SRY‐negative 46,XX testicular/ovotesticular DSD: Long‐term outcomes and early blockade of gonadotropic axis

Abstract

Objective SRY‐negative 46,XX testicular and ovotesticular disorders/differences of sex development (T/OTDSD) represent a very rare and unique DSD condition where testicular tissue develops in the absence of a Y chromosome. To date, very few studies have described the phenotype, clinical and surgical management and long‐term outcomes of these patients. Particularly, early blockade of the gonadotropic axis in patients raised in the female gender to minimize postnatal androgenization has never been reported. Design Retrospective description of sixteen 46,XX T/OTDSD patients. Results Sixteen 46,XX SRY‐negative T/OTDSD were included. Most (12/16) were diagnosed in the neonatal period. Sex of rearing was male for six patients and female for ten, while the clinical presentation varied, with an external masculinization score from 1 to 10. Five patients raised as girl were successfully treated with GnRH analog to avoid virilization during minipuberty. Ovotestes/testes were found bilaterally for 54% of the patients and unilaterally for the others (with a contralateral ovary). Gonadal surgery preserved appropriate tissue in the majority of cases. Spontaneous puberty occurred in two girls and one boy, while two boys required hormonal induction of puberty. One of the girls conceived spontaneously and had an uneventful pregnancy. DNA analyses (SNP‐array, next‐generation sequencing and whole‐exome sequencing) were performed. A heterozygous frameshit mutation in the NR2F2 gene was identified in one patient. Conclusions This study presents a population of patients with 46,XX SRY‐negative T/OTDSD. Early blockade of gonadotropic axis appears efficient to reduce and avoid further androgenization in patients raised as girls.

Ovotesticular Difference of Sex Development: Genetic Background, Histological Features, and Clinical Management

“…The histological hallmark of an ovotestis is the combined presence of ovarian and testicular differentiation in a single gonad [28]. The testicular and ovarian fractions are mostly organized in an end-to-end fashion, and sometimes separated by a transitional zone, or as an ovarian cap surrounding testis tubules, although more mixed patterns have been observed in the South African population [29][30][31], possibly representing different etiologies. FOXL2 and SOX9 immunopositive staining confirms granulosa and Sertoli cell differentiation, respectively [28,32].…”

“…Observational data, based on a meta-analysis of historical series, have suggested a risk of 2.6% [35]. This is likely an overestimation as in more recent series, complemented by a thorough review of 17 in-house available gonadal biopsy and gonadectomy samples from 7 patients, no cases of germ cell neoplasia in situ (GCNIS) or invasive GCT were found in a total of 120 patients ([29, 30, 36] and unpublished data). Indeed, GCT development in DSD has been associated with the presence of the Y chromosome, more specifically the testis-specific protein-Y encoded chromosome, and with incomplete testicular differentiation (“testicularization”) of the gonad [37, 38], 2 risk factors that are absent in most ovotesticular DSD cases.…”

“…GnRH analog-mediated blockage of mini-puberty has been attempted in 5 children with ovotesticular DSD to avoid clitoris growth. Although interesting, this treatment should be regarded as experimental in attendance of further data, which can best be collected in a standardized way through international collaboration given the rareness of the condition [30, 53].…”

“…Limited data indicate that most XX boys with preserved testicular tissue progress through puberty at a normal age and pace; however, testosterone production may decline over time, with testes becoming atrophic and requiring hormone replacement therapy [29]. Cyclic menstruation seems common in girls with ovotesticular DSD who have ovarian tissue in place, and some uneventful pregnancies have been reported [29, 30]. It is currently unclear if their follicle pool is at risk of early decline and/or may be affected by long-term preservation of adjacent testicular tissue or long-term GnRH analog use, but in the absence of evidence, it seems prudent to offer monitoring of ovarian reserve to pubertal girls with ovotesticular DSD and discuss options for oocyte cryopreservation in young adult women.…”

The rare case of 46,XX testicular disorder of sex development carrying a heterozygous p.Arg92Trp variant inNR5A1

“…Approximately 80-90% of these cases are caused by translocation of the SRY allele onto the X chromosome, known as SRY-positive [5]. Testicular development may also occur in SRY-negative conditions and is caused by increased expression of pro-testis genes or insufficient expression of pro-ovarian genes [1,3,6]. SRY-negative (ovo)testicular DSD has been reported in XX individuals with duplications of SOX3, SOX9, and SOX10 [2].…”