A recent clinical report published in JCEM Case Reports has brought to light a significant diagnostic oversight that led to life-altering surgical intervention and a subsequent life-threatening medical emergency. Researchers in Brazil documented the case of a 22-year-old male who, after undergoing a bilateral radical orchiectomy for suspected testicular cancer, fell into an acute adrenal crisis. The investigation following his emergency admission revealed that the patient had been living with untreated congenital adrenal hyperplasia (CAH) for over two decades, and the masses removed by surgeons were not malignant tumors, but rather testicular adrenal rest tumors (TARTs)—a known but frequently overlooked complication of CAH.
The case serves as a critical reminder to the global medical community, particularly urologists and endocrinologists, regarding the necessity of differential diagnosis when presenting with bilateral testicular masses. The failure to recognize the underlying endocrine disorder led to the unnecessary removal of both testes, followed by a systemic collapse as the patient’s body, already struggling with adrenal insufficiency, was pushed beyond its physiological limits by the stress of surgery and the removal of hormone-producing tissue.
The Clinical Presentation and Surgical Intervention
The 22-year-old patient first sought medical attention after noticing progressive masses in both testicles, a condition he had observed developing for approximately three years. Upon presentation to a urological surgical team, a physical examination confirmed the presence of large, firm masses. Given the bilateral nature and the size of the growths, the clinical suspicion leaned heavily toward malignancy.
In preparation for what was assumed to be a standard oncological procedure, the patient underwent sperm cryopreservation to preserve his future fertility—a standard protocol for young men facing radical orchiectomy. Following this, surgeons performed a bilateral radical orchiectomy. The procedure was initially deemed a success, with no immediate perioperative complications reported. The patient was discharged the following day, seemingly on the path to recovery from what was thought to be testicular cancer.
However, the physiological reality was far more complex. Because the patient had undiagnosed CAH, his body was already incapable of producing adequate amounts of cortisol and aldosterone. The TARTs, while abnormal, were composed of vestigial adrenal cells that had likely been providing a marginal, albeit insufficient, level of steroidogenic activity. By removing these masses and the testes themselves, and by subjecting the patient to the physical stress of major surgery without glucocorticoid support, the medical team inadvertently triggered a total adrenal collapse.
Post-Surgical Collapse and the Road to Diagnosis
The gravity of the situation became apparent 18 days after the surgery. The patient was rushed to the emergency department suffering from severe asthenia (physical weakness), persistent nausea, projectile vomiting, and profound dehydration. These are the hallmark symptoms of an acute adrenal crisis, a medical emergency where the body lacks the cortisol necessary to maintain blood pressure and metabolic function.
Recognizing the severity of the systemic symptoms, an endocrinology specialist was consulted. The specialist noted several physical markers that had likely been present but overlooked during the initial urological evaluation: the patient exhibited notably short stature and hyperpigmented macules on his lips. Hyperpigmentation is a classic sign of adrenal insufficiency, caused by the overproduction of adrenocorticotropic hormone (ACTH), which shares a precursor with melanocyte-stimulating hormone.
The patient was immediately started on glucocorticoid replacement therapy, transitioning to oral prednisolone. While he was initially stabilized and discharged, the fragility of his condition was further evidenced eight days later when he was readmitted with symptomatic hyponatremia—a dangerously low level of sodium in the blood, resulting from the lack of aldosterone, the hormone responsible for salt retention.
A History of Missed Opportunities
The subsequent investigation into the patient’s medical history revealed a series of systemic failures in early-life screening and follow-up. The researchers discovered that the patient had not undergone newborn screening for CAH, a standard practice in many developed nations that was not universally applied or accessible in his region at the time of his birth.
A review of records from a different medical institution showed that the patient had actually been seen by a pediatric endocrinologist at the age of three. At that time, he was evaluated for macrogenitosomia (abnormally large genitalia for his age), which is a common early indicator of the simple virilizing form of CAH. While a diagnosis was suspected and medication was prescribed, the history indicates a tragic combination of medication intolerance and a subsequent loss of follow-up. For nearly 20 years, the patient lived without medical supervision, unaware that his body was in a state of chronic endocrine imbalance.
Remarkably, the patient reported no history of "salt-craving" behavior or prior hospitalizations for adrenal crises during his adolescence. This lack of acute episodes likely contributed to the "invisible" nature of his condition until the TARTs grew large enough to be mistaken for cancer. The family history also provided clues: a brother had recently been diagnosed with CAH after exhibiting short stature and precocious puberty, while a sister had died in infancy at just two months of age from an undetermined cause—a death that, in retrospect, was likely a salt-wasting adrenal crisis.
Scientific Analysis: TARTs and the CYP21A2 Gene
To confirm the diagnosis, the research team performed a CT scan, which revealed diffuse bilateral adrenal hyperplasia. This imaging finding, which would have been a vital clue prior to surgery, had not been sought during the initial oncological workup. Laboratory tests conducted 25 days post-surgery showed massively elevated levels of serum 17-hydroxyprogesterone (17-OHP) and androstenedione, which are precursor hormones that accumulate when the 21-hydroxylase enzyme is deficient.
Genetic testing ultimately provided the definitive answer. The patient was found to have a homozygous c.293-13 C > G [I2G] pathogenic variant in the CYP21A2 gene. This specific mutation is associated with 21-hydroxylase deficiency, the most common form of CAH.
Testicular adrenal rest tumors (TARTs) are a well-documented complication of this condition. During embryonic development, adrenal-like cells can become trapped within the descent path of the testes. In a healthy individual, these cells remain dormant. However, in patients with CAH, the lack of cortisol leads to a feedback loop that causes the pituitary gland to overproduce ACTH. This constant stimulation causes the vestigial adrenal cells in the testes to proliferate, forming benign tumors.
Broader Implications for Medical Practice
The case highlights a critical diagnostic trap. Because TARTs are often bilateral and can grow quite large, they mimic the appearance of bilateral primary testicular malignancies. However, the treatment protocols for the two conditions are diametrically opposed. While malignancy requires radical surgery, TARTs are benign and can often be reduced in size through proper glucocorticoid therapy, which suppresses the ACTH driving their growth.
The authors of the paper emphasize that TARTs should be considered in the differential diagnosis of any male patient presenting with bilateral testicular tumors. This suspicion should immediately trigger a clinical workup for CAH, including a review of growth charts (looking for short stature) and laboratory testing for 17-OHP.
Furthermore, the study underscores the need for lifelong screening for male patients known to have CAH. The researchers noted that TARTs can develop even in patients who appear to have adequate biochemical control, though they are much more common in those with poor hormone management. Screening via scrotal ultrasonography should begin in late childhood or early adolescence.
Conclusion and Lessons Learned
The story of this 22-year-old patient is a cautionary tale regarding the silos of medical specialization. Had the urological team considered the possibility of an underlying endocrine disorder or performed a more comprehensive physical assessment, the patient might have avoided the loss of his testicles and the subsequent life-threatening crisis.
The implications of this case extend to the importance of robust newborn screening programs and the necessity of transition-of-care protocols for pediatric patients with chronic conditions. The "loss to follow-up" for 20 years was the primary driver of this surgical error.
As a result of this case, medical educators are calling for increased awareness of CAH manifestations in adult medicine. While often viewed as a pediatric condition, CAH requires lifelong vigilance. For the patient in Brazil, the diagnosis finally provides a path to proper hormonal management, but it came at the cost of his reproductive organs—a price that underscores the vital importance of the "differential diagnosis" in modern clinical practice.
