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

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

Publikationsverlauf

Eingereicht: 06. Juli 2022

Angenommen: 13. Februar 2023

Artikel online veröffentlicht:
20. März 2023

• 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
• 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
• 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
• 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
• 5 Délot EC, Vilain E. Towards improved genetic diagnosis of human differences of sex development. Nat Rev Genet 2021; 22 (09) 588-602
• 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
• 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
• 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
• 9 Parker KL, Schimmer BP. Steroidogenic factor 1: a key determinant of endocrine development and function. Endocr Rev 1997; 18 (03) 361-377
• 10 Schimmer BP, White PC. Minireview: steroidogenic factor 1: its roles in differentiation, development, and disease. Mol Endocrinol 2010; 24 (07) 1322-1337
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 24 Zhao H, Li Z, Cooney AJ, Lan ZJ. Orphan nuclear receptor function in the ovary. Front Biosci 2007; 12 (09) 3398-3405
• 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
• 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
• 27 Song Y, Fan L, Gong C. Phenotype and molecular characterizations of 30 children from China with NR5A1 mutations. Front Pharmacol 2018; 9: 1224
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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