Loss of DMRT1 gene in a Mos 45,XY,-9[8]/46,XY,r(9)[29]/47,XY,+idic r(9)× 2[1]/46,XY,idic r(9)[1]/46,XY[1] female presenting with short stature

Abstract

Background: A 46,XY sex reversal syndrome is characterized by discordant genetic and phenotypic sex, leading to normal external female genitalia, undeveloped gonads and presence of Müllerian structures in an otherwise 46,XY individual. Chromosome 9pter aberrations, such as ring chromosome have been reported to cause 46,XY disorders of sex development (DSD), due to involvement of DMRT1 gene located at the 9p24.3 region.

Case presentation: This study presents a unique case of a 12-year-old female with mos 46,XY, (r)9[31]/45,XY,-9[9] karyotype, presenting with intellectual disability and short stature, mimicking Turner syndrome. Re-karyotyping was performed using standard GTL-banding technique. Further cytogenetic study using standard metaphase fluorescent in situ hybridization (FISH) technique was applied to cultured lymphocytes from peripheral blood, hybridized using green control probe specific to 9q21 loci, and red DMRT1 probe specific to 9p24.3 loci. Cytogenetics and FISH analysis revealed mos 45,XY,-9[8]/46,XY,r(9)[29]/47,XY,+idic r(9)× 2[1]/46,XY,idic r(9)[1]/46,XY[1] and haploinsufficiency of DMRT1 gene in most cells. CGH array revealed a deletion around 1.25 Mb at 9p24.3 loci [arr 9p24.3(204,193-1,457,665)× 1] and three duplications around 13 Mb [9p24.3p22.3(1,477,660-14,506,754)× 3] near the breakage point that formed the ring chromosome 9.

Conclusions: The clinical presentation of the subject that mimics Turner syndrome highlights the importance of cytogenetic analysis to detect the possibility of ring chromosome 9. Sex reversal due to haploinsufficiency of DMRT1 gene in ring chromosome 9 structures is exceedingly rare with only a handful of cases ever reported. This finding further highlights the importance of DMRT1 gene in sex determination and differentiation in males. More research is required to pinpoint the exact mechanism that underlies sex reversal caused by DMRT1 haploinsufficiency.

Keywords: 46,XY-DSD; DMRT1; Ring-chromosome-9; Sex-reversal; Short-stature.

Fig. 1

Karyotype results of 46,XY,r(9) (shown left) and 46,XY,idic r(9)× 2 (right)

Fig. 2

Karyotype results containing isodicentric ring chromosome 9 (left) and the other with monosomy 9 (right)

Fig. 3

Panel a Normal 46 XY with both control (green) and DMRT1(red) probe signals detected. Panel b Ring chromosome 9 without DMRT 1 signal

Fig. 4

Isodicentric ring chromosome 9 with absence of DMRT1 signal (arrow)

Fig. 5

Interphase preparation showing two cells without one copy of DMRT1 signal (arrow) and isodicentric ring shown by detection of two adjacent green control probes (cirlce)

Fig. 6

Array-CGH log2 ratio profile of our case showing and an ideogram of chromosome 9 showing the deleted region (red) and duplicated region (green), the mutated genes are also noted

Fig. 7

Adapted from McClintok B. 1938. Ring chromosome undergoes three pathways, a even or no SCE pulled in the same direction results in normal division, b an number of SCE pulled in the opposite results in interlocked rings, c and odd number of SCE caused rings to merge into a mobius-like giant ring. d At any point of the process’ rings may break, causing the chromosome to be degraded