Summary

Congenital adrenal hyperplasia (CAH) is one of the most common inherited rare endocrine disorders. This case report presents two female siblings with delayed diagnosis of non-classical CAH 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2D/HSD3B2) despite early hospital admission and apparent CAH manifestations such as infections, hirsutism, menstrual disturbances, and PCOS phenotype. Initially, sister 1 was misdiagnosed with PCOS and then 11-hydroxylase deficiency (CYP11B1), based on ultrasound, biochemical findings, and negative genetic testing for 21-hydroxylase deficiency (CYP21A2). Additional diagnostic workup was performed when sister 2also presented with symptoms of androgen excess. Genetic testing for CAH/steroid disorders finally revealed that both siblings were compound heterozygous for two variants in the HSD3B2 gene: a frameshift variant, c.558dup, p.(Thr187Hisfs*17) and a novel missense variant, c.65T>C, p.(Leu22Ser). A Synacthen test showed an insufficient cortisol increase. In vitro studies of the variants in a cell model revealed loss of function for the p.(Thr187Hisfs*17) and partial activity for p.(Leu22Ser) confirming non-classic CAH. Overlapping symptomatology and lack of specialized knowledge on steroid biosynthesis and associated rarest forms of CAH may explain the delayed diagnosis. However, with newer diagnostic methods comprising a less biased approach, very rare forms of non-classical CAH may no longer be overlooked in the future.

Learning points

• Non-classic 3βHSD2 is likely underdiagnosed.

• Late diagnosis of mild non-classic 3βHSD2 does occur and one should be aware of this diagnosis.

• Early diagnosis of NCCAH may prevent many consequences such as severe hirsutism, prolonged menstrual irregularities, infertility, or even adrenal crisis with severe infections.

• Comprehensive steroid profiling and genetic testing should be used earlier, especially when in doubt about a diagnosis.

Summary

Multiple endocrine neoplasia type 2 (MEN2) is a hereditary cancer syndrome caused by germline-activating pathogenic variants in the RET proto-oncogene. MEN2A is the most common subtype, with a risk for medullary thyroid cancer (MTC), pheochromocytoma (PHEO), and primary hyperparathyroidism (PHPT), whereas MEN2B is less common and associated with MTC and PHEO along with mucosal neuromas. Little is known about the specific RET germline heterozygous variant K666N. This variant has been described in very few families, and in most cases, patients were diagnosed with a very indolent MTC as the only feature. There is one case of MTC and bilateral PHEO. The RET K666N variant is not stratified yet by the American Thyroid Association, and data are limited on pathogenicity; therefore, appropriate screening and treatment of asymptomatic RET K666N carriers are unclear. Here, we report a family with a heterozygous germline RET K666N variant. The proband was identified when she experienced cardiogenic shock and multi-organ failure after an elective hysterectomy and subsequently was found to have PHEO, with genetic testing revealing the RET K666N germline variant. Patient consent was obtained through IRB protocol COMIRB #15-0516.

Learning Points

• The specific RET germline heterozygous variant K666N is rare and described in very few families, and in most cases, patients were diagnosed with a very indolent MTC as the only feature. Our proband is much younger and has PHEO, MTC, and PHPT.

• The RET K666N germline variant appears to be a low penetrance variant for MEN2.

Summary

Neonatal adrenal hemorrhage (NAH) occurs in up to 3% of infants and is the most common adrenal mass in newborns. The most common presentation of NAH is an asymptomatic palpable flank mass which resolves over time without intervention. In rare cases, NAH can present as hemorrhage, shock, or adrenal insufficiency. This case describes a preterm infant born with severe anemia in the setting of bilateral adrenal hemorrhages with resulting adrenal insufficiency. The infant was successfully treated with blood transfusions and steroids. This is a unique presentation of NAH as it was bilateral, presented with severe anemia, and resulted in prolonged adrenal insufficiency.

Learning points

• Consider adrenal hemorrhage for cases of severe anemia at birth.

• Adrenal insufficiency is a rare complication of adrenal hemorrhage.

• Adrenal recovery can take months, if not years.

Summary

Approximately 80% of adrenal incidentalomas are benign, and development into adrenal cortical cancer is extremely rare. This is a major reason behind clinical guidelines recommending surveillance of incidentalomas for a relatively short duration of up to 5 years. Surveillance of lesions less than 1 cm is not routinely recommended. A 70-year-old lady was diagnosed with a non-hyperfunctioning 8 mm right adrenal lesion. She underwent annual biochemical and radiological assessment for 5 years before surveillance was extended to 2-yearly intervals. The lesion was stable in size, and radiological characteristics were consistent with a benign adenoma. Seven years after the initial detection of the adrenal lesion, she developed acute abdominal pain. Imaging revealed a 7 cm right adrenal lesion, which was surgically resected and histologically confirmed to be adrenal cortical cancer. She died 1 year later. Clinical guidelines have moved towards a shortened duration of surveillance of incidentalomas. Even though malignant transformation is a rare event, it is possible that this will result in a delayed diagnosis of adrenal cortical cancer, a highly aggressive malignancy with a poor prognosis. To our knowledge, this is the first published case of an adrenal lesion of less than 1 cm developing into adrenal cortical cancer.

Learning points

• Adrenal incidentalomas are increasingly common.

• Clinical practice guidelines exist to aid in differentiating benign and malignant lesions and assessing functional status.

• Transformation of adrenal incidentalomas to adrenal cortical carcinomas is a rare but recognised event.

Summary

Pheochromocytomas are rare adrenal tumors characterized by excessive catecholamine secretion. Symptoms and signs associated with pheochromocytomas are usually intermittent and chronic but can rarely develop into life-threatening crises. We describe a case of acute severe congestive heart failure in a previously healthy female, who recovered rapidly (4 days after admission) with acute medical therapy. The etiology on evaluation was a spontaneous bleed in a previously undiagnosed pheochromocytoma, resulting in a pheochromocytoma crisis and transient stress cardiomyopathy, followed by quick recovery of cardiac function. Our aim is to describe pheochromocytoma as a rare cause of stress cardiomyopathy. We discuss the evaluation of pheochromocytoma during critical illness and triggers/treatment strategies for pheochromocytoma crises.

Learning points

• Hemorrhage in a pheochromocytoma can result in a pheochromocytoma crisis, with sudden release of excess catecholamines resulting in multisystem organ dysfunction and high mortality.

• Acute decompensated heart failure can be a rare presentation of pheochromocytoma, in a patient with no cardiac risk factors.

• Measurement of metanephrines in acutely stressful clinical situations can have considerable overlap with the biochemical picture of pheochromocytoma. Early imaging studies may help with the differential diagnosis.

• Pheochromocytoma should be ruled out before performing an adrenal biopsy.

• Emergent adrenalectomy in pheochromocytoma crisis results in high mortality. Medical management of the acute crisis followed by elective adrenalectomy after alpha-blockade results in better outcomes.

Summary

Symptoms of primary adrenal insufficiency (PAI) are commonly nonspecific, causing the disease to be misdiagnosed or often delayed, and patients may present to the hospital with a life-threatening crisis. Previous case reports have documented that patients in this condition often require lifelong glucocorticoid replacement therapy. This study aimed to present a noteworthy outcome of PAI caused by adrenal tuberculosis infection, demonstrating complete recovery after six months of glucocorticoid replacement therapy. A 38-year-old Indonesian man presented to the endocrinology clinic in a tertiary hospital with a chief complaint of epigastric pain. The patient experienced nausea, vomiting, loss of consciousness, weight loss, excessive sweat, decreased appetite, weakness, and dizziness in the past 2 weeks. Laboratory examinations revealed hyponatremia, elevated adrenocorticotropic hormone, and suppressed morning plasma cortisol level. A non-contrast-enhanced abdominal MRI showed unilateral right-side adrenal enlargement and calcification. The patient’s Mantoux test was positive. Corticosteroids and anti-tuberculosis therapy were administered. After 6 months, hydrocortisone was discontinued due to the patient’s good clinical condition and normal morning plasma cortisol levels. After a 1-year follow-up, the patient remained asymptomatic with normal cortisol levels. We hypothesized several reasons for this unique outcome: (i) the patient was relatively young compared to previous cases, suggesting an adequate immune system may play a role; (ii) despite a 1-month delay in diagnosis and treatment, the absence of skin hyperpigmentation suggested an acute presentation, potentially contributing to the favorable outcome; and (iii) the absence of comorbidities potentially positively impacted the patient's outcome.

Learning points

• Symptoms of adrenal insufficiency are often nonspecific and may only become apparent once significant damage has occurred to the adrenal gland.

• Clinical adjustments and a comprehensive understanding of epidemiological knowledge are necessary for diagnosing patients with endocrine diseases in limited-resource settings.

• Complete recovery in primary adrenal insufficiency caused by tuberculosis infection might be due to younger age, acute presentation, and absence of comorbidities

Summary

Mitotane is used for treatment of advanced adrenocortical carcinoma. It is administered when the carcinoma is unresectable, metastasized, or at high-risk of recurrence after resection. In addition, mitotane is considered to have direct adrenolytic effects. Because of its narrow therapeutic–toxic range, therapeutic drug monitoring (TDM) is warranted. In 2020, a left-sided adrenal gland tumor was found (5.8 cm) in a 38-year-old man. Considering the size of this lesion and inability to exclude an adrenocortical carcinoma on imaging, a laparoscopic adrenalectomy was performed. Histopathologic examination determined presence of an adrenocortical carcinoma (pT2N0M0 ENSAT stadium II; ki67 10–15%). There was no evidence for residual or metastatic disease but given the high risk of recurrence, adjuvant therapy with mitotane was initiated. During TDM, a sudden and spuriously high level of mitotane was observed but without signs or symptoms of toxicity. After exploration, it was found that this high concentration was completely due to uncontrolled hypertriglyceridemia. After correction thereof, mitotane levels were again in the therapeutic range. This observation underscores the importance of TDM sampling in a fasting state with concurrent control of prevalent or incident dyslipidemia.

Learning points

• TDM of mitotane is advocated to achieve therapeutic levels while avoiding toxicity. For correct TDM, sampling should be done at least 12 h after last intake of mitotane.

• Although sampling in fasting conditions in not explicitly mentioned in the guidelines, fasting state should be considered as elevated serum triglyceride levels might cause spuriously high mitotane levels.

• In patients undergoing treatment with mitotane and presenting with too high or unexplained fluctuating mitotane levels without signs or symptoms of toxicity, hypertriglyceridemia as a possible cause should be investigated.

• If dyslipidemia occurs in patients under mitotane treatment, other causes than mitotane (e.g. alcohol abuse and diabetes) should be considered and appropriate treatment should be initiated.

Summary

New-onset primary adrenal insufficiency is rare in pregnancy. The symptoms of adrenal insufficiency such as nausea, vomiting and dizziness may be attributed to the pregnancy itself, which can lead to a delay in the diagnosis. The presence of hypotension, hypoglycemia or hyperkalemia should raise the suspicion for adrenal insufficiency. We report the case of a 25-year-old woman who presented with tachycardia, left flank pain and vomiting at 36 weeks’ gestation. She was found to have primary adrenal insufficiency and started on hydrocortisone and fludrocortisone with resolution of the vomiting and tachycardia. MRI of the abdomen revealed an acute nonhemorrhagic infarct of the left adrenal gland. The contralateral adrenal gland was normal. Autoimmune and infectious etiologies of primary adrenal insufficiency were ruled out and the adrenal insufficiency was attributed to the unilateral adrenal infarction. Adrenal insufficiency persisted after delivery and then resolved at approximately 16 months post partum. This case highlights the need to test women with unilateral adrenal infarction in pregnancy for the presence of primary adrenal insufficiency.

Learning points

• Adrenal insufficiency should be considered when a pregnant woman develops nausea, vomiting and dizziness in association with hypotension or hypoglycemia. Hypovolemic hyponatremia related to vomiting can occur in pregnancy, but the failure to correct hyponatremia despite adequate IV hydration should raise the suspicion for adrenal insufficiency.

• Adrenal infarction should be in the differential diagnosis for unilateral flank pain in pregnancy. Other common etiologies for flank pain in pregnancy include nephrolithiasis, pyelonephritis and acute cholecystitis.

• Unilateral adrenal infarction in pregnancy can lead to the development of primary adrenal insufficiency. Following delivery, these patients need to be monitored for the resolution of the adrenal insufficiency.

Summary

Severe Cushing’s syndrome from an ectopic adrenocorticotropic hormone-producing tumour is rare but often demands rapid diagnostics and treatment of hypercortisolism with its comorbidities. Pharmacotherapy of hypercortisolism by ketoconazole, metyrapone and osilodrostat is currently available. If unsuccessful or insufficient a bilateral adrenalectomy is an option. We present a 28-year-old female with severe Cushing’s syndrome caused by a bronchial metastatic neuroendocrine tumour (NET). Hypercortisolism was efficiently treated by osilodrostat with block–replace and then titration regimen. A once-daily dose was finally used with normalised cortisol levels. Androgen levels measured by liquid chromatography–mass spectrometry were slightly elevated during the treatment but without any symptoms. A simple once-daily use of osilodrostat with titration regimen led to normalised cortisol levels in a severe Cushing’s syndrome patient with an uncurable bronchial NET. Transient hypocortisolism during treatment appeared but was easily treated by hydrocortisone.

Learning points

• Cushing’s syndrome from an ectopic adrenocorticotropic hormone-producing tumour is rare.

• Cortisol upregulation is often severe and rapid, though clinical signs are not always fully pronounced.

• Rapid treatment is a key for preventing and reducing complications such as fractures, thromboembolism, bleeding, hyperglycaemia, and arterial hypertension.

• The novel potent steroidogenesis inhibitor osilodrostat can be used as first-line treatment for reducing hypercortisolism.

Summary

A 42-year-old female patient was referred to our hospital with hypertension and hypokalemia and was diagnosed with primary aldosteronism. Dynamic contrast-enhanced computed tomography images revealed a 13-mm nodule on the lateral segment of the left adrenal gland and a fine venous connection between the nodule and the prominent renal capsular vein running nearby. The venograms in the left lateral tributary with a microcatheter confirmed alternative drainage to the left renal capsular vein during adrenal venous sampling, and the left renal capsular vein sampling was added. The patient was diagnosed with a left aldosterone-producing adenoma (APA) using the lateralization index (48.3) and a higher plasma aldosterone concentration (PAC) of the left lateral tributary (66 700 pg/mL) than other tributary samples after adrenocorticotropic hormone stimulation. Furthermore, markedly higher PAC (224 000 pg/mL) was observed in the left renal capsular vein blood than in the left adrenal central vein (45 000 pg/mL) and tributaries, confirming the diagnosis. Laparoscopic left partial adrenalectomy and following histopathological analysis revealed a CYP11B2-positive adrenocortical adenoma. Complete clinical and biochemical success for primary aldosteronism was achieved after 6 months. Direct evidence of APA blood venous drainage into the renal capsular vein has been demonstrated. Sampling from an alternative drainage pathway could be beneficial for APA diagnosis if such APA blood drainage is assumed.

Learning points

• Aldosterone-producing adenomas may drain blood into an alternative pathway but for the adrenal vein.

• The presence of alternative venous drainage could be assumed by contrast-enhanced computed tomography or venogram during adrenal venous sampling.

• Sampling in the alternative drainage veins and demonstrating elevated aldosterone levels could help in diagnosing aldosterone-producing adenoma.