17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a rare autosomal recessive disorder caused by variants in the CYP17A1 gene, accounting for approximately 1% of congenital adrenal hyperplasia (CAH) cases (1, 2). The enzyme plays a pivotal role in steroidogenesis by catalyzing two reactions: 17α-hydroxylase activity which is essential for cortisol production, and 17,20-lyase activity for generating sex hormone precursors (dehydroepiandrosterone and androstenedione). Consequently, the deficiency leads to a characteristic clinical trial: (1) hypocortisolemia (84.5%) due to impaired cortisol synthesis, (2) hypergonadotropic hypogonadism with disordered sexual development (59.5%) from sex steroid deficiency, and (3) hypertension (57%) with hypokalemia (45.4%) resulting from mineralocorticoid excess (3).

Clinically, 17-OHD manifests as a spectrum of disease severity, which is classified into complete and partial forms based on residual enzymatic activity (1). While the classic manifestations are well-recognized, emerging evidence reveals that there are some atypical features of the 17-OHD, including short stature due to the absence of a pubertal growth spurt during adolescence (4), the development of testicular tumors (5), and malignant mixed germ cell tumors (6). This phenotypic variability often leads to diagnostic delays or misdiagnosis, emphasizing the need for clinicians to recognize the broad clinical spectrum of 17-OHD.

To date, adrenal hyperplasia and ovarian cysts remain the most documented imaging findings in 17-OHD (7, 8). While breast underdevelopment is widely reported, 64.2% of patients exhibit some degree of breast development, and only 4.3% demonstrate near-complete to complete development (3). In this study, we describe bilateral breast nodules as an unusual manifestation in a patient with 17-OHD, which showed near-complete resolution following hormonal therapy. Additionally, we conducted a systematic review of previously reported 17-OHD cases presenting with nearly complete breast development. These findings underscore the importance of considering steroidogenic disorders in the differential diagnosis of breast pathology, potentially preventing unnecessary surgical interventions through early endocrine evaluation.

The clinical manifestations of 17-OHD demonstrate significant heterogeneity, depending on varying degrees of residual enzymatic function associated with different sequencing variants. While breast underdevelopment has been well-documented in classical cases, we report for the first time a partial 17-OHD case presenting primarily with breast nodules and ductal ectasia. Notably, these mammary manifestations showed marked improvement following hormonal therapy, suggesting that appropriate diagnosis and endocrine management may prevent unnecessary surgical interventions in such patients.

As a rare subtype of CAH which have the prevalence of 1:14,000 to 1:18,000 in most populations (10, 11), 17-OHD demonstrates significant clinical heterogeneity due to varying degrees of residual enzymatic activity. Only 15–20% of these patients present with the classic triad of hypertension, hypokalemia, and disordered sexual development (12), making the diagnosis particularly challenging, especially in individuals with partial forms. Although breast underdevelopment is widely recognized as a typical feature of 17-OHD, previous reports indicate that approximately 6% (n = 445) of patients achieve advanced breast development, corresponding to Tanner stage 4-5 (3). The presence of breast development may lead to delayed diagnosis or misdiagnosis of 17-OHD. For instance, a 19-year-old patient with 46,XY, raised as a girl, was initially misdiagnosed with complete androgen insensitivity syndrome due to the presence of spontaneous Tanner stage 5 breast development (13), underscoring how atypical breast phenotypes can obscure the underlying diagnosis of 17-OHD.

In our analysis of the subset of the 17-OHD with advanced breast development, 69% were found to have a 46,XX karyotype, while 28.6% were 46,XY including four phenotypic males. Furthermore, we identified a rare case with mosaicism (47,XXX[3]/46,XX[47]) (14). These findings suggest that although estrogen deficiency is a typical feature of 17-OHD, a subset of patients may still attain near-complete secondary sexual development, regardless of chromosomal sex. Notably, the average diagnosis age of these patients was 26.9 years, with three individuals older than 50 years (14–16). Additionally, patients with 46,XX were diagnosed at a significantly older age than those with 46,XY. Individuals with 46,XY possibly present earlier due to more conspicuous phenotypes such as female external genitalia with absent secondary sexual development or primary amenorrhea, prompting earlier endocrine evaluation. In contrast, patients with 46,XX may exhibit milder or less specific symptoms such as menstrual irregularities or infertility, leading to delayed diagnosis (3). This age discrepancy likely reflects differences in the timing of clinical presentation and diagnosis between the two karyotype groups.

CYP17A1 is primarily expressed in the adrenal cortex and gonads, but not in breast tissue, indicating that the breast development in patients with 17-OHD is secondary to the systemic hormonal changes (17). To better characterize the hormonal profiles of these patients, we analyzed available endocrine data and found that the majority (over 80%) exhibited low levels of androgens including testosterone, DHEAS and androstenedione, alongside elevated progesterone levels (85.3%). Estradiol levels were generally low to within the normal range, with 53.1% of these cases falling into normal range. Interestingly, although androgens are known precursors for estrogen biosynthesis, estradiol levels were within the normal range despite markedly reduced androgen levels. This observation suggests the existence of alternative or compensatory pathways for estrogen synthesis (18). It is possible that small amounts of androgen precursors such as DHEA or androstenedione are sufficient for downstream conversion, potentially facilitated by increased efficiency of local aromatase activity (19). Aromatase (cytochrome P450 19A1), the enzyme capable of converting C19 steroids into estrogens, is widely expressed in extragonadal tissues, including adipose tissue and brain (20). In fact, in prepubertal girls and postmenopausal women, extragonadal sites are the main sources of estrogens (21).

Estrogens play a central role in breast development (22) and also contribute to pubertal gynecomastia (20). However, estradiol level alone may not fully explain the degree of breast development observed, as some patients with 17-OHD with breast development still exhibited lower level of estradiol. It is also important to consider that “normal” estradiol levels may vary depending on institutional reference ranges. Furthermore, breast development is a complex, multi-hormonal process involving not only estrogens, but also growth hormone, insulin-like growth factor 1, and other regulators (22, 23), which warrant further investigation in the context of 17-OHD.

Interestingly, in our case, beyond the presence of developed breasts, the patient also presented with bilateral breast nodules and mammary duct ectasia, which showed significant clinical improvement after the hormonal therapy of 17-OHD. The development of these breast features likely results from a complex interplay of hormonal imbalances due to CYP17A1 deficiency. Among the contributing factors, elevated progesterone is of particular interest, which was significantly decreased following hormonal therapy. Progesterone has been widely implicated in promoting breast cancer cell proliferation through multiple mechanisms, including activation of estrogen receptors, progesterone receptors, and G protein-coupled receptors such as GPR126 (24–26). The progesterone/RANKL signaling axis is recognized as a major regulator of breast epithelial proliferation (27), and progesterone antagonists can effectively inhibit progesterone-driven proliferation in mammary epithelial cells (25, 28). Supporting this association, a previous study identified a protein-truncating variant in CYP17A1 in three sisters with early-onset breast cancer (29). Collectively, these findings underscore the importance of careful breast evaluation in patients with 17-OHD, not only for assessing secondary sexual development but also for the early detection of potential malignancies.

The vast majority of patients exhibiting breast development carried at least one non-null variant, strongly suggesting that partially retained 17,20-lyase activity is the key molecular driver for estrogen synthesis and subsequent initiation of puberty. Furthermore, variants were predominantly located in exons 5–8, with exon 8 being a particular hotspot. This region encodes the core catalytic domain of the enzyme, including the substrate-binding pocket and the crucial heme-binding region (8). This finding is consistent with previous studies which have identified sequencing variants in exons 6 and 8 as the prevalent variants in patients with 17-OHD (30). Moreover, missense variants like p.Arg347Cys and p.Arg449Cys, identified in this region, have been functionally characterized in previous studies (31). These sequencing variants severely impair but do not completely eliminate enzymatic activity (e.g., p.Arg347Cys retains 13.6% of 17α-hydroxylase activity (32)), which perfectly explains how they allow for partial sex hormone synthesis and lead to an incomplete clinical phenotype. In our case, the variants c.1459_1467del and c.1226C>G, located in exon 8 and exon 7 respectively, have both been documented as pathogenic (33). The in-frame deletion c.1459_1467del removes three amino acids (p.Asp487_Phe489del) and represents a common pathogenic variant in 17-OHD (4/52 alleles in a cohort of 26 patients), particularly in complete combined 17-OHD (33). Similarly, the c.1226C>G (p.Pro409Arg) variant has also been described in multiple cases (34, 35). In patients homozygous for c.1226C>G, phenotype severity varies by karyotype, with 46,XX showing milder manifestations, whereas a 46,XY case presented with a more severe phenotype (33, 34, 36).

Additionally, the low aldosterone in our case was confirmed through repeated testing at an independent third-party laboratory and a significantly elevated corticosterone level of 474.10 nmol/L (reference range: 1.53–45.08 nmol/L) was detected. As previously reported, the absence of 17-hydroxylase activity shunts steroidogenesis toward corticosterone instead of cortisol via 11-deoxycorticosterone, which is typically a minor adrenal product in humans but highly in rodent (1, 37). Consequently, the lack of cortisol synthesis in 17-OHD does not lead to true glucocorticoid deficiency because corticosterone excess compensates for glucocorticoid activity. Crucially, this excess 11-deoxycorticosterone and corticosterone strongly suppresses the renin–angiotensin–aldosterone system, resulting in the characteristic low-renin hypertension and profoundly suppressed aldosterone synthesis (38). Thus, the biochemical profile of our patient—low aldosterone, elevated corticosterone, hypertension, and hypokalemia—aligns closely with the established pathophysiology of 17-OHD.

Due to its rarity and diverse clinical manifestations, 17-OHD is frequently overlooked or misdiagnosed in clinical practice. This study broadens the recognized phenotypic and hormonal spectrum of 17-OHD with advanced breast development, combined with low androgen levels, elevated progestogens, and hypergonadotropic hypogonadism, may serve as important diagnostic clues. Bilateral breast nodules and mammary duct ectasia may represent overlooked manifestations in patients with atypical breast development. Our findings emphasize the importance of increased clinical vigilance for these features, which may help avoid unnecessary surgical interventions and reduce the risk of delayed diagnosis or long-term oncologic complications.