Puberty in a case with novel 17-hydroxylase mutation and the putative role of estrogen in development of pubic hair

Abstract

Objective: 17-Hydroxylase/17,20-lyase deficiency (17OHD) results from mutations in the CYP17A1 gene, leading to failure to synthesize cortisol, adrenal androgens, and gonadal steroids. Adrenarche is a consequence of the increased production of adrenal androgens. Here, we report a case carrying novel R239Q mutation causing complete functional loss of CYP17A1, and thus absence of adrenal and gonadal sex hormone production. The patient has had unexpected pubic hair development and insufficient breast development with estrogen replacement therapy. Possible mechanisms leading to pubic hair development and breast underdevelopment are discussed. Patient and methods: A 15-year-old female born to consanguineous parents presented with the lack of full breast development and irregular menses after the age of 14 years. She had Tanner III breast development on one side, Tanner I on the other side and Tanner I pubic hair and, no axillary hair development. The serum levels of FSH, LH, and progesterone were high and, estradiol was low. The measurement of basal and ACTH-stimulated steroids was consistent with the diagnosis of 17OHD. Genetic analysis revealed novel homozygous mutation R239Q in CYP17A1 gene. Therapy with hydrocortisone was initiated and followed by the addition of conjugated estrogen. Her breast development did not improve considerably, however, pubic hair development started after estrogen treatment in spite of undetectable serum levels of androgens. Conclusion: This case study suggests that estrogen exerts a permissive effect on pubic hair development in girls, even in the presence of very low-circulating androgens, and impaired breast development might be due to estrogen/progesterone imbalance in breast tissue.

Rare Missense P450c17 <b><i>(CYP17A1)</i></b> Mutation in Exon 1 as a Cause of 46,XY Disorder of Sexual Development: Implications of Breast Tissue ‘Unresponsiveness' despite Adequate Estradiol Substitution

“…The underlying cause of the breast tissue unresponsiveness to estradiol treatment remains unknown. Similar though not identical observations have been made in a naïve female 46,XX patient with 17OHD which presented with a lack of full breast development [Turan et al, 2009]. Turan et al [2009] speculated that the disparity of progesterone and estradiol expression at the age of pubertal development leads to impaired responsiveness in terms of breast tissue evolution.…”

“…Similar though not identical observations have been made in a naïve female 46,XX patient with 17OHD which presented with a lack of full breast development [Turan et al, 2009]. Turan et al [2009] speculated that the disparity of progesterone and estradiol expression at the age of pubertal development leads to impaired responsiveness in terms of breast tissue evolution. However, in contrast to our observations, breast development could be at least partially achieved up to Tanner stage III after initiation of treatment with estradiol in the 46,XX patient.…”

“…Additionally, it has been proposed that 46,XY individuals with 17OHD have more pronounced clinical symptoms than their 46,XX siblings with the same mutation and, among others, lack of breast development [Bee et al, 2012]. The spectrum of stages of breast development but also responses to estradiol treatment in this group of patients seems to be relatively wide [Turan et al, 2009]. In the female 46,XX patient with the identical CYP17A1 mutation, breast development neither at baseline nor after treatment follow-up has been documented [Brooke et al, 2006], and no conclusion about the association between this mutation and breast development can be drawn.…”

“…Consequently, plasma renin activity is suppressed and aldosterone is either suppressed or only slightly elevated [Turan et al, 2009].…”

A unique exonic splicing mutation in the CYP17A1 gene as the cause for steroid 17α-hydroxylase deficiency

“…Normal even elevated levels of aldosterone have long been a controversial phenomenon. Various assay methods, dietary sodium intake, and differing severity of the enzymatic defect further complicate the problem (1,22,23). However, Dhir et al (22) have pointed out that the degree of hypertension seems to be more closely related to the time span without treatment than to the CYP17A1 genotype.…”