Changes (mutations) in the NR5A1 gene can result in many different conditions. These range from rare conditions associated with a variant sex development (grouped under the umbrella term differences of sex development (DSD)) to more frequent conditions like male infertility and early menopause. Additionally, NR5A1 variants rarely also impact adrenal function, resulting in primary adrenal insufficiency (PAI).
Disorders of sex development (46,XY and 46,XX DSD)
DSDs are a group of rare congenital conditions characterized by atypical development of either chromosomal (XX or XY chromosomes), gonadal (testes or ovaries) or anatomical sex. In the earliest phases of development, our gonads are undifferentiated and bipotential. Typically, when XY chromosomes are present, these precursor gonads will differentiate into testes, when XX chromosomes are present, they will turn into ovaries.
Children with a DSD condition can present at birth when their external genitalia look different. Sometimes doctors may even not be able to tell parents if the child is a girl or a boy without doing further investigations. For instance, a girl can be born with an enlarged clitoris and/or partial fusion of the labia or a boy can be born with a micropenis or hypospadias (a condition in which the urethral meatus is not on the top of the penis but along its shafts). For these children follow-up by a specialist team can start immediately.
Alternatively, when the aspect of external genitalia is unremarkable, girls can present in adolescence because of absent pubertal development. Diagnostic work-up will then reveal, unexpectedly, 46,XY chromosomes. For more information on DSD conditions, please visit: www.dsdfamilies.org and www.dsdteens.org.
Male infertility
NR5A1 mutations can also be the underlying cause of male infertility. In these cases, infertility is the result of a decreased number of sperm cells (oligospermia) or absence of sperm cells (azoospermia).
Primary ovarian insufficiency (POI)
POI is an important cause of female infertility and is characterized by the absence of menses before the age of 40 in combination with low blood levels of estrogen and high levels of gonadotropins (LH and FSH). Amenorrhea can be both primary, when the girl/women never had a (regular) menstrual cycle, or secondary. Most POI-associated NR5A1 mutations are found in women with a familial history of 46,XY DSD however they also explain 1.4-1.6% of POI cases who do not have a family member with similar symptoms.
Primary adrenal failure (PAI)
A minority of patients with an NR5A1 mutation present with primary adrenal insufficiency (PAI), a potentially life-threatening condition for which accurate diagnosis and treatment, by means of glucocorticoid and mineralocorticoid supplementation, are mandatory. Symptoms include: nausea, diarrhoea, vomiting, abdominal pain, low blood pressure, salt loosing and craving, hyperpigmentation, weight loss and decreased appetite, extreme fatigue. In newborns the main symptoms of adrenal insufficiency are muscle weakness, feeding problems and vomiting. Furthermore, these children have dry skin and lips.
Abnormal spleen development
More recently, NR5A1 mutations were also shown to be involved in abnormal spleen development (asplenia, polysplenia). Given the importance of the spleen for the immune system, these patients may be at risk for fulminant infectious diseases and extra considerations should be taken with respect to vaccination etc.