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

46,XX DSD can result from fetal or postnatal androgen excess or from maldevelopment of internal genitalia, with variable clinical phenotypes.

• DSD refers to congenital conditions associated with atypical development of chromosomal, gonadal, and/or anatomical sex.
• Clinical presentation ranges from atypical genitalia at birth to progressive virilization during adolescence or pubertal delay.
• Conditions may be diagnosed at birth in newborns with atypical genitalia, or later in life.
• The most common cause of 46,XX DSD is congenital adrenal hyperplasia due to 21-hydroxylase deficiency, but this review focuses on rarer causes outside CAH.

Understanding the molecular bases of gonadal and adrenal development is crucial for diagnosis and management of 46,XX DSD outside CAH.

• Physiological development of gonadal and adrenal structures underpins the diagnostic framework for these conditions.
• The review covers genetic, clinical, pubertal, and fertility outcomes of rare 46,XX DSD conditions.
• Rare causes of 46,XX DSD include conditions beyond 21-hydroxylase deficiency-related congenital adrenal hyperplasia.
• Sex hormone replacement therapy is discussed as a component of management for these patients.

46,XX DSD outside CAH encompasses a heterogeneous group of rare conditions with distinct genetic etiologies affecting gonadal or adrenal development.

• Conditions reviewed include rare causes of androgen excess and maldevelopment of internal genitalia in 46,XX individuals.
• The review summarizes the most relevant data on genetics, clinical aspects, puberty, and fertility outcomes.
• These conditions can present at various life stages, complicating timely diagnosis.
• Pubertal outcomes and fertility potential vary depending on the specific underlying condition.

Sex hormone replacement therapy is a relevant treatment consideration in 46,XX DSD outside CAH, particularly in the context of puberty and fertility management.

• The review specifically addresses sex hormone replacement therapy as a management strategy for these patients.
• Puberty and fertility outcomes are discussed in the context of the underlying DSD condition.
• Clinical management requires individualized approaches given the variable phenotypic presentations.
• The review synthesizes available data to guide treatment decisions for these rare conditions.