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Androgen Insensitivity Syndrome: Somatic Mosaicism of the Androgen Receptor in Seven Families and Consequences for Sex Assignment and Genetic Counseling

Service d’Hormonologie (B.K., S.L., F.A., C.S.), Centre Hospitalier Universitaire Montpellier and Institut National de la Santé et de la Recherche Médicale U540, 34295 Montpellier, France; Services d’Endocrinologie Pédiatrique, Hôpital Robert-Debré (J.L., P.C.), 75730 Paris, France, and Hôpital Necker (G.P.), 75935 Paris, France; Service de Pédiatrie (F.K.), Hôpital de Saint-Avold, 57502 Saint-Avold, France; Servicios de Genètica, Hospital Vall d’Hebron (E.S.G.), 08035 Barcelona, Spain; Department of Pediatrics (M.S.), University Federico II, 80143 Naples, Italy; Department of Pediatric Endocrinology (T.S.), 117036 Moscow, Russia; and Unité d’Endocrinologie Pédiatrique (C.S.), Centre Hospitalier Universitaire, 34295 Montpellier, France

Address all correspondence and requests for reprints to: Dr. Serge Lumbroso, Service de Biochimie, Centre Hospitalier Universitaire, 30029 Nimes, France. E-mail: lumbroso{at}montp.inserm.fr.

Androgen insensitivity syndrome (AIS) is caused by numerous mutations of the androgen receptor (AR) gene. The phenotype may range from partial AIS (PAIS) with ambiguous genitalia to complete AIS (CAIS) with female genitalia. In 70% of the cases, AR mutations are transmitted in an X-linked recessive manner through the carrier mothers, but in 30%, the mutations arise de novo. When de novo mutations occur after the zygotic stage, they result in somatic mosaicisms, which are an important consideration for both virilization in later life—because both mutant and wild-type receptors are expressed—and genetic counseling. We report here six patients with AIS due to somatic mutations of the AR and one mother with somatic mosaicism who transmitted the mutation twice. Of the four patients with PAIS, three presented spontaneous or induced virilization at birth or puberty. These cases underline the crucial role of the remnant wild-type AR for virilization because the same mutations, when they are inherited, lead to CAIS. We also report two novel mutations of the AR, with somatic mosaicism, detected in patients with CAIS. Thus, the remnant wild-type receptor does not always lead to virilization. In one of these patients, a high ratio of wild-type to mutant AR expression was found in the gonads and genital skin fibroblasts. Although no prenatal virilization occurred, the possibility of virilization at puberty could not be excluded, and early gonadectomy was performed. A seventh patient had a CAIS with a novel germline AR mutation. The mutation was inherited from the mother, in whom mosaicism was detected in blood and who transmitted the mutation to a second, XX, offspring. The detection of somatic AR mutations is particularly important for the clinical management and genetic counseling of patients with AIS. Before definite sex assignment, a testosterone treatment trial should be performed in all patients with PAIS, but it becomes crucial when an AR mosaicism has been detected. In patients with CAIS or severe PAIS raised as female, there is no consensus about when (early childhood or puberty) gonadectomy should be performed. When somatic AR mutations are detected, however, gonadectomy should be performed earlier because of the risk of virilization during puberty. When a germline de novo mutation is identified in the index case, the risk of transmission to a second child due to a possible germ cell mosaicism in the mother cannot be excluded. However, given the high number of AR de novo mutations and the rarity of such reports, this risk appears to be very low.

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