Incidental discovery of neglected 11β-hydroxylase deficiency causing 46,XX disorder of sex development in a 35-year-old adult: A radiologically driven diagnosis

A 35-year-old individual, registered and raised male at birth, married since 2018, previously seeking evaluation for 8 years of primary infertility, presented to a general practitioner with a 1-month history of abdominal pain. He had a known history of hypertension since age 25, managed with amlodipine 10 mg/d with suboptimal control, and reported chronic pelvic pain, decreased libido, and erectile dysfunction. Family history was notable for the neonatal death of a sister at 1 month of age from an undetermined cause. Abdominal contrast-enhanced CT (arterial and portal venous phases) then a dedicated MRI (1.5 T) using T2, T1 DIXON, performed to eliminate a secondary cause of revealed bilateral retroperitoneal masses, each dominated by a macroscopic fat component (attenuation −60 HU on CT) that appeared markedly hyperintense on T2-weighted sequences. On in-phase and out-of-phase T1-weighted imaging (chemical-shift technique), the lesions showed a substantial signal drop on the out-of-phase sequence, confirming the presence of fat within the masses, while fat-saturated T1-weighted images acquired after intravenous gadolinium injection suppressed the background fat signal and unmasked a solid, peripherally enhancing component, without hemorrhage, necrosis, or an infiltrative margin ( Fig. 1 , Fig. 2 ). A visible rim of residual adrenal parenchyma shouldered the periphery of each mass (Claw Sign) identified them as adrenal in origin. This feature, along with their bilaterality, the well circumscribed solid enhancing component, the absence of heterogenicity, hemorrhage or necrosis, allowed these retroperitoneal masses to be characterized as bilateral adrenal myelolipomas, rather than liposarcomas or any other retroperitoneal macroscopic fat-containing lesion, on a background of macronodular bilateral adrenal hyperplasia. The right adrenal gland was barely visible, and the largest right lesion measured 15 cm in diameter. The left adrenal gland was diffusely enlarged with multiple similar lesions, the largest measuring 10.5 cm. This combination, bilateral myelolipomas arising on a background of macronodular adrenal hyperplasia, is a well-documented radiological pattern in CAH, reflecting chronic ACTH hyperstimulation of the adrenal cortex, and its presence in a young patient is considered highly suggestive of an underlying enzymatic defect, which supported our diagnosis [ 3 , 4 ]. Fig. 1 Axial contrast-enhanced computed tomography in the portal venous phase (A) and coronal reconstruction (B) demonstrating multiple bilateral adrenal masses consistent with myelolipomas. The lesions are voluminous, well-delineated, and heterogeneous, exhibiting a dominant macroscopic fatty component with attenuation values measured at −60 Hounsfield units (HU), admixed with a solid peripherally non enhancing soft-tissue component (Yellow arrows). The left adrenal gland is markedly hypertrophied with a multinodular architecture, reflecting the underlying macronodular adrenal hyperplasia (Blue arrow). Fig 1 dummy alt text Fig. 2 Adrenal MRI confirming bilateral myelolipomas on a background of macronodular adrenal hyperplasia. Axial (A) and coronal T2 (B) sequences show voluminous, well-delineated bilateral adrenal masses (blue arrows) with heterogeneous signal and a dominant hyperintense fatty component. In-phase T1 (C) demonstrates high signal intensity within the lesions; out-of-phase T1 (chemical-shift imaging) (D) confirms signal loss consistent with macroscopic fat. Fat-saturated T1-weighted postgadolinium images (E and F) show focal enhancing components related to myeloid content (red arrows), in addition to diffuse nodular enhancement of the hypertrophied left adrenal gland (yellow arrow), reflecting the underlying macronodular hyperplasia. Fig 2 dummy alt text Axial contrast-enhanced computed tomography in the portal venous phase (A) and coronal reconstruction (B) demonstrating multiple bilateral adrenal masses consistent with myelolipomas. The lesions are voluminous, well-delineated, and heterogeneous, exhibiting a dominant macroscopic fatty component with attenuation values measured at −60 Hounsfield units (HU), admixed with a solid peripherally non enhancing soft-tissue component (Yellow arrows). The left adrenal gland is markedly hypertrophied with a multinodular architecture, reflecting the underlying macronodular adrenal hyperplasia (Blue arrow). Adrenal MRI confirming bilateral myelolipomas on a background of macronodular adrenal hyperplasia. Axial (A) and coronal T2 (B) sequences show voluminous, well-delineated bilateral adrenal masses (blue arrows) with heterogeneous signal and a dominant hyperintense fatty component. In-phase T1 (C) demonstrates high signal intensity within the lesions; out-of-phase T1 (chemical-shift imaging) (D) confirms signal loss consistent with macroscopic fat. Fat-saturated T1-weighted postgadolinium images (E and F) show focal enhancing components related to myeloid content (red arrows), in addition to diffuse nodular enhancement of the hypertrophied left adrenal gland (yellow arrow), reflecting the underlying macronodular hyperplasia. Pelvic acquired images demonstrated a retro vesical structure resembling a uterus, confirmed on complementary ultrasound—a finding entirely unknown to the patient, whose gender assignment and upbringing since birth had left him with no prior awareness of a chromosomal or anatomical anomaly, which prompted a complementary pelvic MRI. A dedicated pelvic MRI (1.5 T; T2-weighted sequences in 3 orthogonal planes, axial DWI with ADC mapping, and postcontrast fat-saturated T1-weighted sequences) confirmed an inter-vesico-rectal structure corresponding to a uterus, markedly enlarged at 153 × 94 mm, with a massively thickened junctional zone reaching 45 mm (normal < 12 mm) and interspersed T2-hyperintense microcystic foci — the MRI hallmark of diffuse Adenomyosis. A penile structure with 2 well-developed corpora cavernosa and a corpus spongiosum was present. A proximal periurethral structure with signal characteristics resembling prostatic parenchyma was identified — consistent with androgen-driven hypertrophy of the Skene (paraurethral) glands [ 5 ] ( Fig. 3 ). Both ovaries were atrophic and pauci-follicular. No testicular structures were visualized ( Fig. 4 ). Fig. 3 Pelvic MRI findings using sagittal T2-weighted image (A) demonstrates a markedly enlarged uterus with diffuse adenomyosis, evidenced by massive junctional zone thickening (double headed red arrow) containing interspersed T2-hyperintense microcystic foci, alongside hypotrophy of the cervical and vaginal walls (Blue arrows). A penile structure with well-developed corpora cavernosa and a corpus spongiosum was present (White arrow). Axial T2-weighted image (B) demonstrates periurethral soft tissue with signal characteristics resembling prostatic parenchyma (red arrow), consistent with androgen-driven hypertrophy of the Skene paraurethral glands. Fig 3 dummy alt text Fig. 4 Axial T2-weighted images (A and B) confirm the presence of bilateral ovarian follicular structures on either side of the uterine corpus already depicted in Figure 3 (red arrows). Fig 4 dummy alt text Pelvic MRI findings using sagittal T2-weighted image (A) demonstrates a markedly enlarged uterus with diffuse adenomyosis, evidenced by massive junctional zone thickening (double headed red arrow) containing interspersed T2-hyperintense microcystic foci, alongside hypotrophy of the cervical and vaginal walls (Blue arrows). A penile structure with well-developed corpora cavernosa and a corpus spongiosum was present (White arrow). Axial T2-weighted image (B) demonstrates periurethral soft tissue with signal characteristics resembling prostatic parenchyma (red arrow), consistent with androgen-driven hypertrophy of the Skene paraurethral glands. Axial T2-weighted images (A and B) confirm the presence of bilateral ovarian follicular structures on either side of the uterine corpus already depicted in Figure 3 (red arrows). The patient was referred to our endocrinology department. On examination, height was 147 cm (−3.5 SD) and weight 54 kg (BMI 24.9 kg/m 2 ). Blood pressure was 159/96 mmHg. Clinical examination of the external genitalia demonstrated Prader stage 5 virilization: a micropenis with the urethral meatus at the penile tip, a pigmented empty scrotum, and complete absence of a vaginal orifice at the perineum. No hypospadias was present and no gynecomastia was noted. Basal 17-hydroxyprogesterone (17-OHP) was 62.90 ng/mL (∼31 × ULN) and ACTH was 798.73 pg/mL (∼12 × ULN), reflecting profound HPA-axis dysregulation. DOC was approximately 140 times the upper limit of normal—the discriminating biochemical marker of 11β-OHD, in which DOC accumulates due to blocked conversion to corticosterone by CYP11B1, exerting mineralocorticoid receptor agonism responsible for the low-renin hypertension, renal potassium wasting, and hypokalemia [ 1 , 6 ]. This biochemical pattern is what allows classical 11β-OHD to be distinguished from the more common 21-hydroxylase deficiency (21-OHD) without molecular testing: elevated 17-OHP reflects adrenal steroidogenic blockade common to both enzyme defects and is not by itself discriminating, but the clinical picture of hypertension and hypokalemia—rather than the salt-wasting and hypotension that define 21-OHD—together with a markedly elevated DOC (a metabolite specific to the CYP11B1 pathway and not produced in excess in 21-OHD) is considered diagnostic of 11β-OHD in the endocrinology literature, independent of genetic confirmation [ 1 , 6 ]. Cortisol was low-normal at 11.2-16.25 µg/dL despite extreme ACTH stimulation. The absence of frank adrenal crisis is explained by glucocorticoid receptor activation by accumulated precursor steroids [ 6 ]. DHEA-S (1259 µg/dL) and testosterone (5.9 ng/mL) were elevated, reflecting adrenal androgen overproduction as the driver of complete in-utero virilization. FSH and LH were profoundly suppressed (<0.12 IU/L each), with absent AMH and undetectable Inhibin B—confirming functional absence of testicular tissue, consistent with the imaging findings. β-hCG was negative. Plasma metanephrines were negative, excluding pheochromocytoma. Renal function was preserved (creatinine clearance 90-102 mL/min) with significant proteinuria (0.56-0.9 g/24 hours) consistent with hypertensive nephropathy. CYP21A2 molecular analysis was submitted to formally exclude 21-OHD as the underlying enzyme defect; CYP11B1 sequencing, which would have provided direct molecular confirmation of 11β-OHD, was unavailable locally, so the diagnosis rests on the clinical-biochemical reasoning above ( Table 1 ). Table 1 Biochemical, hormonal and genetic results. Table 1 dummy alt text Test Result Reference Interpretation Potassium (nadir) 2.2 mEq/L 3.5-5.0 mEq/L Severe hypokalemia Kaliuresis (24 h) 98.7 mEq/24 h <30 in hypokalemia Renal wasting 24 h proteinuria 0.56-0.9 g/24 h <0.15 g/24 h Hypertensive nephropathy 17-Hydroxyprogesterone 62.90 ng/mL <2 ng/mL 31× ULN ACTH (08 h) 798.73 pg/mL 7.2-63.3 pg/mL 12× ULN DHEA-S 1259 µg/dL <350 µg/dL Markedly elevated 11-Deoxycorticosterone (DOC) ∼140 × ULN <10 pg/mL Markedly elevated and confirmatory for 11β-OHD Cortisol (08 h) 11.2-16.25 µg/dL 6.2-19.4 µg/dL Low-normal FSH/LH <0.12/<0.12 IU/L 1.5-12/1.7-8 IU/L Profoundly suppressed AMH/Inhibin B 0.35 ng/mL/80 Absent Sertoli function Karyotype 46, XX — Confirms disorder of sex development (DSD) 11β-OHD, 11β-hydroxylase deficiency; ACTH, adrenocorticotropic hormone; AMH, anti-Müllerian hormone; DHEA-S, dehydroepiandrosterone sulfate; DOC, 11-deoxycorticosterone; DSD, disorder of sexual development; FSH, follicle-stimulating hormone; h, hour(s); LH, luteinizing hormone; ULN, upper limit of normal. Biochemical, hormonal and genetic results. 11β-OHD, 11β-hydroxylase deficiency; ACTH, adrenocorticotropic hormone; AMH, anti-Müllerian hormone; DHEA-S, dehydroepiandrosterone sulfate; DOC, 11-deoxycorticosterone; DSD, disorder of sexual development; FSH, follicle-stimulating hormone; h, hour(s); LH, luteinizing hormone; ULN, upper limit of normal.

The patient remained under multidisciplinary follow-up involving endocrinology, nephrology, cardiology, and psychiatry. Surgical discussion—including the indication for hysterectomy and bilateral gonadectomy—given the theoretical, albeit unquantified, malignancy risk associated with retained dysgenetic gonadal tissue (atrophic, pauci-follicular ovaries for instance) was reviewed with the patient, who refused surgical management; this decision was respected. Longer-term surveillance was planned for monitoring glucocorticoid adequacy and ACTH suppression; blood pressure optimization and proteinuria evolution; baseline PSA measurement and periodic pelvic MRI to monitor the periurethral prostatic tissue—given the documented risk of prostatic adenocarcinoma in 46, XX CAH patients with longstanding androgen exposure [ 6 ].

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Glucocorticoid replacement was initiated with hydrocortisone 20 mg/d in a split regimen (10 mg at 08 hours, 5 mg at 12 hours, 5 mg at 16 hours), targeting ACTH suppression to reduce DOC production, adrenal androgen excess, and the attendant cardiovascular and metabolic consequences. Hypokalemia was managed with intravenous and oral potassium supplementation throughout admission, with kayexalate for subsequent hyperkalemia during correction. Anti-hypertensive therapy was intensified: ramipril 10 mg/d was added to amlodipine 10 mg/d, with nephrology review for the proteinuria. Psychiatric assessment was obtained given the profound psychological impact of the diagnosis.

Congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive disorders of adrenal steroidogenesis. 11β-hydroxylase deficiency (11β-OHD), caused by loss-of-function mutations in CYP11B1, accounts for 5%-8% of all CAH cases, with an estimated incidence of 1 in 100,000 live births [ 1 ]. The enzyme deficiency impairs conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone (DOC) to corticosterone, leading to cortisol deficiency, ACTH-driven adrenal hyperplasia, androgen excess, and DOC accumulation—a potent mineralocorticoid precursor causing low-renin hypertension and hypokalemia [ 1 , 2 ]. In 46,XX individuals, chronic fetal androgen excess can virilize the external genitalia from Prader stage 1-5, while Müllerian structures are preserved due to absent anti-Müllerian hormone (AMH). Severely virilized 46,XX individuals are occasionally assigned male sex at birth and may reach adulthood undiagnosed, particularly where access to care is limited [ 3 , 4 ]. Late adult diagnosis of CAH has been documented, most often as an incidental imaging finding obtained for an unrelated indication. We report the oldest undiagnosed case of classical 11β-OHD at our institution, and among the most radiologically complex, in which imaging drove the entire diagnostic pathway.

This case demonstrates that classical 11β-hydroxylase deficiency can remain undiagnosed into adulthood, presenting as an incidental radiological finding with a complex anatomical phenotype. MRI—both abdominal and pelvic—can provide a comprehensive noninvasive characterization of the DSD phenotype that constitutes a complete diagnostic roadmap when clinical photography is unavailable or ethically precluded. The constellation of bilateral adrenal myelolipomas on imaging, clinically documented Prader stage 5 virilization, and MRI-demonstrated periurethral prostatic tissue and adenomyosis in a never-menstruating uterus documents, clinically, radiologically, and biochemically, the full systemic consequences of 3 decades of untreated adrenocortical enzyme deficiency. Prompt glucocorticoid replacement to suppress ACTH, careful management of the mineralocorticoid-driven cardiovascular sequelae, and ongoing multidisciplinary support for the profoundly complex personal and surgical decisions that this diagnosis entails are the pillars of management.

This case illustrates the radiological unmasking of classical 11β-OHD in an adult, registered and raised male, whose 46,XX DSD had remained unrecognized for 35 years. The initial presentation—abdominal pain prompting cross-sectional imaging—is consistent with the recognized pattern of late CAH diagnosis as an incidental radiological finding [ 7 ], and the bilateral adrenal myelolipomas served as the sentinel radiological finding. Myelolipomatous transformation of the adrenal glands is a well-established consequence of sustained ACTH hyperstimulation over years to decades, and bilateral giant myelolipomas in a young patient should always prompt evaluation for an underlying enzymatic CAH defect [ 3 , 8 ]. Other causes of bilateral virilizing adrenal masses, notably bilateral androgen-secreting adrenal tumors, were considered but were rendered unlikely by the diffuse macronodular hyperplastic background of both glands (rather than a discrete unilateral secreting mass) and by the markedly elevated DOC, which is not a feature of androgen-secreting adrenal neoplasms and specifically points to CYP11B1 blockade. The association between adrenal myelolipoma and CAH is well documented at the population level: a systematic review and meta-analysis of patients with CAH found an overall adrenal tumor prevalence of 29.3%, with myelolipoma specifically accounting for 7.4% of cases, and showed that patients who developed myelolipomas were disproportionately those with late-diagnosed or poorly controlled disease—a pattern directly mirrored by this patient's 35-year diagnostic delay [ 4 ]. The pelvic MRI provided findings of exceptional radiological and clinical significance. The combination of complete external genital masculinization, periurethral prostatic-type tissue, a preserved but pathological uterus with severe adenomyosis, and absent testicular structures in a single patient constitutes a radiological phenotype that reflects the full anatomical consequence of lifelong 11β-OHD: complete virilization of structures dependent on DHT (external genitalia, periurethral tissue) and preservation of Müllerian structures that develop independently of gonadal hormones in the absence of AMH [ 2 , 5 ]. This anatomical paradox—male external anatomy coexisting with female internal reproductive organs—is the defining feature of severely virilized 46, XX CAH and has been characterized in imaging studies of DSD [ [5] , [9] ]. The finding of diffuse adenomyosis with a 45 mm junctional zone in a patient who has never menstruated is, to our knowledge, rarely reported in the 11β-OHD literature, although we cannot exclude that similar findings have gone unrecognized or unreported elsewhere given the rarity of adult-diagnosed cases. As a hypothesis rather than a demonstrated mechanism, we propose that peripheral aromatization of chronically elevated adrenal androgens to estrogens, in the absence of any progesterone counterbalance from nonfunctional ovaries, may have generated a sustained estrogenic drive at the uterine level sufficient to contribute to junctional zone invasion and myometrial hypertrophy—the pathological substrate of adenomyosis [ 10 ]. This proposed mechanism was not confirmed by estradiol/progesterone measurements or uterine histopathology in this case and should be interpreted with appropriate caution; it nonetheless underscores the extent to which untreated adrenal hyperandrogenism could plausibly alter pelvic organ physiology far beyond external virilization. From a diagnostic standpoint, the discrimination between 11β-OHD and 21-OHD in this case rested on 3 converging clinical and biochemical observations: (1) the presence of longstanding hypertension rather than hypotension or salt-wasting; (2) severe hypokalemia with urinary potassium wasting, reflecting mineralocorticoid excess from DOC accumulation; and (3) DOC at ∼140× ULN—the enzymatic signature of CYP11B1 deficiency. Elevated 17-OHP occurs in both defects and is not discriminatory in isolation [ 1 , 6 ]. The absence of frank adrenal crisis despite 35 years of untreated disease was attributable to partial glucocorticoid receptor activation by accumulated steroid precursors, as has been described in other cases of adult-diagnosed CAH [ 8 ]. The diagnosis of classical 11β-OHD in this patient rests on a strongly compatible clinical and biochemical phenotype—longstanding hypertension, severe hypokalemia, and DOC at ∼140 × ULN—rather than on molecular confirmation. CYP11B1 genetic sequencing was not available locally and could not be performed; only CYP21A2 analysis, to exclude 21-hydroxylase deficiency, was submitted. This diagnosis should therefore be regarded as biochemically and clinically established but molecularly unconfirmed. As a single-patient case report, the proposed adenomyosis mechanism and the assessment of the adrenal lesions are similarly limited by the absence of hormonal (estradiol/progesterone) and histopathological correlation. Beyond the immediate biochemical and radiological diagnosis, this case raises management questions for which the literature offers a framework rather than fixed rules . Surveillance of the periurethral (Skene) prostatic-type tissue is warranted because chronic androgen exposure in 46,XX CAH can drive genuine glandular hyperplasia of this structure, and prostate-type carcinoma arising from androgen-stimulated periurethral tissue has been reported in this population [ 7 ]; annual PSA measurement together with periodic pelvic MRI has therefore been proposed as a pragmatic, noninvasive surveillance strategy in virilized 46,XX patients, and was adopted in this patient's follow-up plan [ 11 ]. The decision regarding gonadectomy and hysterectomy is similarly individualized rather than automatic: contemporary guidance on gonad management in DSD emphasizes weighing the malignancy risk—typically low but difficult to quantify precisely in atrophic, nondysgenetic ovarian tissue such as this patient's—against the endocrine and psychological value of retaining the gonads, and favors shared decision-making over a uniform prophylactic approach [ 12 ]. In this patient, both ovaries were atrophic and nonfunctional and the uterus was symptomatic from adenomyosis, making gonadectomy and hysterectomy reasonable options to discuss rather than mandatory interventions—the latter also informed by the recognized, if incompletely understood, association between long-standing adenomyosis and myometrial or endometrial neoplasia, which adds a surveillance and risk-reduction dimension to the morbidity-based rationale [ 13 ].

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