosaic distribution of cells bearing constitutively active adenylate cyclase. MAS is heterogeneous: beyond the classic triad, a number of atypical or partial presentations have been reported. We present here the results of a systematic search for Gs mutations in patients presenting with at least one of the signs of MAS, using a PCR-based sensitive method. We studied 113 patients (98 girls and 15 boys), 24% presenting the classic triad, 33% with two signs, and 40% with only one classic sign. Overall, the mutation was identified in 43% of the patients. When an affected tissue was available, the mutation was found in more than 90% of the patients, whatever the number of signs. Skin was a noteworthy exception because only three of the 11 skin samples were positive. The mutation was detected in 46% of blood samples in patients presenting the classic triad, whereas this figure fell to 21% and 8% in patients with two and one sign, respectively. Our results highlight the frequency of partial forms of MAS and the usefulness of sensitive techniques to confirm the diagnosis at the molecular level. It should be emphasized that we found the mutation in 33% of the 39 cases of isolated peripheral precocious puberty. This study has further widened the definition of MAS. Affections as clinically different as monostotic fibrous dysplasia, isolated peripheral precocious puberty, neonatal liver cholestasis, and the classic MAS all appear to be components of a wide spectrum of diseases based on the same molecular defect.

This work was presented in part as an oral communication at the 82nd Annual Meeting of The Endocrine Society in Toronto, Canada, in June, 2000.

Abbreviations: AC, Adenylate cyclase; FD, fibrous dysplasia; Gs, guanine-nucleotide-binding protein (G protein) -subunit; MAS, McCune-Albright syndrome; PBL, peripheral blood leukocytes; PRL, prolactin.

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