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J Pediatr Genet
DOI: 10.1055/s-0044-1801353
Case-Based Review

46,XX Disorders of Sex Development: A Case with p.Arg92Trp Variant in NR5A1

Mehmet Ali Oktay 
1   Gazi University Faculty of Medicine Department of Pediatric Endocrinology, Ankara, Türkiye
,
Agah Akın 
1   Gazi University Faculty of Medicine Department of Pediatric Endocrinology, Ankara, Türkiye
,
Esra Döğer 
1   Gazi University Faculty of Medicine Department of Pediatric Endocrinology, Ankara, Türkiye
,
Gülsüm Kayhan 
2   Gazi University Faculty of Medicine Department of Genetics, Ankara, Türkiye
,
Gizem Eşme Kocaman 
1   Gazi University Faculty of Medicine Department of Pediatric Endocrinology, Ankara, Türkiye
,
Mahmut Orhun Çamurdan 
1   Gazi University Faculty of Medicine Department of Pediatric Endocrinology, Ankara, Türkiye
,
Aysun Bideci 
1   Gazi University Faculty of Medicine Department of Pediatric Endocrinology, Ankara, Türkiye
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Abstract

Ovotesticular (OT) disorders of sex development (DSDs) are marked by the simultaneous presence of ovarian and testicular tissues within the gonads. The appearance of external genitalia does not necessarily correlate with gonadal histology. Variants in the NR5A1 gene can result in SRY-negative DSD. In this report, we present a case involving a variant in the NR5A1 gene. A 3-year-old phenotypic male presenting with micropenis, penile hypospadias, and a bifid scrotum was identified to have a c.274C > T, p.Arg92Trp variant in the NR5A1 gene, along with a 46,XX karyotype. Genetic factors such as variants in the NR5A1 gene, independent of SRY, can lead to the development of both testicular and OT DSDs, possibly manifesting in varying gender phenotypes.

Keywords

NR5A1 - p.Arg92Trp - 46,XX disorders of sex development


Publikationsverlauf

Eingereicht: 04. September 2024

Angenommen: 27. November 2024

Artikel online veröffentlicht:
26. Dezember 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 

  • References

  • 1 Kousta E, Papathanasiou A, Skordis N. Sex determination and disorders of sex development according to the revised nomenclature and classification in 46,XX individuals. Hormones (Athens) 2010; 9 (03) 218-131
    CrossrefPubMedSuche in Google Scholar
  • 2 Barros BA, Guaragna MS, Fabbri-Scallet H, Palandi de Mello M, Guerra-Júnior G, Maciel-Guerra AT. Are NR5A1 variations a frequent cause of 46,XX ovotesticular disorders of sex development? Analysis from a single center and systematic review. Sex Dev 2022; 16 (04) 242-251
    CrossrefPubMedSuche in Google Scholar
  • 3 Bashamboo A, Donohoue PA, Vilain E. et al; Members of UDN. A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development. Hum Mol Genet 2016; 25 (16) 3446-3453
    CrossrefPubMedSuche in Google Scholar
  • 4 Grinspon RP, Nevado J, Mori Alvarez MdeL. et al. 46,XX ovotesticular DSD associated with a SOX3 gene duplication in a SRY-negative boy. Clin Endocrinol (Oxf) 2016; 85 (04) 673-675
    CrossrefPubMedSuche in Google Scholar
  • 5 Eggers S, Sadedin S, van den Bergen JA. et al. Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. Genome Biol 2016; 17 (01) 243
    CrossrefPubMedSuche in Google Scholar
  • 6 Suntharalingham JP, Buonocore F, Duncan AJ, Achermann JC. DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease. Best Pract Res Clin Endocrinol Metab 2015; 29 (04) 607-619
    CrossrefPubMedSuche in Google Scholar
  • 7 Hoivik EA, Lewis AE, Aumo L, Bakke M. Molecular aspects of steroidogenic factor 1 (SF-1). Mol Cell Endocrinol 2010; 315 (1-2): 27-39
    CrossrefPubMedSuche in Google Scholar
  • 8 Luppino G, Wasniewska M, Coco R. et al. Role of NR5A1 gene mutations in disorders of sex development: molecular and clinical features. Curr Issues Mol Biol 2024; 46 (05) 4519-4532
    CrossrefPubMedSuche in Google Scholar
  • 9 Harrison SM, Campbell IM, Keays M. et al. Screening and familial characterization of copy-number variations in NR5A1 in 46,XY disorders of sex development and premature ovarian failure. Am J Med Genet A 2013; 161A (10) 2487-2494
    CrossrefPubMedSuche in Google Scholar
  • 10 Swartz JM, Ciarlo R, Guo MH. et al. A 46, XX ovotesticular disorder of sex development likely caused by a steroidogenic factor-1 (NR5A1) variant. Horm Res Paediatr 2017; 87 (03) 191-195
    CrossrefPubMedSuche in Google Scholar
  • 11 Igarashi M, Takasawa K, Hakoda A. et al. Identical NR5A1 missense mutations in two unrelated 46, XX individuals with testicular tissues. Hum Mutat 2017; 38 (01) 39-42
    CrossrefPubMedSuche in Google Scholar
  • 12 Baetens D, Stoop H, Peelman F. et al. NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development. Genet Med 2017; 19 (04) 367-376
    CrossrefPubMedSuche in Google Scholar
  • 13 Askari M, Rastari M, Seresht-Ahmadi M. et al. A missense mutation in NR5A1 causing female to male sex reversal: a case report. Andrologia 2020; 52 (06) e13585
    CrossrefPubMedSuche in Google Scholar
  • 14 Knarston IM, Robevska G, van den Bergen JA. et al. NR5A1 gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients. Hum Mutat 2019; 40 (02) 207-216
    CrossrefPubMedSuche in Google Scholar
  • 15 Eggers S, Ohnesorg T, Sinclair A. Genetic regulation of mammalian gonad development. Nat Rev Endocrinol 2014; 10 (11) 673-683
    CrossrefPubMedSuche in Google Scholar
  • 16 Wilhelm D, Englert C. The Wilms tumor suppressor WT1 regulates early gonad development by activation of Sf1. Genes Dev 2002; 16 (14) 1839-1851
    CrossrefPubMedSuche in Google Scholar
  • 17 Sekido R, Lovell-Badge R. Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature 2008; 453 (7197) 930-934
    CrossrefPubMedSuche in Google Scholar
  • 18 Combes AN, Spiller CM, Harley VR. et al. Gonadal defects in Cited2-mutant mice indicate a role for SF1 in both testis and ovary differentiation. Int J Dev Biol 2010; 54 (04) 683-689
    CrossrefPubMedSuche in Google Scholar
  • 19 Kouri C, Sommer G, Martinez de Lapiscina I. et al; SF1next study group. Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex development. EBioMedicine 2024; 99: 104941
    CrossrefPubMedSuche in Google Scholar
  • 20 Takasawa K, Igarashi M, Ono M. et al. Phenotypic variation in 46, XX disorders of sex development due to the NR5A1 p. R92W variant: a sibling case report and literature review. Sex Dev 2017; 11 (5-6): 284-288
    CrossrefPubMedSuche in Google Scholar
  • 21 Achermann JC, Ito M, Ito M, Hindmarsh PC, Jameson JL. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet 1999; 22 (02) 125-126
    CrossrefPubMedSuche in Google Scholar