Poster Presentation ESA-SRB Conference 2015

A case of primary amenorrhoea and hyperandrogenism (#230)

Michelle Isaacs 1 , Sonia Stanton 1
  1. Endocrinology, The Canberra Hospital, Canberra, ACT, Australia

We report the case of a 42 year old female with Müllerian agenesis and hyperandrogenism, with a possible unifying diagnosis of a WNT4 gene mutation. The patient presented with primary amenorrhoea aged 15. She had characteristic features of Müllerian agenesis: normal secondary sex characteristics, female external genitalia, a vaginal introitus but no true vagina, absent uterus on imaging and at laparoscopy, and a single right kidney.  Karyotype was 46XX. There was no definite ovary located initially, though imaging later revealed a 22mm soft tissue mass in the region of the vaginal vault which remained stable in size over subsequent decades. This was presumed to be ovarian tissue as the patient had pre-menopausal range oestradiol and biochemical evidence of ovulation.  She received no further medical care until age 28, when she was noted to have hirsutism and acne. There was mild biochemical hyperandrogenism but 17-hydroxy-progesterone level was normal. She was overweight and insulin resistant, so was diagnosed with probable polycystic ovarian syndrome despite not fulfilling Rotterdam criteria (1). However, we suggest a WNT4 mutation as an alternative diagnosis that could explain the coexistence of Müllerian agenesis and hyperandrogenism in our patient. WNT4 expression is essential for Müllerian duct formation (2). WNT4 knockout female mice have absent Müllerian ducts but Wolffian ducts are present. Their gonads express 3β-hydroxysteroid dehydrogenase and 17α-hydroxylase, which are required for the production of testosterone and are normally suppressed in the ovary (2). Both male and female WNT4 knockout mice have defects in renal development and adrenal function (2). There are four reported cases of human females with Müllerian agenesis and hyperandrogenism due to heterozygous mutations in the WNT4 gene (3-6). However, WNT4 mutations are not the cause for most cases of Müllerian agenesis without hyperandrogenism (5, 7, 8). We are pursuing WNT4 genetic testing in this patient.

  1. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Human reproduction (Oxford, England). 2004;19(1):41-7.
  2. Vainio S, Heikkila M, Kispert A, Chin N, McMahon AP. Female development in mammals is regulated by Wnt-4 signalling. Nature. 1999;397(6718):405-9.
  3. Biason-Lauber A, Konrad D, Navratil F, Schoenle EJ. A WNT4 mutation associated with Mullerian-duct regression and virilization in a 46,XX woman. The New England journal of medicine. 2004;351(8):792-8.
  4. Biason-Lauber A, De Filippo G, Konrad D, Scarano G, Nazzaro A, Schoenle EJ. WNT4 deficiency--a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report. Human reproduction (Oxford, England). 2007;22(1):224-9.
  5. Philibert P, Biason-Lauber A, Rouzier R, Pienkowski C, Paris F, Konrad D, et al. Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and mullerian duct abnormalities: a French collaborative study. The Journal of clinical endocrinology and metabolism. 2008;93(3):895-900.
  6. Philibert P, Biason-Lauber A, Gueorguieva I, Stuckens C, Pienkowski C, Lebon-Labich B, et al. Molecular analysis of WNT4 gene in four adolescent girls with mullerian duct abnormality and hyperandrogenism (atypical Mayer-Rokitansky-Kuster-Hauser syndrome). Fertility and sterility. 2011;95(8):2683-6.
  7. Chang X, Qin Y, Xu C, Li G, Zhao X, Chen ZJ. Mutations in WNT4 are not responsible for Mullerian duct abnormalities in Chinese women. Reproductive biomedicine online. 2012;24(6):630-3.
  8. Clement-Ziza M, Khen N, Gonzales J, Cretolle-Vastel C, Picard JY, Tullio-Pelet A, et al. Exclusion of WNT4 as a major gene in Rokitansky-Kuster-Hauser anomaly. American journal of medical genetics Part A. 2005;137(1):98-9.