Ann Pediatr Endocrinol Metab.  2014 Jun;19(2):108-112. 10.6065/apem.2014.19.2.108.

A Korean boy with 46,XX testicular disorder of sex development caused by SOX9 duplication

• Lee GM
• Ko JM
• Shin CH
• Yang SW

• KMID: 1803864
• DOI: http://doi.org/10.6065/apem.2014.19.2.108

Abstract

The 46,XX testicular disorder of sex development (DSD), also known as 46,XX male syndrome, is a rare form of DSD and clinical phenotype shows complete sex reversal from female to male. The sex-determining region Y (SRY) gene can be identified in most 46,XX testicular DSD patients; however, approximately 20% of patients with 46,XX testicular DSD are SRY-negative. The SRY-box 9 (SOX9) gene has several important functions during testis development and differentiation in males, and overexpression of SOX9 leads to the male development of 46,XX gonads in the absence of SRY. In addition, SOX9 duplication has been found to be a rare cause of 46,XX testicular DSD in humans. Here, we report a 4.2-year-old SRY-negative 46,XX boy with complete sex reversal caused by SOX9 duplication for the first time in Korea. He showed normal external and internal male genitalia except for small testes. Fluorescence in situ hybridization and polymerase chain reaction (PCR) analyses failed to detect the presence of SRY, and SOX9 intragenic mutation was not identified by direct sequencing analysis. Therefore, we performed real-time PCR analyses with specific primer pairs, and duplication of the SOX9 gene was revealed. Although SRY-negative 46,XX testicular DSD is a rare condition, an effort to make an accurate diagnosis is important for the provision of proper genetic counseling and for guiding patients in their long-term management.

Keyword

XX male syndrome; Sex determining region Y-box 9; Sex-determining region gene on Y; Disorders of sex development

MeSH Terms

46, XX Testicular Disorders of Sex Development
Diagnosis
Disorders of Sex Development
Female
Fluorescence
Genes, sry
Genetic Counseling
Genitalia, Male
Gonads
Humans
In Situ Hybridization
Korea
Male
Phenotype
Polymerase Chain Reaction
Real-Time Polymerase Chain Reaction
Sexual Development*
Testis

Figure

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  Fig. 1 (A) The genitalia photograph of the patient was taken at 4.2 years of age. His external genitalia show complete male phenotypes without ambiguity. (B) Normal internal genital organs are visible, and there is no evidence of female genital organs on the T2-weighted magnetic resonance image.

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  Fig. 2 Results of real-time polymerase chain reaction analysis using two sets of specific primer pairs (A, proximal primer pair; B, distal primer pair) show the increased copy number of SOX9 in the patient (approximately 1.5 times) compared with a control male. RQ, relative quantification.

Reference

1. Boucekkine C, Toublanc JE, Abbas N, Chaabouni S, Ouahid S, Semrouni M, et al. Clinical and anatomical spectrum in XX sex reversed patients: relationship to the presence of Y specific DNA-sequences. Clin Endocrinol (Oxf). 1994; 40:733–742. PMID: 8033363.

2. Zenteno JC, Lopez M, Vera C, Mendez JP, Kofman-Alfaro S. Two SRY-negative XX male brothers without genital ambiguity. Hum Genet. 1997; 100:606–610. PMID: 9341880.

3. Ono M, Harley VR. Disorders of sex development: new genes, new concepts. Nat Rev Endocrinol. 2013; 9:79–91. PMID: 23296159.

4. Huang B, Wang S, Ning Y, Lamb AN, Bartley J. Autosomal XX sex reversal caused by duplication of SOX9. Am J Med Genet. 1999; 87:349–353. PMID: 10588843.

5. Cox JJ, Willatt L, Homfray T, Woods CG. A SOX9 duplication and familial 46,XX developmental testicular disorder. N Engl J Med. 2011; 364:91–93. PMID: 21208124.

6. Vetro A, Ciccone R, Giorda R, Patricelli MG, Della Mina E, Forlino A, et al. XX males SRY negative: a confirmed cause of infertility. J Med Genet. 2011; 48:710–712. PMID: 21653197.

7. Benko S, Gordon CT, Mallet D, Sreenivasan R, Thauvin-Robinet C, Brendehaug A, et al. Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development. J Med Genet. 2011; 48:825–830. PMID: 22051515.

8. Seeherunvong T, Ukarapong S, McElreavey K, Berkovitz GD, Perera EM. Duplication of SOX9 is not a common cause of 46,XX testicular or 46,XX ovotesticular DSD. J Pediatr Endocrinol Metab. 2012; 25:121–123. PMID: 22570960.

9. Lee JW, Hong CH, Kim HR, Sin JB. A case of SRY negative 46, XX male syndrome with deletion on long arm of X chromosome. Korean J Perinatol. 2006; 17:353–358.

10. Moalem S, Babul-Hirji R, Stavropolous DJ, Wherrett D, Bagli DJ, Thomas P, et al. XX male sex reversal with genital abnormalities associated with a de novo SOX3 gene duplication. Am J Med Genet A. 2012; 158A:1759–1764. PMID: 22678921.

11. De la chapelle A, Hortling H, Niemi M, Wennstroem J. XX chromosomes in a human male. First case. Acta Med Scand. 1964; 175(Suppl 412):25–28. PMID: 14154995.

12. 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. International Consensus Conference on Intersex. Pediatrics. 2006; 118:e488–e500. PMID: 16882788.

13. de la Chapelle A. Analytic review: nature and origin of males with XX sex chromosomes. Am J Hum Genet. 1972; 24:71–105. PMID: 4622299.

14. De Santa Barbara P, Bonneaud N, Boizet B, Desclozeaux M, Moniot B, Sudbeck P, et al. Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Mullerian hormone gene. Mol Cell Biol. 1998; 18:6653–6665. PMID: 9774680.

15. Ergun-Longmire B, Vinci G, Alonso L, Matthew S, Tansil S, Lin-Su K, et al. Clinical, hormonal and cytogenetic evaluation of 46,XX males and review of the literature. J Pediatr Endocrinol Metab. 2005; 18:739–748. PMID: 16200839.

16. Maciel-Guerra AT, de Mello MP, Coeli FB, Ribeiro ML, Miranda ML, Marques-de-Faria AP, et al. XX Maleness and XX true hermaphroditism in SRY-negative monozygotic twins: additional evidence for a common origin. J Clin Endocrinol Metab. 2008; 93:339–343. PMID: 18056774.

17. de la Chapelle A, Hastbacka J, Korhonen T, Maenpaa J. The etiology of XX sex reversal. Reprod Nutr Dev. 1990; (Suppl 1):39s–49s. PMID: 1976312.

18. Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, Smith MJ, et al. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature. 1990; 346:240–244. PMID: 1695712.

19. McElreavey K, Vilain E, Abbas N, Herskowitz I, Fellous M. A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development. Proc Natl Acad Sci U S A. 1993; 90:3368–3372. PMID: 8475082.

20. Wagner T, Wirth J, Meyer J, Zabel B, Held M, Zimmer J, et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell. 1994; 79:1111–1120. PMID: 8001137.