SF-1 Mutations Cause Isolated Gonadal Dysgenesis and Insufficiency
Raphaël Rappaport, MD
Steroidogenic factor-1 (SF-1; also called Ad4BP, encoded by NR5A1 gene) was a concept proposed in the early 1990s. It was conceived to be an activator of multiple steps in steroidogenesis (a common protein acting as a regulatory element in the proximal region of the cytochrome P450 steroid hydroxylase genes). The corresponding gene orphan nuclear receptor factor-1 (now termed NR5A1) was mapped to the long arm of the chromosome 9 in humans. The expression pattern of this gene plays a central role in regulating the transcription of multiple genes involved in adrenal development, gonadal determination and differentiation, and hypothalamic-pituitary control of reproduction and metabolism.
In 1999 Achermann et al1 identified the first human SF-1 mutation in a patient with the full phenotype (previously observed in NR5A1 knock-out mice); the patient had primary adrenal failure and sex reversal with 46,XY gonadal dysgenesis with Mullerian structures present. This patient had a de novo heterozygous loss of function SF-1 mutation that was shown to impair the SF-1 ability to activate the promoters of several target genes. The clinical picture was primary adrenal failure that developed after birth, small intra-abdominal gonads with immature seminiferous tubules accounting for the disorder of sex differentiation (DSD) aspect. A second patient with a similar phenotype was reported shortly thereafter.2 The parents were first cousins and the patient had a homozygous mutation of SF-1.
The possibility that milder or variant changes in NR5A1 could be associated with different phenotypes was discussed at length in a paper of Lin and Achermann that focused on testis development.3 In a recent review, Schimmer and White summarized most data on disease and developmental defects.4 It is now recognized that changes in NR5A1 can cause developmental and functional disorders of the gonads in 46,XY and 46,XX individuals, without adrenal insufficiency. This is a new and important consideration in the clinical diagnosis of gonadal dysgenesis. Search for NR5A1 mutations has become part of the genetic work-up in intersex patients even in the absence of adrenal failure, when other known causes have been ruled out.
NR5A1 Mutations and 46,XY DSD
Heterozygous loss of function mutations in NR5A1 have been found in children and adults with 46,XY and apparently normal adrenal function. The first case was diagnosed in an adult patient with clitoromegaly and primary amenorrhea. She had an absent uterus and impaired breast development. In two further cases ambiguous genitalia were observed with dysgenetic testes and the presence of a uterus (in one case). More recently within two cohorts of 46,XY DSD, NR5A1 changes could be identified in approximately 15% of the patients. Interestingly, the external genitalia were female in three cases (uterus present in one case, remnants or absence in the other two cases), and ambiguous in 12 cases, most of them lacking a uterus.5,6
Most of the NR5A1 mutations appear to arise de novo. However, in one-third of the heterozygous patients mutations were inherited from the mother in a sex-limited dominant fashion; the mother carried the heterozygous change without presenting ovarian dysfunction and she passed on the gene to her affected sons. This condition may be falsely diagnosed as partial androgen insensitivity syndrome. This sex-limited dominant inheritance can mimic an X-linked disorder. This mode of inheritance is important for the strategy of molecular investigation in these patients.
SF-1 (NR5A1) Gene Mutation as a Frequent Cause of Primary Amenorrhea in 46,XY Female Adolescents
In a recent paper, Philibert et al7 turned to a selected population of female adolescents with 46,XY and primary amenorrhea, normal female external genitalia, and clitoromegaly. Subjects were separated into two groups according to their plasma testosterone values. Normal or high values suggested androgen insensitivity or 5-alpha reductase type 2 deficiency. A group of 15 of 31 patients had testosterone levels that were low for age with elevated gonadotropins. Direct sequencing identified two new SRY mutations and one new LH receptor mutation. Five patients had NR5A1 mutations, two patients had normal external genitalia, and clitoromegaly was present in the other three cases. However, in vitro studies to demonstrate the impact of the mutations were not performed.
It is known that patients with 46,XY DSD include a large phenotypic range, from complete sex reversal (and absence of a uterus) to those much less affected. In an earlier study, the same group reported 24 patients with bilateral anorchidia (vanishing testes syndrome) with or without micropenis.8 In one patient they found a variant in NR5A1 reducing to one-half the SF-1 dependant transcriptional activation. Very rarely, a link between changes in NR5A1 and late and less severe clinical changes (such as cryptorchidism and/or, vanishing testis) could be investigated. This should be looked for in at least the familial cases.
SF-1 (NR5A1) Gene Mutation and Primary Ovarian Insufficiency in 46,XX Females
Primary ovarian insufficiency (POI) is haracterized by primary or secondary amenorrhea, estrogen deficiency and elevated gonadotropins in women younger than 40 years of age. Several genetic causes of syndromic and non-syndromic forms of POI have been identified in recent years. Syndromic forms include monosomy X and the fragile X mental retardation syndrome 1 (FMR 1 gene). In this group other gene mutations include autosomal recessive mutations in the APECED, EIF2B, and GALT genes. POI can also be associated with the blepharophimosis-ptosis-epicanthus inversus syndrome caused by mutations in the FOXL2 gene.
A key role for NR5A1 in ovarian development and function has been observed in mice. It is expressed in multiple cell types in the fetal, postnatal, prepubertal, and mature ovary. There is also evidence of a role at the terminal stages of follicle differentiation and/or ovulation with reduced levels of AMH and aromatase expression in granulosa cells.
Lourenço et al9 showed, for the first time, that NR5A1 mutations are associated in 46,XX females with primary ovarian insufficiency and that they may combine with 46,XY DSD in some families, without adrenal insufficiency. They identified new mutations in four families and in two of 25 subjects with sporadic POI. The mode of inheritance of the phenotype in the families is consistent with either autosomal recessive or autosomal dominant transmission. The familial cases are shown in the Figure with associated description in the Table.
NR5A1 (SF-1) mutations may be a significant cause of non-syndromic human ovarian failure. However it remains to be shown if there is a progressive loss of ovarian function in mutation carriers. In addition the incomplete penetrance and variable expressivity as seen in these families may be explained by other endogenous or environmental factors leading to a more complex picture.
The reader is also referred to a review on SF-1 Mutations in Humans by Tomonobu Hasegawa10 published in GGH (May 2008 Vol. 24, No. 1) and a minireview on the subject by Schimmer and White.4 However, the assessment of SF-1 and NR5A1 mutations requires specialized laboratory tests not generally available to endocrinologists who are not practicing in academic medical centers. Furthermore, in the US the medical insurance payer for these patients may not approve the reimbursement for such tests. (In the US, the test is available at Boston University School of Medicine, Center for Human Genetics. They recommend that an insured patient have the tests authorized in advance by the insurance company because payment is quite often denied and patients are left with a bill of $1395 for the SF-1 and NR5A1 gene mutation tests.) However, these tests seem to be necessary for an accurate diagnosis of patients with amenorrhea, signs of virilization, and any other developmental and functional disorders of the gonads in 46,XY and 46,XX individuals.
Fima Lifshitz, MD
References - (linked to )