Congenital adrenal hyperplasia with bilateral testicular adrenal rest tumors: a case description emphasizing early ultrasound detection

Background

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders arising from enzyme deficiencies in the biosynthesis of glucocorticoids. Testicular adrenal rest tumors (TARTs) could develop in patients with CAH and pose diagnostic dilemmas in the presence of testicular enlargement. We report the ultrasound findings of a TART in a patient with CAH.

Case presentation

A 23-year-old male was admitted with complaints of bilateral scrotal swelling for 5 years and intermittent pain for 4 days. Physical examination revealed normal blood pressure. Cutaneous inspection showed unremarkable skin pigmentation without hyperpigmentation. The patient’s anthropometric profile included a height of 170 cm, weight of 67 kg, and body mass index (BMI) of 23 kg/m². Three years prior, physical examination revealed a right adrenal mass with elevated adrenocorticotropic hormone (ACTH), prompting right adrenalectomy. Pathology confirmed cortical adenoma, yet ACTH remained persistently elevated postoperatively with routine monitoring. All systemic examinations were unremarkable. Urological examination revealed bilaterally hardened, non-transilluminating testes with substantial enlargement (right: ~9 cm × 6 cm; left: ~10 cm × 7 cm), measuring over twice the normal adult testicular size range (3.5–5.5 cm in length × 2–3 cm in width). Subsequently, the surgeon prescribed a routine ultrasound, contrast-enhanced ultrasound, and pelvic enhanced magnetic resonance imaging (MRI). Enhanced MRI of the scrotum and pelvis (Figure S1) showed homogeneously enhancing bilateral testicular enlargement, which initially raised suspicion for testicular malignancy. However, testicular ultrasound (Figures S2,S3) demonstrated well-defined heterogeneous, mainly hypoechoic masses in both testes, with rich blood supply on color Doppler. After the administration of SonoVue 2.4 mL, increased enhancement and subsequent late washout were observed (Figure S4). Abdominal CT showed a big well-defined triangular low-density lesion in the left suprarenal region. Laboratory investigations revealed: (I) glucocorticoid axis: cortisol: normal at both 8 AM and 4 PM (within institutional reference range); ACTH: markedly elevated [8 AM: 202.4 pmol/L (normal, 1.59–13.9 pmol/L); 4 PM: 65.6 pmol/L (normal, 0–10 pmol/L)]. (II) Mineralocorticoid axis: norepinephrine: 163.8 pg/mL (deficient; normal, 217–1,109 pg/mL); renin activity: 14.09 ng/mL/h (elevated; normal, 0.25–5.82 ng/mL/h). (III) Androgen pathway: 17-OHP: >2,000 ng/dL (severely elevated; normal, <220 ng/dL); androstenedione: >10,000 pg/mL (markedly elevated; normal, 400–1,500 pg/mL); total testosterone: 8,214 pg/mL (normal, 2,400–9,500 pg/mL). The extreme 17-OHP elevation (>2,000 ng/dL), mineralocorticoid deficiency markers, and hyperandrogenism confirm classic salt-wasting CAH, despite the absence of acute electrolyte imbalance at presentation. This represents a compensated salt-wasting phenotype. Semen analysis showed azoospermia. The patient refused genetic testing. Given that his clinical manifestations, diagnostic blood tests, and imaging findings were all consistent with TARTs, biopsy was not performed. Medical treatment consisted of hormonal therapy with oral dexamethasone in order to reduce the levels of ACTH. Follow-up ultrasounds at 3- and 6 months post-treatment demonstrated both decreased testicular volume (baseline: right ~9 cm × 6 cm, left ~10 cm × 7 cm → 3 months: right ~9 cm × 4 cm, left ~9.5 cm × 5.5 cm → 6 months: right ~8 cm × 4 cm, left ~9 cm × 5 cm) and reduction in TART size.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this study and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

TARTs conventionally have been associated with classic 21-hydroxylase deficiency CAH. The first description was provided by Wilkins et al. in 1940 (1). The majority of cases of CAH are caused by a deficiency of 21-hydroxylase (2). The enzymatic block disrupts the negative feedback of the hypothalamic-pituitary-adrenal axis, leading to compensatory overproduction of ACTH, with subsequent adrenal hyperplasia. During fetal development, remnants of adrenal cortical tissue may aberrantly adhere to the gonads and descend to the testes, persisting as incidental findings in some neonates. Pathologically, these ectopic adrenal rests become clinically significant when hyperstimulated by elevated ACTH in CAH, developing into TARTs. TARTs typically arise along the embryonic migratory pathway—extending from the suprarenal region to the scrotum—and may present as multiple unilateral lesions. By an analogous mechanism, females with CAH can develop ovarian adrenal rest tumors (OARTs) (3). It is also recognized that conditions associated with chronic elevation of ACTH, including Nelson’s and Addison’s syndromes, have been associated with the development of TARTs.

Notably, TARTs can rarely serve as the initial manifestation of undiagnosed CAH. Recent case reports highlight this phenomenon:

• ❖ A 24-year-old male presented with bilateral testicular masses (3.2 cm right, 2.8 cm left), later confirmed as TARTs leading to 21-hydroxylase deficiency CAH diagnosis (4).

• ❖ Similarly, an 18-year-old with unilateral TART (2.5 cm) showed no classic CAH symptoms until genetic testing revealed CYP21A2 mutations (5).

These cases emphasize that idiopathic testicular lesions in young males warrant endocrinological evaluation to exclude CAH.

The classic CAH is divided into salt-wasting type and simple virilizing type, according to the electrolyte imbalance and depending on the severity of the enzyme defect (2). The degree of enzyme deficiency associated with CAH is directly related to the clinical severity and may present as ambiguous genitalia, precocious puberty and TARTs (6). TARTs can disrupt spermatogenesis and endocrine function and have emerged as one of the major causes of infertility in male CAH patients. Claahsen-van der Grinten et al. developed a five-stage developmental classification for TARTs and emphasized that early ultrasound screening of the scrotum from age 8 years could be important in male CAH patients (7).

Generally, TARTs appear as hypoechoic, hypervascular lesions close to the testicular mediastinum (8). The differentiation of TART from malignant testicular tumors, lymphomas, and Leydig cell tumors is very important in view of different treatments and prognosis. TARTs tend to be located in the same region of the testicle and are often bilateral. Malignant tumors tend to be unilateral. Ultrasound and

MRI serve as well-suited modalities for both the detection and follow-up study. Ultrasound should be the imaging technique of choice for first presentations simply because it is cheaper and more accessible than other techniques. Yilmaz et al. demonstrated that ultrasonography readily detects adrenal rest lesions as small as a few millimeters in diameter and enables longitudinal monitoring of TART evolution during follow-up, including tumor regression, size reduction, or stability. Although MRI identifies all sonographically diagnosed TARTs and provides lesional morphology/signal characteristics, routine MRI sequences do not confer additional diagnostic value beyond ultrasonography (9).

Conclusions

This case further underlines that early detection with ultrasound is of paramount importance for the protection of testicular function and fertility in male CAH patients with TARTs. Given that improved hormonal control may induce tumor regression, ultrasonography is critical for monitoring treatment response. We therefore recommend periodic scrotal ultrasound surveillance in male CAH patients to prevent long-term complications.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this study and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.