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Open access

Sally Tantawy, Lin Lin, Ilker Akkurt, Guntram Borck, Dietrich Klingmüller, Berthold P Hauffa, Heiko Krude, Heike Biebermann, John C Achermann and Birgit Köhler

Background

Steroidogenic factor 1 (SF-1, NR5A1) is a key transcriptional regulator of many genes involved in the hypothalamic–pituitary–gonadal axis and mutations in NR5A1 can result in 46,XY disorders of sex development (DSD). Patients with this condition typically present with ambiguous genitalia, partial gonadal dysgenesis, and absent/rudimentary Müllerian structures. In these cases, testosterone is usually low in early infancy, indicating significantly impaired androgen synthesis. Further, Sertoli cell dysfunction is seen (low inhibin B, anti-Müllerian hormone). However, gonadal function at puberty in patients with NR5A1 mutations is unknown.

Subjects and methods

Clinical assessment, endocrine evaluation, and genetic analysis were performed in one female and one male with 46,XY DSD who showed spontaneous virilization during puberty. The female patient presented at adolescence with clitoral hypertrophy, whereas the male patient presented at birth with severe hypospadias and entered puberty spontaneously. Molecular analysis of NR5A1 was performed followed by in vitro functional analysis of the two novel mutations detected.

Results

Testosterone levels were normal during puberty in both patients. Analysis of NR5A1 revealed two novel heterozygous missense mutations in the ligand-binding domain of SF-1 (patient 1: p.L376F; patient 2: p.G328V). The mutant proteins showed reduced transactivation of the CYP11A promoter in vitro.

Conclusion

Patients with 46,XY DSD and NR5A1 mutations can produce sufficient testosterone for spontaneous virilization during puberty. Phenotypic females (46,XY) with NR5A1 mutations can present with clitoromegaly at puberty, a phenotype similar to other partial defects of androgen synthesis or action. Testosterone production in 46,XY males with NR5A1 mutations can be sufficient for virilization at puberty. As progressive gonadal dysgenesis is likely, gonadal function should be monitored in adolescence and adulthood, and early sperm cryopreservation considered in male patients if possible.

Open access

Birgit Köhler, Lin Lin, Inas Mazen, Cigdem Cetindag, Heike Biebermann, Ilker Akkurt, Rainer Rossi, Olaf Hiort, Annette Grüters and John C Achermann

Objective

Hypospadias is a frequent congenital anomaly but in most cases an underlying cause is not found. Steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) is a key regulator of human sex development and an increasing number of SF-1 (NR5A1) mutations are reported in 46,XY disorders of sex development (DSD). We hypothesized that NR5A1 mutations could be identified in boys with hypospadias.

Design and methods

Mutational analysis of NR5A1 in 60 individuals with varying degrees of hypospadias from the German DSD network.

Results

Heterozygous NR5A1 mutations were found in three out of 60 cases. These three individuals represented the most severe end of the spectrum studied as they presented with penoscrotal hypospadias, variable androgenization of the phallus and undescended testes (three out of 20 cases (15%) with this phenotype). Testosterone was low in all three patients and inhibin B/anti-Müllerian hormone (AMH) were low in two patients. Two patients had a clear male gender assignment. Gender re-assignment to male occurred in the third case. Two patients harbored heterozygous nonsense mutations (p.Q107X/WT, p.E11X/WT). One patient had a heterozygous splice site mutation in intron 2 (c.103-3A/WT) predicted to disrupt the main DNA-binding motif. Functional studies of the nonsense mutants showed impaired transcriptional activation of an SF-1-responsive promoter (Cyp11a). To date, adrenal insufficiency has not occurred in any of the patients.

Conclusions

SF-1 (NR5A1) mutations should be considered in 46,XY individuals with severe (penoscrotal) hypospadias, especially if undescended testes, low testosterone, or low inhibin B/AMH levels are present. SF-1 mutations in milder forms of idiopathic hypospadias are unlikely to be common.

Open access

Wafa Kallali, Ewan Gray, Muhammad Zain Mehdi, Robert Lindsay, Louise A Metherell, Federica Buonocore, Jenifer P Suntharalingham, John C Achermann and Malcolm Donaldson

Objective

CYP11A1 mutations cause P450 side-chain cleavage (scc) deficiency, a rare form of congenital adrenal hyperplasia with a wide clinical spectrum. We detail the phenotype and evolution in a male sibship identified by HaloPlex targeted capture array.

Family study

The youngest of three brothers from a non-consanguineous Scottish family presented with hyperpigmentation at 3.7 years. Investigation showed grossly impaired glucocorticoid function with ACTH elevation, moderately impaired mineralocorticoid function, and normal external genitalia. The older brothers were found to be pigmented also, with glucocorticoid impairment but normal electrolytes. Linkage studies in 2002 showed that all three brothers had inherited the same critical regions of the maternal X chromosome suggesting an X-linked disorder, but analysis of NR0B1 (DAX-1, adrenal hypoplasia) and ABCD1 (adrenoleukodystrophy) were negative.

In 2016, next-generation sequencing revealed compound heterozygosity for the rs6161 variant in CYP11A1 (c.940G>A, p.Glu314Lys), together with a severely disruptive frameshift mutation (c.790_802del, K264Lfs*5). The brothers were stable on hydrocortisone and fludrocortisone replacement, testicular volumes (15–20 mL), and serum testosterone levels (24.7, 33.3, and 27.2 nmol/L) were normal, but FSH (41.2 µ/L) was elevated in the proband. The latter had undergone left orchidectomy for suspected malignancy at the age of 25 years and was attending a fertility clinic for oligospermia. Initial histology was reported as showing nodular Leydig cell hyperplasia. However, histological review using CD56 staining confirmed testicular adrenal rest cell tumour (TART).

Conclusion

This kinship with partial P450scc deficiency demonstrates the importance of precise diagnosis in primary adrenal insufficiency to ensure appropriate counselling and management, particularly of TART.