American Journal of Medical Genetics zyx 52:3M3 (1994) Gonadal Agenesis in zyxw XX and zyx XY Sisters: Evidence for the Involvement of an Autosomal Gene Bercnice B. Mendonqa, h g e l a S. Barbosa, Ivo J.P. Arnhold, Ken McElreavey, Marc Fellow, and Carlos A. Moreira-Filho Gonads and Intersex Unit, Diuisron of Endocrinology, Department zyxwv of Medicine, Hospital das Clinicas, University of Sbo Paulo Medical School (B.B.M., I. J.P.A.), Sbo Paulo, Brazil; Laboratoire d'lmmunogdne'tique Humaine, INSERM U.276, Institut Pasteur (K;M., M.F.), Paris, France; and Department of Immunology, Biomedical Sciences Institute, University of Sdo Paulo (A.S.B., zyxwvutsrq C.A.M.-F.), Sbo Paulo, Brazil Two agonadic sisters, one with a 46,XY and the other with a 46,XX karyotype, both with normal female external genitalia and hypoplastic Miillerian derivatives, born to a consanguineous marriage, were studied from a clinical, endocrinological, histologi- cal, and genetic perspective. Using PCR amplification, Southern hybridization, and DGGE analysis, it was found that the XY pa- tient had no mutations in the conserved se- quence of the SRY gene, the putative testis- determining gene in mammals, whereas her XX affected sister is SRY-negative. To oiur knowledge, this is the first report of XY and XX sibs in familial gonadal agenesis without other somatic abnormalities. The involve- ment of an autosomal locus impeding go- nadal development in both sexes is dis- cussed. zyxwvutsr @ 1994 Wiley-Liss, zyxwvutsr Inc. KEY WORDS: familial gonadal agenesis, SRY gene, sex determination INTRODUCTION The syndrome of XY gonadal agenesis [Sarto and Opitz, 19731 encompasses a range of phenotypes, from those with normal female external genitalia to the anorchic phenotypic male [Edman et al., 1977; Josso and Briard, 19801. Internal genitalia are usually lack- ing, an exception being the case described by De Marchi et al. 119811where internal and external genitalia were female. Familial recurrence and consanguinity were reported, favoring autosomal recessive inheritance [Rosenberg et al., 19841. Here we present three sisters, Received for publication September 7, 1993; revision received March 1, 1994. Address reprint requests to Carlos A. Moreira-Filho, Depto. de Imunologia do ICB-USP, Av. Prof. Lineu F'restes 2415, SBo I'aulo, SP 05508-900 Brazil, zyxwvutsr 0 1994 Wiley-Liss, Inc. born to first-cousin parents, with two agonadic pheno- typic females, one of them having a 46,XY and the other a 46,XX chromosome constitution. Both patients have normal female external genitalia and hypoplastic fe- male internal genitalia. The SRY (sex-determining region on the Y chromo- some) gene was present in the XY patient and absent in her XX affected sister, as shown by polymerase chain reaction (PCR) and Southern hybridization. Denatur- ing gradient gel electrophoresis (DGGE) showed that the XY patient had no mutations within the SRY "HMG (high mobility group) box," a conserved sequence that probably plays an essential role in primary sex deter- mination [Sinclair et al., 1990; Berta et al., 19901. PATIENTS AND METHODS Patients The two patients were referred €or clinical and genetic studies because of primary amenorrhea. They were born to healthy parents; mother and father are first cousins. The mother had her first period at 11 years. The normal sister, age 19 years at the time of this study, also had her menarche at 11 years. No other cases of primary amenorrhea are known in the family. The index patient, E.G.F. (290565), was referred to us at age 25 years. This patient sought med- ical attention at age 15 years because of primary amen- orrhea and absence of secondary sexual characteristics. Diagnostic tests showed high basal levels of LH and FSH and a 46,XY karyotype. She received estrogen supplementation for the following 5 years. From the start of treatment she began to have breast enlarge- ment and periodic vaginal bleeding. Estrogen therapy was stopped at age 20 years: episodes of vaginal bleed- ing ceased but some progression of breast development still occurred. Birth, neonatal development, and child- hood were unremarkable. Physical examination showed an eunuchoid habitus (height 173.3 cm, weight 77 kg, lower segment 96 cm, and span 182 cm) and no developmental abnormalities. Breast development was at Tanner stage zy IV and pubic hair at Tanner stage V. The external genitalia were fe- male with separate urethral and vaginal openings; no clitoromegaly or hypoplastic labia minora were noted. Patient zyxw 1.