American Journal of Medical Genetics 136A:386–389 (2005) Clinical Report Unusual Mixed Gonadal Dysgenesis Associated With Mu ¨ llerian Duct Persistence, Polygonadia, and a 45,X/46,X,idic(Y)(p) Karyotype Gloria Queipo, 1 Karem Nieto, 1 Patricia Grether, 4 Sara Frı ´as, 3 Rebeca A ´ lvarez, 1 Icela Palma, 1 Luis Eran ˜ a, 5 Yolanda R. Pen ˜ a, 5 and Susana Kofman-Alfaro 1,2 * 1 Department of Human Genetics,Hospital General de Me´xico, Me´xico 2 Facultad de Medicina, Universidad Nacional Auto´noma de Me´xico, Mexico City, Mexico 3 Department of Cytogenetics, Instituto Nacional de Pediatrı´a, Mexico City, Mexico 4 American British Cowdray Hospital, Mexico City, Mexico 5 Department of Urology, Hospital Infantil de Me´xico Federico Go ´mez, Mexico City, Mexico Mixed gonadal dysgenesis (MGD) is a develop- mental anomaly in which most of the patients have a dysgenetic testis, a contralateral streak and a 45,X/46,XY karyotype. This entity involves an heterogeneous group of gonadal and phenoty- pic abnormalities with a wide clinical spectrum. The phenotype depends on the ratio of testicular tissue which induces virilization. Although the karyotype in these patients is 45,X/46,XY, no genotype–phenotype correlation has been found to date. Mu ¨ llerian ducts persistence (MDP) in MGD is rare; however, four patients with both entities and different karyotypes have been described. Here we present the data on a newborn patient with an atypical MGD associated with MDP, two left testes, a gonadal streak on the right, and absence of Wolffian derivatives. PCR analysis identified all the Y-derived sequence tested in the father, while the patient had them all except the AZF b,c regions which were lost. FISH analysis of the paternal Y chromosome documented Yq para- centric inversion while the patient’s karyotype was 45,X/46,X,idic(Yp). No mutations were observ- ed in MIS/MISRII genes. ß 2005 Wiley-Liss, Inc. KEY WORDS: mixed gonadal dysgenesis; Mu ¨ l- lerian ducts persistence; Yp iso- dicentric INTRODUCTION A frequent cause of intersexuality affecting gonadal devel- opment is related to a 45,X/46,XY karyotype. This clinical condition involves a heterogeneous group of gonadal and phenotypic abnormalities, with a wide spectrum ranging from female individuals with Turner syndrome to patients with bilateral dysgenetic testis and male phenotype. However, most 45,X/46,XY cases have an asymmetric gonadal differentiation with a dysgenetic testis on one side and a contralateral streak. This condition was termed mixed gonadal dysgenesis (MGD) [Robboy et al., 1982; Telvi et al., 1999]. In these cases, the phenotype depends on the ratio of testicular tissue which induces partial virilization of the external genitalia, resulting in various degrees of sexual ambiguity. Internal genitalia on the testicular side are usually Wolffian derivatives, while differentiation of the Fallopian tubes always occurs proximal to the streak; a uterus is always present [Me ´ndez et al., 1993]. Although the karyotype in these patients is 45,X/46,XY, no genotype–phenotype correlation has been found to date and the Y chromosome is often abnormal [Bergada et al., 1986; Chemes et al., 2003]. Persistent Mu ¨ llerian-duct syndrome (PMDS) is the most frequent type of Mu ¨ llerian duct retention, and can be caused by abnormalities in the Mu ¨ llerian inhibiting substance (MIS) gene (19p) or its receptor gene (MISRII)(12p) [Loeff et al., 1994; Josso et al., 1997; Belville et al., 1999; Knebelmann et al., 1999; Belville et al., 2004]. The syndrome has also been associated with transverse testicular ectopia (TTE) [Martin et al., 1992; Karnak et al., 1997]. MDP in MGD is rare; however, four patients with both entities and different karyotypes have been described [Renton, 1975; Yu, 2002]. We present the clinical and molecular data in a newborn patient with an atypical MGD associated with MDP, absence of Wolffian derivatives and a 45,X/46,X,idic(Yp) karyotype. SUBJECT AND METHODS This newborn male assigned proband was presented and evaluated for ambiguous genitalia. He had a 2 cm phallus with perineal hypospadias, bifid scrotum, labio-scrotal folds and a urogenital sinus. A left structure was palpable in the inguinal canal. The endocrine profile was normal: Testosterone and Dihydrotestosterone were also normal after an hCG stimula- tion test (72 hr). Chromosomal analysis was performed in the proband and in his father, 100 metaphases were analyzed in each case. The patient’s original karyotype was 45,X[6]/ 46,XY[94], while the father’s karyotype was 46,XY. Interest- ingly, the Y-chromosome in the patient was smaller than his father’s Y, which had a very long Yq (Fig. 1). Laparotomy revealed a Fallopian tube in the left inguinal canal and two gonads of different sizes resembling testes situated on its side. No Wolffian derivatives or spermatic cords were present. On the right side, a streak gonad and a Fallopian tube were ob- served and a central hypoplastic uterus was present. Histo- logical analysis revealed that both left gonads were dysgenetic testes, while the right one was a haemorrhagic streak. PCR analysis of PABY, SRY, AMELY, Ycen, and Yqh was perform- ed in DNA obtained from blood leukocytes from the proband and his father. The primer sequence, annealing temperature Grant sponsor: CONACYT; Grant number: 45209-M; Grant sponsor: PAPPIT; Grant number: 206902. *Correspondence to: Susana Kofman-Alfaro, Department of Genetics, Hospital General de Me ´xico-Facultad de Medicina, UNAM. Dr. Balmis 148 Col. Doctores, CP 06726, Mexico City, Mexico. E-mail: skofman@servidor.unam.mx Received 13 December 2004; Accepted 12 February 2005 DOI 10.1002/ajmg.a.30737 ß 2005 Wiley-Liss, Inc.