The management of children and adults with an NR5A1 mutation depends on the observed phenotype.
Variant sex development (Disorders of sex development, DSD)
Management of variant sex development resulting from an NR5A1 mutation follows the same principles as for other DSD conditions. Care for DSD patients requires the professional expertise of a multidisciplinary team in which each member has specific knowhow about one of the different aspects of these conditions, thereby enabling a holistic approach for each patient. The multidisciplinary team should include a (pediatric) endocrinologist, urologist, gynaecologist, psychologist, biochemist and geneticist. As the frequency of all DSD conditions is low, DSD care should be organised in centers of expertise.
Diagnosis of a DSD condition leans on three important pillars: physical examination, biochemical analysis and genetic testing. Structured clinical assessment of the appearance of the genitals is usually based on Prader and/or external masculinization scores (EMS). Physical examination should also include attention for other features (e.g. dysmorphism), as they might direct the diagnostic process towards a specific condition. Laboratory investigations guide further diagnostic tests and permit an evaluation of gonadal and adrenal function. Thirdly, genetic testing can complete the diagnostic process.
It is important to emphasize that the presence of ambiguous genitalia is not a medical emergency per se, meaning that decisions e.g. regarding sex of rearing should not be taken before all tests results have become availalble and that there is no reason to restrain parent-child interaction. However, when associated with adrenal insufficiency, rapid steroid and salt replacement therapy are mandatory.
For more information on the management of children with a DSD condition, we like to refer to following articles:
- Cools M et al. Caring for individuals with a difference of sex development (DSD): a consensus statement. Nat Rev Endocrinol. 2018;14(7):415-429.
- Ahmed SF et al. Society for Endocrinology UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development. Clin Endocrinol. 2016;84(5):771-88.
- Audi L et al. Approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 ‘DSDnet’. Eur J Endocrinol. 2018;179,R197–R206.
Male infertility and primary ovarian insufficiency
Infertility affects approximately 1/6 to 1/10 couples and represents an important burden for healthcare. Reproductive options should be explored and discussed with the patient.
The reproductive potential of women who have POI is largely unknown: some women might become pregnant after suppression of elevated FSH levels by ethinylestradiol or gonadotrophin-releasing hormone analogues and induction of ovulation with low-dose gonadotropins, for other women oocyte donation or adoption are the only options. Furthermore, POI results in ovarian loss of estrogen and progesterone secretion, impacting on the women’s general health such as bone mass maintenance, cognitive functioning, sexuality and general wellbeing. Therefore, many of these women are advised to have sex steroid replacement therapy similar to women with menopausal complaints.
Primary adrenal insufficiency
Primary adrenal insufficiency poses a potentially life-threatening medical emergency. Patients should be treated with mineralo- and glucocorticoid replacement therapy, including stress dose adjustments whenever appropriate.