Pediatric Urology 46,XX SRY-Negative True Hermaphrodite Siblings Faith Y. Dorsey, Michael H. Hsieh, and David R. Roth The sex-determining region on the Y chromosome (SRY) gene guides male sexual development. However, individuals with sex reversal syndrome (46,XX males and 46,XX true hermaphrodites) lack the SRY gene and yet can still develop testes. We present 2 siblings with XX true hermaphroditism. Most cases of sex reversal syndrome are sporadic; however, reports have been published of familial occurrence, suggesting that 46,XX maleness and 46,XX true hermaphroditism are actually different manifestations of the same disorder of gonadal development, likely an autosomal dominant mutation with variable penetrance or an X-linked mutation. UROLOGY 73: 529 –531, 2009. © 2009 Elsevier Inc. I n a normal 46,XY male, the sex-determining region on the Y chromosome (SRY) gene is activated in the bipotential gonad to trigger a cascade of gene expres- sion leading to testicular differentiation. 1,2 It has been shown that testicular differentiation can occasionally oc- cur in the absence of a Y chromosome, leading to XX sex-reversed individuals. 3 There are 3 clinical categories of sex-reversed 46,XX SRY-negative individuals: XX males with normal external and internal genitalia, XX males with ambiguous genitalia, and true hermaphrodites with ovarian and testicular tissue. 4 Most cases of 46,XX males and 46,XX true hermaph- rodites occur sporadically. However, some reports have been published of more than 2 affected individuals in the same family. 3,5 We report the occurrence of 2 46,XX SRY-negative true hermaphrodite siblings. CASE REPORT Case 1 The first patient was born full term after a normal preg- nancy. On the physical examination at birth, he was found to have a scrotum with descended gonads, a very small phallus, and a hypospadiac urethral meatus. The initial workup was negative for congenital adrenal hyper- plasia and included measurements of 17-hydroxyproges- terone (107 ng/dL; normal 7-77 ng/dL), 11-deoxycortisol (54 ng/dL; normal 13-147 ng/dL), D4 androstenedione (104 ng/dL; normal 20-209 ng/dL), and dehydroepi- androsterone (516 ng/dL; normal 65-1250 ng/dL), and a human chorionic gonadotropin stimulation test, with normal findings. The karyotype was 46,XX SRY negative. The standard method was used for G-banded chromo- some analysis and included high-resolution analysis for all blood specimens. Fluorescent in situ hybridization analysis of SRY was performed on metaphase chromo- somes. Probes for the X centromere and SRY were used simultaneously to determine whether the SRY gene was deleted or translocated to the X chromosome. SOX9 and DAX1 analyses were not done, because we were satisfied with the 46,XX, SRY-negative finding. Pelvic ultrasonog- raphy showed testicular-like structures in the scrotum, no ovaries, and a large cystic uterus or utricle posterior and caudal to the bladder. Consideration was given to repro- ductive potential, good sexual function, overall gender- appropriate appearance, and parental preference, and a male sex was adopted. Elective testicular biopsies were scheduled as an outpatient procedure. Before the scheduled biopsies, the patient, at 10 months of age, presented to our emergency department with right testicular torsion and severe epididymo-orchi- tis and underwent right orchiectomy. Histologic exami- nation revealed testicular and ovarian tissue composed of primary and primordial follicles with intervening ovarian stroma. Case 2 The second patient, the younger sibling of patient 1, was born after a normal pregnancy at 39.4 weeks’ gestation. He was referred to our institution for investigation at age 1 day for ambiguous genitalia. The patient had a small phallus (1.5 cm in length), penoscrotal hypospadias with significant chordee, and palpable gonads bilaterally in the groin. The initial evaluation included serum 3- hydrox- ysteroid dehydrogenase, normal luteinizing hormone/ follicle-stimulating hormone, and a baseline low tes- tosterone level (42 ng/dL; normal 187 ng/dL) that increased to 128 ng/dL after a human chorionic gonad- otropin challenge test. Because of the measurements of 17-hydroxyprogesterone (49 ng/dL; normal 7-77 ng/dL), 17-hydroxypregnenolone (851 ng/dL; normal 10-829 ng/ dL), D4 androstenedione (61 ng/dL; normal 20-290 ng/dL), and dehydroepiandrosterone (82 ng/dL; normal 65-1250 From the Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas Reprint requests: Michael H. Hsieh, M.D., Ph.D., Department of Urology, Texas Children’s Hospital, Baylor College of Medicine, CCC, Suite 660, 6621 Fannin Street, Houston, TX 77030. E-mail: mhhsieh@stanfordalumni.org Submitted: June 12, 2008, accepted (with revisions): September 23, 2008 © 2009 Elsevier Inc. 0090-4295/09/$34.00 529 All Rights Reserved doi:10.1016/j.urology.2008.09.050