Three patients with 9p deletions including DMRT1 and DMRT2: A girl with XY complement, bilateral ovotestes, and extreme growth retardation, and two XX females with normal pubertal development

Abstract

It is well documented that distal 9p monosomy can be associated with XY sex reversal. Recently, the possibility of DMRT1 and/or DMRT2 (the genes for doublesex and mab-3 related transcription factor 1 and 2) being the sex determining genes(s) at 9p has been raised. DMRT1 and DMRT2 map near the 9p telomere, distal of marker D9S1779. We describe here three unrelated females with distal 9p monosomy, one with XY complement and two with XX complements. In each individual, fluorescent in situ hybridization predicted the loss of the DMRT genes. Patient 1, an XY individual with monosomy 9pter --> p24.1 approximately 24.2 and trisomy 7q32 --> qter had normal female external genitalia, a blind ending vagina, no uterus, a Fallopian tube on the right, and bilateral ovotestes with primitive ovarian tissue. She also had extreme growth retardation. Around 80 cases of distal 9p monosomy have been reported previously, but there has been no report of ovotestes or gonads comprising ovarian tissue in a XY patient with 9p deletion. Findings in Patient 1 suggest that the phenotypic spectrum of the heterozygous DMRT deletion may include true hermaphroditism. Patients 2 and 3 were 12- and 14-year-old females with XX complements, normal external genitalia, and normal pubertal development. Patient 2 had pure monosomy 9pter --> p23 and Patient 3 had monosomy 9pter --> p22.3 approximately 23 combined with trisomy 3pter --> p23 approximately 24. To date, detailed reports on the gonadal status of XX 9p-females have been limited to prepubertal girls. Patients 2 and 3 are the first females reported to have distal 9p monosomy and a normal puberty.

Partial deletion of DMRT1 causes 46,XY ovotesticular disorder of sexual development

“…It is not clear why one deletion (present case) is associated with ovotesticular DSD and the other deletion with XY gonadal dysgenesis. The size of the deletion does not explain the different phenotypes as Õ unap et al (23) reported on a patient with bilateral ovotestes and an unbalanced translocation 46,XY,der(9)t(7;9)(q32;p24) leading to a deletion of DMRT1/DMRT2.…”

DM Domain Genes: Sexual and Somatic Development During Vertebrate Embryogenesis

“…Second, DMRT1 was expressed exclusively in testes among 50 investigated human tissues. Further evidence for DMRT1 as a male sexual regulator came either from the later studies of its expression in human embryos (Moniot et al, 2000) or from additional reports describing sex-reversed patients with the monosomy of 9p (Raymond et al, 1999a;Muroya et al, 2000;Õunap et al, 2004;Privitera et al, 2005;Vinci et al, 2007). In the meantime, the group of Zarkower from the University of Minnesota (Raymond et al, 1999b) and the group of Sinclair from the University of Melbourne (Smith et al, 1999a) published very important data about DMRT1 expression during mouse, chicken and alligator embryogenesis.…”

Regulation of Sexual Dimorphism: Mutational and Chemogenetic Analysis of the Doublesex DM Domain

“…1D). The deletion of human DM genes on chromosome 9p is associated with intersexual development (6,27,31,49,55,59,63). Although originally described in relation to sex-determining pathways (67), an extended family of DM genes is proposed to function in general aspects of developmental patterning in vertebrates (35).…”