SRY-positive 46,XX testicular disorder of sex development in adult monozygotic twins

Abstract

46,XX testicular disorder of sex development (DSD), also known as De la Chapelle syndrome, is a rare condition characterized by a male phenotype in individuals with a 46,XX karyotype, most commonly caused by translocation of the sex-determining region Y (SRY) gene. Diagnosis is frequently delayed until adulthood because external genitalia are typically unambiguous. We report adult monozygotic twins referred for infertility evaluation who were found to have azoospermia and markedly reduced testicular volume. Cytogenetic analysis revealed a 46,XX karyotype in both individuals, and molecular testing confirmed the presence of the SRY gene and complete absence of all azoospermia factor regions. Endocrine evaluation demonstrated low serum testosterone concentrations with normal to mildly elevated gonadotropins, consistent with primary testicular failure. Imaging revealed no residual Müllerian duct structures. This exceptionally rare twin presentation highlights the importance of genetic testing in men presenting with azoospermia, provides insight into the timing of sex-determining genetic events, and underscores the need for long-term endocrine follow-up in individuals with 46,XX testicular DSD.

Introduction

46,XX testicular disorder of sex development (DSD), also known as De la Chapelle syndrome, is a rare clinical–genetic condition characterized by a male phenotype in individuals with a 46,XX karyotype [1, 2]. The estimated incidence is approximately 1 in 20 000–25 000 male births [1, 3]. Despite the absence of the Y chromosome, affected individuals typically present with male external genitalia and are most often diagnosed during adolescence or adulthood due to infertility or hypogonadism [4, 5].

In approximately 80-90% of cases, the condition results from translocation of the SRY gene from the Y chromosome to the X chromosome during paternal meiosis [1, 3, 6]. Expression of the SRY gene activates downstream pathways involved in testicular development, including SOX9 signaling, thereby promoting differentiation of Sertoli cells and male gonadal development [7]. In contrast, genes located within the AZF regions are essential for normal spermatogenesis, explaining the universal infertility observed in affected individuals [4, 8, 9]. Endocrine findings usually reflect primary testicular failure, with low serum testosterone levels and normal to elevated gonadotropins [5, 9].

Reports of 46,XX testicular DSD in monozygotic twins are exceptionally rare [10]. Such cases provide unique insight into the timing of genetic events underlying sex determination and have particular clinical relevance for the evaluation of infertility. We describe adult monozygotic twins with SRY-positive 46,XX testicular DSD diagnosed during infertility assessment.

Case presentation

Two 26-year-old monozygotic twin brothers were referred for infertility evaluation after azoospermia had been identified during routine reproductive assessment. Monozygosity was inferred from the history of a twin pregnancy, lifelong phenotypic identity, and identical genetic findings; formal zygosity testing was not performed. Both patients reported normal male gender identity, libido, erectile function, and ejaculation. Both patients reported spontaneous pubertal development. They recalled somewhat delayed development of facial hair compared with peers, and facial and body hair remained sparse in adulthood. No medical evaluation had been sought during puberty. Family history was negative for disorders of sex development, infertility, or genetic disease. Twin 1 measured 178 cm in height and weighed 110 kg (body mass index [BMI] 34.7 kg/m²), whereas Twin 2 measured 177 cm and weighed 110 kg (BMI 35.1 kg/m²).

Diagnostic assessment

Physical examination revealed bilateral gynecomastia, obesity, sparse facial and body hair, with Tanner stage 3 of pubic hair, typical penile morphology and markedly reduced testicular volume (2.3-3.1 mL), measured using Lambert measurement formula. Repeated semen analyses confirmed azoospermia in both patients. Hormonal evaluation demonstrated primary testicular dysfunction characterized by low serum testosterone concentrations with non-suppressed gonadotropins. Anti-Müllerian hormone levels were markedly reduced. Serum prolactin concentrations were within the reference range in both patients. Pelvic ultrasonography demonstrated no residual Müllerian duct structures.

Dual-energy X-ray absorptiometry demonstrated preserved bone mineral density at the lumbar spine and hip in both patients. However, trabecular bone score assessment revealed partially degraded trabecular microarchitecture (trabecular bone score [TBS] 1.293 and 1.279, respectively). Vitamin D deficiency and insulin resistance were present in both brothers.

Cytogenetic analysis demonstrated a 46,XX karyotype in both individuals. Molecular analysis using polymerase chain reaction confirmed the presence of the SRY gene and complete absence of the AZFa, AZFb, and AZFc regions, establishing the diagnosis of SRY-positive 46,XX testicular DSD. Endocrine findings are summarized in Table 1.

Table 1.

Endocrine profile of both patients at presentation

Parameter	Twin 1	Twin 2	Reference range
FSH	11.2 IU/L	12.6 IU/L	1.5-12.4 IU/L
LH	6.7 IU/L	7.8 IU/L	1.7-8.6 IU/L
Total testosterone	5.86 nmol/L (169 ng/dL)	3.52 nmol/L (101 ng/dL)	10.2-27.0 nmol/L (294-778 ng/dL)
Estradiol	47.3 ng/L (47.3 pg/mL)	50.5 ng/L (50.5 pg/mL)	<52 ng/L (<52 pg/mL)
SHBG	10.5 nmol/L	9.0 nmol/L	18-54 nmol/L
AMH	0.576 ng/mL (0.576 µg/L)	0.312 ng/mL (0.312 µg/L)	1.4-11.6 ng/mL (1.4-11.6 µg/L)
PRL	207 mIU/L (9.8 ng/mL)	146 mIU/L (6.9 ng/mL)	54-381 mIU/L (2.5-18.0 ng/mL)

Abbreviations: AMH, anti-Müllerian hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; PRL, prolactin; SHBG, sex hormone-binding globulin. Values are shown as SI units followed by conventional units in parentheses where applicable. Reference ranges are provided for adult males.

Treatment

Vitamin D supplementation and lifestyle modification were recommended. Testosterone replacement therapy was discussed with both patients because of biochemical hypogonadism. However, neither patient reported significant hypogonadal symptoms, and both expressed reluctance to initiate lifelong hormonal therapy immediately following diagnosis because of the psychological burden associated with the diagnosis and infertility. Treatment was therefore deferred according to patient preference, with plans for reassessment during follow-up. Genetic counseling was provided, and the implications of infertility and available reproductive options were discussed in detail.

Outcome and follow-up

Both patients were referred for outpatient endocrinology treatment and follow-up to monitor gonadal function, metabolic health, and bone density. Ongoing counseling and long-term surveillance were recommended.

Discussion

This report describes an exceptionally rare presentation of SRY-positive 46,XX testicular DSD in adult monozygotic twins diagnosed during infertility evaluation. Twin cases provide a unique perspective on the timing of sex-determining genetic events and effectively exclude postzygotic mosaicism [1, 10].

In SRY-positive 46,XX individuals, translocation of the SRY gene initiates testicular differentiation despite the absence of a Y chromosome [2, 6, 9]. However, complete absence of the AZF regions results in irreversible impairment of spermatogenesis [4, 8, 11]. Such cases strongly suggest that the SRY translocation occurred during paternal meiosis prior to fertilization, with subsequent embryonic splitting resulting in 2 genetically identical affected individuals. The identical genetic findings observed in both brothers therefore support a prezygotic origin of the underlying chromosomal rearrangement [2, 10]. In contrast to SRY-negative 46,XX individuals, who may present with varying degrees of genital ambiguity because testicular differentiation depends on alternative genetic pathways [12], SRY-positive patients typically develop unambiguous male external genitalia. The differential diagnosis also includes 46,XX/46,XY chimerism and Klinefelter syndrome, both of which may present with infertility and hypogonadism but differ substantially in karyotype, endocrine profile, and pathophysiology.

Beyond infertility, both patients exhibited features typical of primary testicular failure, underscoring that 46,XX testicular DSD represents a lifelong endocrine condition [5]. This case emphasizes the importance of routine genetic testing in men with non-obstructive azoospermia, regardless of phenotypic appearance [11, 13].

Learning points

• 46,XX testicular disorder of sex development may remain undiagnosed until adulthood when external genitalia are unambiguous.

• Genetic evaluation should be performed in all men presenting with azoospermia and reduced testicular volume.

• Monozygotic twin cases provide insight into the timing of sex-determining genetic events.

Abbreviations

AZF

azoospermia factor

BMI

body mass index

DSD

disorder of sex development

SRY

sex-determining region Y

Contributors

All authors made individual contributions to authorship. V.P.: clinical, physical, and ultrasonographic evaluation of the patients; coordination of the diagnostic work up. M.T.-G.: genetic, molecular, and cytogenetic evaluation, genetic counseling. M.M.: DXA and trabecular bone score assessments, endocrine evaluation. T.B.: patients counseling, psychological support during clinical evaluation, contribution in physical evaluation. S.V.: endocrine evaluation, clinical management of patients. All authors reviewed and approved the final manuscript.

Funding

No public or commercial funding.

Disclosures

The authors declare no relevant conflicts of interest.

Informed patient consent for publication

Signed informed consent was obtained directly from the patients.

Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.