This medical case, recently documented in the peer-reviewed journal JCEM Case Reports, provides a stark illustration of the complexities involved in diagnosing rare endocrine disorders and the potentially life-threatening consequences of clinical misinterpretation. Researchers in Brazil have detailed the harrowing medical journey of a 22-year-old man who, after living for two decades with undiagnosed congenital adrenal hyperplasia (CAH), underwent an unnecessary bilateral radical orchiectomy that precipitated a severe acute adrenal crisis.
The case serves as a critical reminder to the global medical community regarding the necessity of considering systemic endocrine conditions when presented with bilateral testicular masses. The patient’s ordeal began not with the surgery itself, but with a series of missed diagnostic opportunities and a decades-long lapse in medical follow-up that left him vulnerable to a physiological collapse following the surgical removal of what were thought to be malignant tumors.
The Pathological Context: CAH and TARTs
To understand the severity of this case, one must first examine the underlying pathology. Congenital Adrenal Hyperplasia (CAH) refers to a group of autosomal recessive disorders characterized by deficiencies in enzymes required for cortisol synthesis in the adrenal cortex. The most common form, accounting for approximately 95% of cases, is 21-hydroxylase deficiency, caused by mutations in the CYP21A2 gene.
When the body cannot produce sufficient cortisol, the pituitary gland attempts to compensate by overproducing adrenocorticotropic hormone (ACTH). This chronic elevation of ACTH leads to hyperplasia (overgrowth) of the adrenal glands and the excessive production of adrenal androgens. A well-recognized but often overlooked complication of poorly controlled CAH in males is the development of Testicular Adrenal Rest Tumors (TARTs). These tumors are composed of vestigial adrenal cells that migrate with the gonads during embryonic development. Under the stimulus of high ACTH levels, these cells proliferate within the testes, often leading to infertility and, as seen in this case, being mistaken for primary testicular malignancies.
A Decades-Long Diagnostic Gap
The patient’s medical history reveals a significant failure in long-term pediatric-to-adult care transition. Though the patient was not screened for CAH at birth—a common issue in various regions depending on the era and local healthcare infrastructure—records from a separate institution indicated that he had been evaluated by pediatric endocrinologists at the age of three. At that time, he presented with macrogenitosomia (abnormal enlargement of the external genitalia), a classic sign of the simple virilizing form of CAH.
However, the medical records suggest an early-in-life misdiagnosis or, at the very least, an intolerance to the prescribed medication. This led to the patient’s family discontinuing treatment and a subsequent loss of follow-up that lasted for nearly 20 years. Remarkably, the patient survived into adulthood without the standard glucocorticoid and mineralocorticoid replacement therapy usually required for CAH patients. During this two-decade hiatus, he reported no salt-craving behavior or previous hospitalizations that would suggest prior adrenal crises, a fact that likely contributed to the eventual clinical oversight by his surgical team.
The Surgical Misstep and Post-Operative Crisis
At age 22, the patient sought medical attention after noticing progressive masses in both testicles over a three-year period. Urological surgeons, observing the bilateral nature of the masses and their growth, suspected malignancy. Despite the rarity of bilateral primary testicular cancer, the decision was made to perform a bilateral radical orchiectomy.
Prior to the surgery, the patient underwent sperm cryopreservation, and the procedure itself was completed without immediate perioperative complications. He was discharged the following day. However, the removal of the TARTs, combined with the physiological stress of surgery, removed a source of peripheral hormone production and placed an unsustainable demand on his already compromised adrenal system.
The "honeymoon period" following the surgery lasted only 18 days. The patient was then admitted to the emergency department suffering from severe asthenia (physical weakness), persistent nausea, vomiting, and profound dehydration—all hallmark symptoms of an acute adrenal crisis. It was only at this stage that an endocrinology specialist was consulted.
Clinical Findings and Genetic Confirmation
Upon physical examination by the endocrinology team, several physical markers of CAH became immediately apparent. The patient exhibited short stature and hyperpigmented macules on his lips—the latter being a classic sign of primary adrenal insufficiency caused by the overproduction of pro-opiomelanocortin (POMC), the precursor to both ACTH and melanocyte-stimulating hormone (MSH).
The medical team acted quickly to stabilize the patient, transitioning him to oral prednisolone for glucocorticoid replacement. Despite this, the patient’s recovery was non-linear; eight days after his initial discharge for the crisis, he was readmitted with symptomatic hyponatremia (dangerously low blood sodium levels), further confirming the mineralocorticoid deficiency associated with CAH.
Subsequent diagnostic imaging and laboratory testing provided the definitive evidence that had been missing prior to surgery. A CT scan revealed diffuse bilateral adrenal hyperplasia, a finding that had been overlooked or not sought during the preoperative workup. Laboratory results showed markedly elevated levels of serum 17-hydroxyprogesterone (17-OHP) and androstenedione, which are biochemical signatures of 21-hydroxylase deficiency.
Finally, genetic testing confirmed the diagnosis. The patient was found to possess a homozygous c.293-13 C > G [I2G] pathogenic variant in the CYP21A2 gene. This specific mutation is typically associated with the "simple virilizing" form of CAH, which explains how the patient survived to adulthood without treatment, yet remained at high risk for crisis under physiological stress.
Family History and Hereditary Implications
The researchers’ investigation into the patient’s family history further underscored the systemic nature of the condition. The patient’s brother, who also exhibited short stature and had experienced precocious puberty, was only recently confirmed to have CAH. Interestingly, scrotal ultrasonography did not reveal TARTs in the brother, highlighting that while TARTs are common in CAH, they are not universal.
Even more tragically, the patient had a sister who died at only two months of age from an undetermined cause. In the context of the patient’s confirmed CAH, it is highly probable that the sister suffered from the "salt-wasting" form of the disease, which causes fatal adrenal crises in infancy if not treated immediately with hormone replacement. This family history provides a somber backdrop to the patient’s own narrow escape from a similar fate.
Analysis of Clinical Implications
This case highlights a critical "blind spot" in surgical oncology and urology. The researchers emphasize that TARTs are a well-recognized complication of CAH, and their development is intrinsically linked to inadequate glucocorticoid treatment. While TARTs can occur in patients with seemingly adequate hormonal control, they are almost guaranteed in untreated cases.
The broader implication for medical practice is the necessity of a multidisciplinary approach. In any instance of bilateral testicular tumors, TARTs must be included in the differential diagnosis. The presence of bilateral masses should immediately trigger a clinical suspicion of CAH, leading to biochemical screening for 17-OHP before any irreversible surgical intervention like an orchiectomy is considered.
From a surgical perspective, the tragedy of this case lies in the fact that TARTs are often reversible. With proper glucocorticoid therapy to suppress ACTH levels, these tumors can shrink significantly, often eliminating the need for surgery and preserving the patient’s hormonal and reproductive function. By misinterpreting the masses as malignant, the surgical team performed an irreversible procedure that not only failed to address the underlying disease but also stripped the patient of his primary source of testosterone and any remaining fertility.
Recommendations for Future Screening
The authors of the paper conclude with a call for more rigorous screening protocols. They argue that all male patients diagnosed with CAH should undergo regular scrotal ultrasound screening starting in late childhood or early adolescence. This is essential regardless of the patient’s current biochemical status, as TARTs can develop even when blood tests appear relatively stable.
Furthermore, this case serves as a warning about the dangers of the "lost to follow-up" phenomenon in pediatric endocrinology. As patients transition from pediatric to adult care, there is a significant risk that chronic conditions may be forgotten or misunderstood by the patient and their new providers.
Conclusion
The 22-year-old patient is now receiving appropriate treatment with glucocorticoids and mineralocorticoids, and his condition has stabilized. However, he must live with the lifelong consequences of a bilateral orchiectomy—a procedure that could have been avoided with a more comprehensive preoperative evaluation and a deeper understanding of his pediatric medical history.
The Brazilian researchers hope that by publishing this case, they can prevent similar occurrences. The medical community must remain vigilant: bilateral testicular masses are not always cancer, and sometimes, the key to a patient’s survival lies not in the scalpel, but in a thorough review of their endocrine health and genetic heritage. This case stands as a definitive argument for the integration of genetic awareness and endocrine screening in the standard workup for urological anomalies.
