Download PDF
J Pediatr Genet 2024; 13(03): 181-184
DOI: 10.1055/s-0043-1764480
Original Article

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

Suttipong Wacharasindhu 
1   Division of Pediatric Endocrinology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
,
Chupong Ittiwut
2   Central Laboratory, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
,
Rungnapa Ittiwut
3   Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
4   Department of Pediatrics, Center of Excellence for Medical Genomics, Medical Genomics Cluster, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
,
Suphab Aroonparkmongkol
1   Division of Pediatric Endocrinology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
,
Kanya Suphapeetiporn
3   Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
4   Department of Pediatrics, Center of Excellence for Medical Genomics, Medical Genomics Cluster, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
› Author Affiliations Funding This work was supported by the Rachadapiseksompotch Fund (RA 59/008), Faculty of Medicine, Chulalongkorn University.
› Further Information
Also available at
    Permissions and Reprints

Abstract

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.

Keywords

disorders of sex development - NR5A1 - novel - mutation


Publication History

Received: 06 July 2022

Accepted: 13 February 2023

Article published online:
20 March 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Lee PA, Houk CP, Ahmed SF, Hughes IA. . International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Consensus statement on management of intersex disorders. Pediatrics 2006; 118 (02) e488-e500
    CrossrefPubMedSearch in Google Scholar
  • 2 Parivesh A, Barseghyan H, Délot E, Vilain E. Translating genomics to the clinical diagnosis of disorders/differences of sex development. Curr Top Dev Biol 2019; 134: 317-375
    CrossrefPubMedSearch in Google Scholar
  • 3 Lee PA, Nordenström A, Houk CP. et al; Global DSD Update Consortium. Global disorders of sex development update since 2006: perceptions, approach, and care. Horm Res Paediatr 2016; 85 (03) 158-180
    CrossrefPubMedSearch in Google Scholar
  • 4 Audi L, Ahmed SF, Krone N. et al; The EU COST Action. GENETICS IN ENDOCRINOLOGY: Approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 ‘DSDnet’. Eur J Endocrinol 2018; 179 (04) R197-R206
    CrossrefPubMedSearch in Google Scholar
  • 5 Délot EC, Vilain E. Towards improved genetic diagnosis of human differences of sex development. Nat Rev Genet 2021; 22 (09) 588-602
    CrossrefPubMedSearch in Google Scholar
  • 6 Morel Y, Rey R, Teinturier C. et al. Aetiological diagnosis of male sex ambiguity: a collaborative study. Eur J Pediatr 2002; 161 (01) 49-59
    CrossrefPubMedSearch in Google Scholar
  • 7 Hughes IA, Houk C, Ahmed SF, Lee PA. . LWPES Consensus Group, ESPE Consensus Group. Consensus statement on management of intersex disorders. Arch Dis Child 2006; 91 (07) 554-563
    CrossrefPubMedSearch in Google Scholar
  • 8 Ata A, Özen S, Onay H. et al. A large cohort of disorders of sex development and their genetic characteristics: 6 novel mutations in known genes. Eur J Med Genet 2021; 64 (03) 104154
    CrossrefPubMedSearch in Google Scholar
  • 9 Parker KL, Schimmer BP. Steroidogenic factor 1: a key determinant of endocrine development and function. Endocr Rev 1997; 18 (03) 361-377
    CrossrefPubMedSearch in Google Scholar
  • 10 Schimmer BP, White PC. Minireview: steroidogenic factor 1: its roles in differentiation, development, and disease. Mol Endocrinol 2010; 24 (07) 1322-1337
    CrossrefPubMedSearch in Google Scholar
  • 11 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
    CrossrefPubMedSearch in Google Scholar
  • 12 Brandt T, Blanchard L, Desai K. et al. 46,XY disorder of sex development and developmental delay associated with a novel 9q33.3 microdeletion encompassing NR5A1. Eur J Med Genet 2013; 56 (11) 619-623
    CrossrefPubMedSearch in Google Scholar
  • 13 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
    CrossrefPubMedSearch in Google Scholar
  • 14 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
    CrossrefPubMedSearch in Google Scholar
  • 15 Ahmed SF, Khwaja O, Hughes IA. The role of a clinical score in the assessment of ambiguous genitalia. BJU Int 2000; 85 (01) 120-124
    CrossrefPubMedSearch in Google Scholar
  • 16 Chongsrisawat V, Damrongphol P, Ittiwut C, Ittiwut R, Suphapeetiporn K, Shotelersuk V. The phenotypic and mutational spectrum of Thai female patients with ornithine transcarbamylase deficiency. Gene 2018; 679: 377-381
    CrossrefPubMedSearch in Google Scholar
  • 17 Wong M, Ramayya MS, Chrousos GP, Driggers PH, Parker KL. Cloning and sequence analysis of the human gene encoding steroidogenic factor 1. J Mol Endocrinol 1996; 17 (02) 139-147
    CrossrefPubMedSearch in Google Scholar
  • 18 Little TH, Zhang Y, Matulis CK. et al. Sequence-specific deoxyribonucleic acid (DNA) recognition by steroidogenic factor 1: a helix at the carboxy terminus of the DNA binding domain is necessary for complex stability. Mol Endocrinol 2006; 20 (04) 831-843
    CrossrefPubMedSearch in Google Scholar
  • 19 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
    CrossrefPubMedSearch in Google Scholar
  • 20 Zimmermann S, Schwärzler A, Buth S, Engel W, Adham IM. Transcription of the Leydig insulin-like gene is mediated by steroidogenic factor-1. Mol Endocrinol 1998; 12 (05) 706-713
    CrossrefPubMedSearch in Google Scholar
  • 21 Parker KL, Rice DA, Lala DS. et al. Steroidogenic factor 1: an essential mediator of endocrine development. Recent Prog Horm Res 2002; 57: 19-36
    CrossrefPubMedSearch in Google Scholar
  • 22 Lin L, Achermann JC. Steroidogenic factor-1 (SF-1, Ad4BP, NR5A1) and disorders of testis development. Sex Dev 2008; 2 (4-5): 200-209
    CrossrefPubMedSearch in Google Scholar
  • 23 Anamthathmakula P, Miryala CSJ, Moreci RS. et al. Steroidogenic factor 1 (Nr5a1) is required for sertoli cell survival post sex determination. Sci Rep 2019; 9 (01) 4452
    CrossrefPubMedSearch in Google Scholar
  • 24 Zhao H, Li Z, Cooney AJ, Lan ZJ. Orphan nuclear receptor function in the ovary. Front Biosci 2007; 12 (09) 3398-3405
    CrossrefPubMedSearch in Google Scholar
  • 25 Buaas FW, Gardiner JR, Clayton S, Val P, Swain A. In vivo evidence for the crucial role of SF1 in steroid-producing cells of the testis, ovary and adrenal gland. Development 2012; 139 (24) 4561-4570
    CrossrefPubMedSearch in Google Scholar
  • 26 Tantawy S, Lin L, Akkurt I. et al. Testosterone production during puberty in two 46,XY patients with disorders of sex development and novel NR5A1 (SF-1) mutations. Eur J Endocrinol 2012; 167 (01) 125-130
    CrossrefPubMedSearch in Google Scholar
  • 27 Song Y, Fan L, Gong C. Phenotype and molecular characterizations of 30 children from China with NR5A1 mutations. Front Pharmacol 2018; 9: 1224
    CrossrefPubMedSearch in Google Scholar
  • 28 Domenice S, Machado AZ, Ferreira FM. et al. Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals. Birth Defects Res C Embryo Today 2016; 108 (04) 309-320
    CrossrefPubMedSearch in Google Scholar
  • 29 Faienza MF, Chiarito M, Baldinotti F. et al. NR5A1 gene variants: variable phenotypes, new variants, different outcomes. Sex Dev 2019; 13 (5-6): 258-263
    CrossrefPubMedSearch in Google Scholar
  • 30 Na X, Mao Y, Tang Y. et al. Identification and functional analysis of fourteen NR5A1 variants in patients with the 46 XY disorders of sex development. Gene 2020; 760: 145004
    CrossrefPubMedSearch in Google Scholar
  • 31 Warman DM, Costanzo M, Marino R. et al. Three new SF-1 (NR5A1) gene mutations in two unrelated families with multiple affected members: within-family variability in 46,XY subjects and low ovarian reserve in fertile 46,XX subjects. Horm Res Paediatr 2011; 75 (01) 70-77
    CrossrefPubMedSearch in Google Scholar
  • 32 Fabbri-Scallet H, de Sousa LM, Maciel-Guerra AT, Guerra-Júnior G, de Mello MP. Mutation update for the NR5A1 gene involved in DSD and infertility. Hum Mutat 2020; 41 (01) 58-68
    CrossrefPubMedSearch in Google Scholar
  • 33 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
    CrossrefPubMedSearch in Google Scholar
  • 34 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
    CrossrefPubMedSearch in Google Scholar
  • 35 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
    CrossrefPubMedSearch in Google Scholar
  • 36 Achermann JC, Ozisik G, Ito M. et al. Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner. J Clin Endocrinol Metab 2002; 87 (04) 1829-1833
    CrossrefPubMedSearch in Google Scholar
  • 37 Coutant R, Mallet D, Lahlou N. et al. Heterozygous mutation of steroidogenic factor-1 in 46,XY subjects may mimic partial androgen insensitivity syndrome. J Clin Endocrinol Metab 2007; 92 (08) 2868-2873
    CrossrefPubMedSearch in Google Scholar
  • 38 Wu JY, McGown IN, Lin L. et al. A novel NR5A1 variant in an infant with elevated testosterone from an Australasian cohort of 46,XY patients with disorders of sex development. Clin Endocrinol (Oxf) 2013; 78 (04) 545-550
    CrossrefPubMedSearch in Google Scholar
  • 39 Ciaccio M, Costanzo M, Guercio G. et al. Preserved fertility in a patient with a 46,XY disorder of sex development due to a new heterozygous mutation in the NR5A1/SF-1 gene: evidence of 46,XY and 46,XX gonadal dysgenesis phenotype variability in multiple members of an affected kindred. Horm Res Paediatr 2012; 78 (02) 119-126
    CrossrefPubMedSearch in Google Scholar