Ambiguous Genitalia in a Patient with Ring Chromosome 13

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 631-640-Pediatric Endocrinology Case Reports: Disorders of Sexual Differentiation
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-632
Melanie Leu*1, Luisa Fernanda Gonzalez2, Marcela Vargas Trujillo2, Selma Feldman Witchel2 and Svetlana A Yatsenko3
1Universitty of Pittsburgh, Pittsburgh, PA, 2Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 3University of Pittsburgh, Pittsburgh, PA
Background: Deletions involving the distal long arm of chromosome 13 are rare and are associated with mental retardation, microcephaly, growth retardation, and genital malformations in males. Analysis of male patients with distal 13q microdeletion identified a region critical for genitourinary abnormalities containing 3 genes: D-Amino Acid Oxidase Activator (DAOA), Arginine- and Glutamine-Rich Protein 1 (ARGLU1), and Efrin B2 (EFNB2) (1).  We describe a male patient with abnormal genitalia and monosomy for the distal long arm of chromosome 13.

Clinical Case: This 1548 gram 34 week gestation newborn was delivered prematurely for  IUGR. The newborn had a micropenis (1 cm stretched penile length with small diameter), normal position of the urethral meatus, chordee, fused scrotum, right testis in the inguinal canal, and retractile left testis. Additional features included microcephaly, retrognathia, high arched palate, submucous cleft palate, low set posterior ears, syndactyly of 2nd and 3rd toes, and right pelvic kidney. Bloodwork showed: cortisol: 13.9 µg/dl (9-25), 7-dehydroxycholesterol: 0.27 µg/ml (0.04-0.36), 17-OHP: 406 ng/dl (26-568), total testosterone: 63 ng/dl (37-198), androstenedione: 77 ng/dl (50-449), GH:10.4 ng/ml (0-20), LH: 20.3 mIU/ml (4.85-10), and FSH: 7.6 mIU/ml (1.22-5.19). Pelvic US showed ovoid soft tissue structures in the bilateral inguinal canals. Chromosome analysis was 46,XY with mosaicism for 3 cell lines: ring chromosome 13, double ring 13, and monosomy 13. Array CGH analysis revealed a gain of the 13q12.11-q33.3 chromosome region consistent with a double ring 13, and a loss of the 13q33.3-q34 region encompassing an 8.2 Mb segment. This deletion encompasses 45 genes and partially overlaps with the previously proposed critical region for genitourinary abnormalities.

Discussion: Genotype-phenotype correlation in male patients with genital malformations and deletions of the distal 13q narrowed the critical region to an approximately 130kb segment containing the EFNB2 and ARGLU1 genes. ARGLU1 is involved in mediating estrogen-dependent functions.  EFNB2 is expressed in genitalia and kidney and may play a role in genitourinary development. EFNB2-/+male mice exhibit hypospadias.

Conclusion: This report narrows the critical region responsible for genitourinary anomalies seen in patients with 13q deletion. Hence, we propose that haploinsufficiency of the EFNB2 or/and ARGLU1 genes is responsible for abnormal genitalia development in males.

(1) Walczak-Sztulpa J et al., Am J Med Genet A. 2008;146:337

Nothing to Disclose: ML, LFG, MV, SFW, SAY

*Please take note of The Endocrine Society's News Embargo Policy at

Sources of Research Support: NIH Grant T32 DK07729-16