The index case was a 14 year-old boy who presented to us in 1971 with severe hypertension. On evaluation he was found to have a right adrenal mass with elevated urinary VMA (normal <7 mg/24 hr), confirming the diagnosis of a right adrenal pheochromocytoma. He underwent right adrenalectomy and the post-operative period was uneventful. He was subsequently lost to follow. In 1979, he presented to us again with severe headache and recurrent seizures. On examination his pulse rate was 100/min, blood pressure was 160/130 mm of Hg. Cardiac auscultation revealed a loud 2nd heart sound and a 3rd heart sound. There were no murmurs. Examination of the abdomen revealed a palpable mass in the left hypochondrium. This mass was confirmed as a pheochromocytoma. After adequately controlling his blood pressure he underwent left cortical sparing adrenalectomy. The post-operative period was uneventful. He was on steroid replacement that was subsequently withdrawn after his serum cortisol levels had normalized. His 8 AM cortisol after withdrawal of steroids was 12 µg/dl.He subsequently got married and had two children as shown in Figure 1, who also eventually developed similar tumors.

A 29-year-old hypertensive male with genetic proven VHL syndrome came to the Endocrinology department for evaluation. There was neither any history of paroxysm of sweating or palpitation nor any stigmata of hypercortisolism. He had undergone surgery for cervical (C2–C3) hemangioblastoma 2 years back. His elder sister also had features suggestive of Type 1 VHL syndrome (cerebellar hemangioblastomas, RCC of the left kidney, bilateral renal cysts, and pancreatic serous cystic neoplasm). However, her adrenal glands were normal. None of the other family members have features suggestive of VHL syndrome.Noncontrast computed tomography of the abdomen of our patient revealed a well-defined hypodense (<10 Hounsfield Unit) lesion of 3.2 cm × 3 cm in the left adrenal gland having central necrosis. There was more than 50% washout in postcontrast delayed image suggestive of adrenal adenoma [Figure 1]. In bilateral kidneys, there were multiple hypodense lesions with intense enhancement (RCC) along with nonenhancing cystic areas (renal cysts). Pancreas also showed multiple well-defined fluid attenuating cysts. On hormonal evaluation, plasma-free metanephrine (51.1 pg/ml; Normal < 65 pg/ml) and free normetanephrine (87.3 pg/ml; Normal < 180 pg/ml) levels were within normal limits. Serum dehydroepiandrosterone sulfate (267 μg/dl; Normal 167–591 μg/dl) and electrolytes were also normal. Normal values of 8 am serum cortisol (16.89 μg/dl), midnight awake cortisol (1.96 μg/dl) and overnight 1 mg dexamethasone suppression test (0.81 μg/dl) ruled out the possibility of endogenous hypercortisolism. Although biochemically there was no evidence of pheochromocytoma, metaiodobenzylguanidine (MIBG) scintigraphy was done on high suspicion of it for an adrenal mass in an established case of VHL. However, MIBG scan failed to show any abnormal tracer uptake in the abdomen.Figure 1: Computed tomography scan of adrenal adenoma. (a) Plain computed tomography abdomen showing homogenous, well defined left adrenal mass. (b) Early postcontrast image showing peripheral enhancement of the left adrenal mass. (c) Delayed postcontrast image showing more than 50% washout of contrastClick here to viewThen, the patient underwent left-sided adrenalectomy after controlling hypertension. On gross examination of the adrenal mass, an encapsulated gray-brown lesion measuring 3 cm × 3 cm × 3 cm in size with areas of hemorrhage was found. On microscopic examination, the tumor cells with clear cytoplasm were arranged in a nesting pattern [Figure 2]a. There was no significant atypia of the tumor cells and mitotic figures were also absent. On immunohistochemistry, the tumor cells were positive for Inhibin and Melan A [Figure 2]b and [Figure 2]c and negative for synaptophysin, thereby confirming adrenocortical adenoma and excluding pheochromocytoma. The adjacent adrenal gland was normal. For the largest focus of RCC, right-sided partial nephrectomy was done 3 months later. On histopathological examination, the tumor was circumscribed and measured 4 cm × 3 cm × 2 cm in dimensions. The cut section showed areas of hemorrhage and congestion without any areas of necrosis. On microscopy, the tumor had a sharp demarcation from normal parenchyma and the renal capsule without any evidence of infiltration [Figure 3]a. The tumor cells had minimal atypia, abundant clear/vacuolated cytoplasm, low nuclear grade, and rare mitosis. The morphological features were compatible with the clear cell type of RCC [Figure 3]b.Figure 2: Histopathology of adrenal tumor. (a) H and E stain (×200) of adrenal tumor showing tumor cells with clear cytoplasm arranged in a nesting pattern. (b) Immunohistochemistry of Melan A (×100) of adrenal tumor showing diffuse cytoplasmic positivity in tumor cells. (c) Immunohistochemistry of Inhibin (×100) of adrenal tumor showing strong cytoplasmic positivity in tumor cellsClick here to viewFigure 3: Histopathology of renal tumor. (a) The low magnification image (H and E stain ×100) of renal tumor shows the sharp demarcation between the tumor (left side) and adjacent normal renal parenchyma (right side). (b) The high magnification image (H and E ×400) of renal tumor shows the tumor cells with clear cytoplasm, low nuclear grade, intricate capillary network and lakes of red blood cellsClick here to viewGenetic analysis of VHL gene in this patient revealed a heterogeneous 5' splice site variation of intron 1 of the VHL gene that affects splice site of exon 1 (c. 340 + 1G > A). This mutation was pathogenic for VHL syndrome and previously reported in a few cases.[4],[5],[6]