Mutations and copy number variants of the NR5A1 gene result in a plethora of phenotypes ranging from male infertility and primary ovarian insufficiency (POI) to variant sex development in 46,XY and 46,XX individuals (differences of sex development, DSD). NR5A1 associated phenotypes are characterized by intra- and interfamilial phenotypic variability and incomplete penetrance.
46,XY DSD
NR5A1 mutations and structural variations most commonly result in 46,XY DSD. However, the phenotype varies, presumably based on which NR5A1 targets are affected and at what developmental time point they play a role. It is hypothesized that if the mutated NR5A1 protein only perturbs the activation of steroidogenic enzymes, the resulting phenotype will be characterised by undervirilized external genitalia without affecting gonadal development per se. However, when the mutated protein affects the expression of genes involved in early gonadal differentiation, the phenotype will be characterized by complete or partial gonadal dysgenesis, in combination with ambiguous or female external genitalia.
- The typical 46,XY DSD phenotype
Most children with NR5A1 mutations present at birth with ambiguous genitalia and small inguinal or abdominal testes. Müllerian structures are either absent or have only rudimentary developed. Biochemically, these individuals gradually develop hypergonadotropic hypogonadism from puberty onwards and have low anti-Müllerian hormone (AMH) and Inhibin-B levels, reflecting impaired androgen biosynthesis and partial gonadal dysgenesis.
- The severe 46,XY DSD phenotype
More severe cases associated with an NR5A1 mutation present as 46,XY girls who have complete gonadal dysgenesis with streak gonads, small uterus, normal vagina and typical female external genitalia. They consult at puberty because of primary amenorrhea. Some of these girls develop clitoromegaly or other signs of vilirisation.
- Undervirilization
NR5A1 mutations have also been identified in boys with milder genital phenotypes. These boys present with a micropenis and/or hypospadias and/or cryptorichidism despite structurally normal testes. In these cases, the phenotype is thought to result from an effect of the mutated gene on steroidogenic activity exclusively.
46,XX DSD
Recently it was shown that a specific NR5A1 mutation can lead to testicular or ovotesticular development in 46,XX individuals. Some children with this condition have ambiguous genitalia at birth and may be raised as girls or as boys; others have atypical male genitalia, e.g. micropenis and/or hypospadias.
Primary Adrenal insufficiency (PAI)
A minority of patients with an NR5A1 mutation present with PAI, a potentially life-threatening condition for which accurate diagnosis and treatment with glucocorticoid and mineralocorticoid supplementation, are mandatory. Most of these cases present with both 46,XY DSD and PAI, however recently an NR5A1 mutation was identified in a 46,XX girl with isolated PAI.
The condition is typically diagnosed in infants who have severe failure to thrive and electrolyte disturbances (hyponatremia, hyperkalaemia) in association with elevated ACTH and renin levels. In newborns, the main symptoms are weakness and vomiting or feeding problems. Additional symptoms in older patients include: nausea, diarrhoea, abdominal pain, low blood pressure, salt loosing and craving, hyperpigmentation, weight loss and decreased appetite, extreme fatigue.
Male infertility
Some men attending fertility clinics and who were diagnosed with non-obstructive infertility based on the presence of azoo- or oligospermia were found to be heterozygous NR5A1 mutation carriers. In addition several of them had hypergonadotropic hypogonadism.
Primary ovarian insufficiency
46,XX women in families with a segregating NR5A1 mutation are at risk for developing POI. The age of onset of POI is variable and both primary and secondary amenorrhea are reported. Most of these women are identified following a family history of 46,XY DSD and/or 46,XX POI and penetrance is variable. Nevertheless, NR5A1 mutations explain 1.4-1.6% of sporadic POI cases.
Spleen development anomalies
So far, two families with a segregating NR5A1 variant and abnormal spleen development have been reported. The first case was characterized by asplenia and a peripheral blood smear revealed the presence of target cells, Howell-Jolly bodies and poikilocytosis. At nine years old she had a pneumococcal sepsis. The proband of the second family presented with polysplenia, while her father, who carried the same NR5A1 mutation had been diagnosed with asplenia after a severe pneumococcal sepsis in adulthood.