46,XX Differences of Sex Development outside congenital adrenal hyperplasia: pathogenesis, clinical aspects, puberty, sex hormone replacement therapy and fertility outcomes

Abstract

The term 'differences of sex development' (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, and/or anatomical sex. DSD in individuals with a 46,XX karyotype can occur due to fetal or postnatal exposure to elevated amount of androgens or maldevelopment of internal genitalia. Clinical phenotype could be quite variable and for this reason these conditions could be diagnosed at birth, in newborns with atypical genitalia, but also even later in life, due to progressive virilization during adolescence, or pubertal delay. Understand the physiological development and the molecular bases of gonadal and adrenal structures is crucial to determine the diagnosis and best management and treatment for these patients. The most common cause of DSD in 46,XX newborns is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, determining primary adrenal insufficiency and androgen excess. In this review we will focus on the other rare causes of 46,XX DSD, outside CAH, summarizing the most relevant data on genetic, clinical aspects, puberty and fertility outcomes of these rare diseases.

Keywords: 46; Mayer-Rokitansky-Küster-Hauser syndrome; XX DSD; aromatase deficiency; atypical genitalia; gonadal differentiation; gonadal dysgenesis; ovotestis.

Figure 1

Overview of the genetic pathways involved in gonadal determination. Arrows indicate activation of a downstream target. Lines ending in bars indicate repression of a downstream target. The genes identified as vital for the development of the bi-potential gonad include: nuclear receptor subfamily 5, group A, member 1 (NR5A1); Wilms’ tumor suppressor 1 (WT1) and chromobox homolog 2 (CBX2) (ref (, , –, –30). Various genes have been implicated in the pathways leading the bipotential indifferent gonad either into an ovary or a testis. In XY: SRY determine an increase of Sox9 expression, which then stimulate Fgf9 expression. Both Fgf9 and SOX9 suppress the female specific pathway, especially β-catenin and WNT4, supporting testis specific program. Numerous other genes such as WT1, DAX1, AMH, MAP3K1 and DMRT1 are necessary for the development and maintenance of testicular gonad. In XX: SRY is absent and specific genes are involved in ovarian development: WNT4 and RSPO1 have a synergic role on the activation of β-catenin, that suppress the SOX9/Fgf9 testicular pathway. Moreover, WNT4, RSPO1 and FOXL2 active Fst (follistatin) expression (ref. –19). Figure adapted from Tevosian SG. Genetic control of ovarian development. Sex Dev. 2013;7 (1–3):33–45 (ref.17); Eggers S, Ohnesorg T, Sinclair A. Genetic regulation of mammalian gonad development. Nat Rev Endocrinol. 2014;10 (11):673–683 (ref.18); Ohnesorg T, Vilain E, Sinclair AH. The genetics of disorders of sex development in humans. Sex Dev. 2014;8 (5):262–272 (ref.19). Created with BioRender.com.