NR5A1 Gene Variants: Variable Phenotypes, New Variants, Different Outcomes

Faienza, Maria Felicia; Chiarito, Mariangela; Baldinotti, Fulvia; Canale, Domenico; Savino, Carmela; Paradies, Giuseppe; Corica, Domenico; Romeo, Carmelo; Tyutyusheva, Nina; Caligo, Maria A.; Waśniewska, Małgorzata; Bertelloni, Silvano

doi:10.1159/000507411

Cited by 11 publications

(4 citation statements)

References 29 publications

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“…Whereas, a compensated hypergonadotropic hypogonadism with elevated gonadotropin levels but still normal testosterone levels as recently reported by Faienza et al, was found in all patients with available laboratory data, an evident hypergonaodtropic hypogpnadism with decreased testosterone levels was only observed in two patients with female sex assignment [44].…”

Section: Discussionsupporting

confidence: 70%

Pubertal development in 46,XY patients with NR5A1 mutations

et al. 2021

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Purpose Mutations in the NR5A1 gene, encoding the transcription factor Steroidogenic Factor-1, are associated with a highly variable genital phenotype in patients with 46,XY differences of sex development (DSD). Our objective was to analyse the pubertal development in 46,XY patients with NR5A1 mutations by the evaluation of longitudinal clinical and hormonal data at pubertal age. Methods We retrospectively studied a cohort of 10 46,XY patients with a verified NR5A1 mutation and describe clinical features including the external and internal genitalia, testicular volumes, Tanner stages and serum concentrations of LH, FSH, testosterone, AMH, and inhibin B during pubertal transition. Results Patients who first presented in early infancy due to ambiguous genitalia showed spontaneous virilization at pubertal age accompanied by a significant testosterone production despite the decreased gonadal volume. Patients with apparently female external genitalia at birth presented later in life at pubertal age either with signs of virilization and/or absence of female puberty. Testosterone levels were highly variable in this group. In all patients, gonadotropins were constantly in the upper reference range or elevated. Neither the extent of virilization at birth nor the presence of Müllerian structures reliably correlated with the degree of virilization during puberty. Conclusion Patients with NR5A1 mutations regardless of phenotype at birth may demonstrate considerable virilization at puberty. Therefore, it is important to consider sex assignment carefully and avoid irreversible procedures during infancy.

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Section: Discussionsupporting

confidence: 70%

Pubertal development in 46,XY patients with NR5A1 mutations

et al. 2021

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“…26,27 Previous studies had shown phenotypic variations without any genotype-phenotype correlations. [28][29][30] A study of 30 Chinese children with NR5A1 mutations also demonstrated a wide range of external genitalia and identified p. R87C and p.R313C as the most common mutations in this cohort. In addition, exon 4 is the most frequently affected exon in 40% of the patients.…”

Section: Discussionmentioning

confidence: 89%

A Novel NR5A1 Mutation in a Thai Boy with 46, XY DSD

Wacharasindhu

Ittiwut

et al. 2023

J Pediatr Genet

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Disorders of sex development (DSD) can be classified as 46,XX DSD, 46,XY DSD, and sex chromosome DSD. Several underlying causes including associated genes have been reported. Steroidogenic factor-1 is encoded by the NR5A1 gene, a crucial regulator of steroidogenesis in the growth of the adrenal and gonadal tissues. It has been discovered to be responsible for 10 to 20% of 46, XY DSD cases. Here, we described a 2-month-old infant who had ambiguous genitalia and 46, XY. Using whole exome sequencing followed by polymerase chain reaction–Sanger sequencing, a novel heterozygous nonsense c.1249C > T (p.Gln417Ter) variant in the NR5A1 gene was identified. It is present in his mother but absent in his father and maternal aunt and uncle. At the age of 7 months, the patient received a monthly intramuscular injection of low-dose testosterone for 3 months in a row. His penile length and diameter increased from 1.8 to 3 cm and from 0.8 to 1.3 cm, respectively. The patient also had normal adrenal reserve function by adrenocorticotropic hormone stimulation test. This study identified a novel causative p.Q417X (c.1249C > T) variant in NR5A1 causing 46,XY DSD in a Thai boy which is inherited from his unaffected mother.

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“…This description is in line with that of Mönig et al., who studied 10 NR5A1 mutated patients during adolescence and puberty ( 24 ). Other authors also showed an impaired Sertoli cell function with a normal or subnormal Leydig cell function conserved at least until puberty ( 23 , 25 , 27 ).…”

Section: Discussionmentioning

confidence: 91%

Case Report: Longitudinal follow-up and testicular sperm extraction in a patient with a pathogenic NR5A1 (SF-1) frameshift variant: p.(Phe70Serfs*5)

et al. 2023

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BackgroundSteroidogenic factor 1 (SF-1), encoded by the nuclear receptor subfamily 5 group A member 1 (NR5A1) gene, is a transcriptional factor crucial for adrenal and gonadal organogenesis. Pathogenic variants of NR5A1 are responsible for a wide spectrum of phenotypes with autosomal dominant inheritance including disorders of sex development and oligospermia–azoospermia in 46,XY adults. Preservation of fertility remains challenging in these patients.ObjectiveThe aim was to offer fertility preservation at the end of puberty in an NR5A1 mutated patient.Case reportThe patient was born of non-consanguineous parents, with a disorder of sex development, a small genital bud, perineal hypospadias, and gonads in the left labioscrotal fold and the right inguinal region. Neither uterus nor vagina was detected. The karyotype was 46,XY. Anti-Müllerian hormone (AMH) and testosterone levels were low, indicating testicular dysgenesis. The child was raised as a boy. At 9 years old, he presented with precocious puberty treated by triptorelin. At puberty, follicle-stimulating hormone (FSH), luteinising hormone (LH), and testosterone levels increased, whereas AMH, inhibin B, and testicular volume were low, suggesting an impaired Sertoli cell function and a partially preserved Leydig cell function. A genetic study performed at almost 15 years old identified the new frameshift variant NM_004959.5: c.207del p.(Phe70Serfs*5) at a heterozygous state. He was thus addressed for fertility preservation. No sperm cells could be retrieved from three semen collections between the ages of 16 years 4 months and 16 years 10 months. A conventional bilateral testicular biopsy and testicular sperm extraction were performed at 17 years 10 months of age, but no sperm cells were found. Histological analysis revealed an aspect of mosaicism with seminiferous tubules that were either atrophic, with Sertoli cells only, or presenting an arrest of spermatogenesis at the spermatocyte stage.ConclusionWe report a case with a new NR5A1 variant. The fertility preservation protocol proposed at the end of puberty did not allow any sperm retrieval for future parenthood.

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NR5A1 Gene Variants: Variable Phenotypes, New Variants, Different Outcomes

Cited by 11 publications

References 29 publications

Pubertal development in 46,XY patients with NR5A1 mutations

Pubertal development in 46,XY patients with NR5A1 mutations

A Novel NR5A1 Mutation in a Thai Boy with 46, XY DSD

Case Report: Longitudinal follow-up and testicular sperm extraction in a patient with a pathogenic NR5A1 (SF-1) frameshift variant: p.(Phe70Serfs*5)

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