Ann Pediatr Endocrinol Metab.  2018 Dec;23(4):220-225. 10.6065/apem.2018.23.4.220.

Two Korean girls with complete androgen insensitivity syndrome diagnosed in infancy

• Heo YJ
• Ko JM
• Lee YA
• Shin CH
• Yang SW
• Kim MJ
• Park SS

• KMID: 2432277
• DOI: http://doi.org/10.6065/apem.2018.23.4.220

Abstract

Androgen insensitivity syndrome (AIS) is a rare genetic disease caused by various abnormalities in the androgen receptor (AR). The AR is an essential steroid hormone receptor that plays a critical role in male sexual differentiation and development and preservation of the male phenotype. Mutations in the AR gene on the X chromosome cause malfunction of the AR so that a 46,XY karyotype male has some physical characteristics of a woman or a full female phenotype. Depending on the phenotype, AIS can be classified as complete, partial or mild. Here, we report 2 cases of complete AIS in young children who showed complete sex reversal from male to female as a result of AR mutations. They had palpable inguinal masses and normal female external genitalia, a blind-end vagina and absent Müllerian duct derivatives. They were both 46,XY karyotype and AR gene analysis demonstrated pathologic mutations in both. Because AIS is inherited in an X-linked recessive manner, we performed genetic analysis of the female family members of each patient and found the same mutation in the mothers of both patients and in the female sibling of case 2. Gonadectomy was performed in both patients to avoid the risk of malignancy in the undescended testicles, and estrogen replacement therapy is planned for their adolescence. Individuals with complete AIS are usually raised as females and need appropriate care.

Keyword

Androgen-insensitivity syndrome; Androgen receptors; Disorders of sexual development

MeSH Terms

Adolescent
Androgen-Insensitivity Syndrome*
Child
Disorders of Sex Development
Estrogen Replacement Therapy
Female*
Genitalia
Humans
Karyotype
Male
Mothers
Phenotype
Receptors, Androgen
Sex Differentiation
Siblings
Testis
Vagina
X Chromosome
Receptors, Androgen

Figure

• 

  Fig. 1. (A) No fistula was visualized when contrast was injected into the common urethra, and a short blind-ended vaginal pouch (arrow) was found on genitography. (B) Pelvis sonography revealed both testes. (C) Both testes were subsequently dissected and removed.

• 

  Fig. 2. Pedigrees showed that both the complete androgen insensitivity syndrome patients had pathologic AR mutations, p.R775H for case 1 and p.Y572C for case 2. The mutations are inherited from their mothers, who each carried the mutation heterozygously. Both arrows indicate patients in cases 1 and 2.

• 

  Fig. 3. Histopathological analysis of the gonadectomy specimens revealed immature testis and epididymis with indistinct lumina and maturation arrest of germ cells in 2 cases (A, case 1; B, case 2; A, B, H&E staining, X400). These findings are consistent with androgen insensitivity syndrome.

Reference

References

1. Hughes IA, Davies JD, Bunch TI, Pasterski V, Mastroyannopoulou K, MacDougall J. Androgen insensitivity syndrome. Lancet. 2012; 380:1419–28.

2. Hughes IA, Deeb A. Androgen resistance. Best Pract Res Clin Endocrinol Metab. 2006; 20:577–98.

3. Brinkmann AO. Molecular basis of androgen insensitivity. Mol Cell Endocrinol. 2001; 179:105–9.

4. 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:e488–500.

5. Boehmer AL, Brinkmann O, Brüggenwirth H, van Assendelft C, Otten BJ, Verleun-Mooijman MC, et al. Genotype versus phenotype in families with androgen insensitivity syndrome. J Clin Endocrinol Metab. 2001; 86:4151–60.

6. Nielsen DF, Bülow S. The incidence of male hermaphroditism in girls with inguinal hernia. Surg Gynecol Obstet. 1976; 142:875–6.

7. Morris JM. The syndrome of testicular feminization in male pseudohermaphrodites. Am J Obstet Gynecol. 1953; 65:1192–211.

8. Speroff L, Fritz MA. Clinical gynecologic endocrinology and infertility. 7th ed. Philadelphia (PA): Lippincott Williams & Wilkins;2005. p. 1334.

9. McEwan IJ. Molecular mechanisms of androgen receptor-mediated gene regulation: structure-function analysis of the AF-1 domain. Endocr Relat Cancer. 2004; 11:281–93.

10. Petroli RJ, Maciel-Guerra AT, Soardi FC, de Calais FL, Guerra-Junior G, de Mello MP. Severe forms of partial androgen insensitivity syndrome due to p.L830F novel mutation in androgen receptor gene in a Brazilian family. BMC Res Notes. 2011; 4:173.

11. Tadokoro-Cuccaro R, Hughes IA. Androgen insensitivity syndrome. Curr Opin Endocrinol Diabetes Obes. 2014; 21:499–503.

12. Batch JA, Williams DM, Davies HR, Brown BD, Evans BA, Hughes IA, et al. Androgen receptor gene mutations identified by SSCP in fourteen subjects with androgen insensitivity syndrome. Hum Mol Genet. 1992; 1:497–503.

13. Komori S, Kasumi H, Sakata K, Tanaka H, Hamada K, Koyama K. Molecular analysis of the androgen receptor gene in 4 patients with complete androgen insensitivity. Arch Gynecol Obstet. 1998; 261:95–100.

14. Souhail R, Amine S, Nadia A, Tarik K, Khalid EK, Abdellatif K, et al. Complete androgen insensitivity syndrome or testicular feminization: review of literature based on a case report. Pan Afr Med J. 2016; 25:199.

15. Hughes IA, Acerini CL. Factors controlling testis descent. Eur J Endocrinol. 2008; 159 Suppl 1:S75–82.

16. Mongan NP, Tadokoro-Cuccaro R, Bunch T, Hughes IA. Androgen insensitivity syndrome. Best Pract Res Clin Endocrinol Metab. 2015; 29:569–80.

17. Bouvattier C, Carel JC, Lecointre C, David A, Sultan C, Bertrand AM, et al. Postnatal changes of T, LH, and FSH in 46,XY infants with mutations in the AR gene. J Clin Endocrinol Metab. 2002; 87:29–32.

18. Ahmed SF, Cheng A, Hughes IA. Assessment of the gonadotrophin-gonadal axis in androgen insensitivity syndrome. Arch Dis Child. 1999; 80:324–9.

19. Melo KF, Mendonca BB, Billerbeck AE, Costa EM, Inácio M, Silva FA, et al. Clinical, hormonal, behavioral, and genetic characteristics of androgen insensitivity syndrome in a Brazilian cohort: five novel mutations in the androgen receptor gene. J Clin Endocrinol Metab. 2003; 88:3241–50.

20. Looijenga LH, Hersmus R, Oosterhuis JW, Cools M, Drop SL, Wolffenbuttel KP. Tumor risk in disorders of sex development (DSD). Best Pract Res Clin Endocrinol Metab. 2007; 21:480–95.