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Review
. 2024 May 15:15:1354759.
doi: 10.3389/fendo.2024.1354759. eCollection 2024.

Diagnosis and management of non-CAH 46,XX disorders/differences in sex development

Zehra Yavas Abalı  1 , Tulay Guran  1
Affiliations
Review

Diagnosis and management of non-CAH 46,XX disorders/differences in sex development

Zehra Yavas Abalı et al. Front Endocrinol (Lausanne). .

Abstract

Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in NR3C1, resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the CYP19A1 gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the SRY; copy number variants in NR2F2, NR0B1, SOX3, SOX9, SOX10, and FGF9, and sequence variants in NR5A1, NR2F2, RSPO1, SOX9, WNT2B, WNT4, and WT1. Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD.

Keywords: DSD; aromatase deficiency; disorders/differences in sex development; gonadal dysgenesis; non-CAH 46, XX DSD; primary glucocorticoid resistance; testicular/ovotesticular disorders/differences in sex development.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
An algorithm for the differential diagnosis of 46, XX DSD. Gray boxes indicate the etiologies causing non-CAH 46, XX DSD. Information on SRY gene expression and 170H-Progesterone concentration is essential in the differential diagnosis of 46, XX DSD. DSD, Disorders/Differences in sex development; CAH, Congenital adrenal hyperplasia; 21-OH deficiency, 21α-Hydroxylase deficiency; 11β-OH deficiency, 11β-Hydroxylase deficiency; 3β-HSD2 deficiency, 3β-Hydroxysteroid dehydrogenase type 2 deficiency; POR deficiency P450 oxidoreductase deficiency, PGCR; Primary glucocorticoid resistance.
Figure 2
Figure 2
The hypothalamic-pituitary-adrenal (HPA) axis in physiologic state (A) and in Primary Glucocorticoid Resistance (B). End-organ insensitivity to glucocorticoids (Cortisol) and impaired feedback mechanisms result in excess adrenocorticotrophic hormone (ACTH) secretion with increased circulating cortisol concentration. Excess ACTH leads to adrenal cortex hyperplasia and activates the synthesis of mineralocorticoids (DOC), and androgens. CRH, Corticotropin-releasing hormone; GR, Glucocorticoid receptor; DOC, Deoxycorticosterone.
Figure 3
Figure 3
Biosynthesis of C18 steroids (estrogens). Aromatase (CYP19A1) converts C19 steroids (androgens) to C18 steroids (estrogens) Androstenedione, testosterone, and 16-α-hydroxy dehydroepiandrosterone sulfate are converted to estrone (E1), estradiol (E2), and estriol (E3), respectively E1 is converted to the biologically active E2 in target tissues by enzymatic processes with 17β-HSD activity.
Figure 4
Figure 4
Basic genes and molecular pathways involved in ovarian development. The bipotential gonadal differentiates into ovary as a result of complex interactions between the testicular and ovarian developmental pathways Two components of the Wnt signalling pathway, WNT4 and RSP01 act synergistically to stabilise β-catenin encoded by CTNNB1, which promotes the expression of key ovarian genes, such as WNT4 and FST. Fog2 pathway (GATA4, ZFPM2) is also involved in the ovarian development. The ovary specific genes FOXL2, RSPO1. WNT4 and CTNNB1 (β-catenin) counteract the testicular development through inhibition of SOX9 and FGF9 expression. FOXL2 and ovarian retinoic acid is required in the adult ovary to suppress DMRT1 expression and in the maintenance of granulosa and theca cell populations of the adult ovary.
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