4 Discussion

Nuclear Receptor Subfamily 5 Group A Member 1 (NR5A1) encoded steroidogenic factor-1 (SF-1) regulates transcription of genes involved in steroidogenesis, sexual development and reproduction. SF-1 protein is expressed in the bipotential gonad and later in developing ovaries, testes and adrenal cortex (Domenice et al., 2017). Individuals with heterozygous pathogenic variants in NR5A1 variants present with a spectrum of phenotypes like 46,XX sex reversal 4 (MIM# 617480), 46,XY sex reversal 3 (MIM# 612965), adrenocortical insufficiency (MIM# 612964), premature ovarian failure 7 (MIM#612964) or spermatogenic failure 8 (MIM#613957). Table 2 lists the different phenotypes in 46,XY and 46,XX individuals.

Individuals with 46,XY DSD may have hypospadias, ambiguous genitalia with hypoplastic phallus or complete external female genitalia, infertility due to oligospermia/azoospermia and rarely primary adrenal insufficiency. The most common phenotype is ambiguous genitalia without Mullerian structures (Suntharalingham et al., 2015).

Individuals with 46,XX DSD and NR5A1 variants may develop premature ovarian failure, primary adrenal insufficiency, primary or secondary amenorrhea and defective steroidogenesis. A primary adrenal phenotype is a rare presentation.

One of the proposed reasons for the wide range of phenotypes is interaction of NR5A1 with other target genes like SRY, SOX9, STAR, WT1 and AMH, in gonadal and adrenal developmental pathways. The phenotypic severity of these disorders also varies, suggesting contribution of modifier genes or an oligogenic pattern of inheritance (Fabbri-Scallet et al., 2019).

Most of the variants reported in NR5A1 are in heterozygous state and occur de novo. However around 30% of these variants are known to be inherited from the mother in a sex-limited dominant fashion (Ferraz-de-Souza et al., 2011). In the study by Fabri Scallet et al., 2019, of the 118 individuals whose parental segregation data was available, 47 were de novo, 16 had paternally inherited variants, 41 had maternal inheritance and 3 individuals had biallelic variation. The fathers who carried the variation, did not have abnormal phenotype in majority. However hypospadias was seen in five of them. Premature ovarian failure was observed in 11 of the 41 mothers who carried the variant. The predominant mode of inheritance was then ascertained to be autosomal dominant with variable expressivity and incomplete penetrance (Fabri Scallet et al., 2019).

The variant identified in our patient was originally reported by Kohler et al., 2008 as a presumed de novo variant (the mother of the patient did not have the variant, but the father’s sample was not available for testing) in a patient with 46, XY DSD and ambiguous genitalia (Kohler et al., 2008). The same variant in heterozygous state was later reported in two additional individuals with variable phenotypic features like genital ambiguity, clitoromegaly, inguinal gonads and deranged androgen and gonadotropin levels (Robevska et al., 2018). Information on parents’ genotype was not available. This variant was seen in one apparently healthy East Asian male in gnomAD database with an allele frequency of 0.000004114. This could be because of variability in severity of phenotype resulting in mild manifestations. All types of single nucleotide variants including loss-of-function variants (nonsense and frameshift variants) as well as missense variants in primary or alternate DNA binding domains of NR5A1, are known to cause 46,XY DSD (Fabbri-Scallet et al., 2018). Small deletions, insertions and intronic variations are also reported in some individuals (Fabbri-Scallet et al., 2019).

In the family we describe, the proband inherited the variant from his mother who appeared non-penetrant for this variant. This phenomenon of sex-limited dominant inheritance poses a challenge in genetic counseling of such families. Females with heterozygous variants in NR5A1 are at risk for premature ovarian failure. But sometimes these women may not demonstrate signs of early menopause or may have completed their family before onset of menopause. In such instances, it may appear that they are non-penetrant and they may transmit the variant to their sons who may be affected (Ferraz-de-Souza et al., 2011). This could resemble an X linked recessive pattern of inheritance. The mother of the child we saw was advised evaluation for premature ovarian failure. Though the chance of inheriting the same variant in proband’s siblings is 50%, the phenotypic features and severity in an affected individual will be highly variable and determined by the chromosomal sex. Also, phenotypic variability would not be detected by antenatal ultrasonography or any other prenatal diagnostic modality. Families should be offered adequate support for making decisions regarding sex of rearing, medical and surgical management and reproductive planning. Some of the important aspects to be discussed on follow-up are risk of adrenal insufficiency and testicular tumors. Where applicable, options of fertility preservation should be considered for affected individuals as there are reports of progressive decline in testicular function as well as the possibility of ovarian dysfunction/ primary ovarian insufficiency in 46,XX carriers (Philibert et al., 2011)

This report depicts the phenotypic variability and specific counseling issues in NR5A1- related disorders. Families dealing with such complex issues may confront significant psychological stress related to gender identity development and gender dysphoria. Hence, a multi-disciplinary approach of experts in clinical genetics, newborn care, psychologists/psychiatrists and endocrinologists are warranted for comprehensive care of these individuals and families.

References