Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors of the adrenal glands and the sympathetic and parasympathetic paraganglia. They can occur sporadically or as a part of different hereditary tumor syndromes. About 30% of PCCs and PGLs are currently believed to be caused by germline mutations and several novel susceptibility genes have recently been discovered. The clinical presentation, including localization, malignant potential, and age of onset, varies depending on the genetic background of the tumors. By reviewing more than 1700 reported cases of hereditary PCC and PGL, a thorough summary of the genetics and clinical features of these tumors is given, both as part of the classical syndromes such as multiple endocrine neoplasia type 2 (MEN2), von Hippel–Lindau disease, neurofibromatosis type 1, and succinate dehydrogenase-related PCC–PGL and within syndromes associated with a smaller fraction of PCCs/PGLs, such as Carney triad, Carney–Stratakis syndrome, and MEN1. The review also covers the most recently discovered susceptibility genes includingKIF1Bβ, EGLN1/PHD2, SDHAF2, TMEM127, SDHA, andMAX, as well as a comparison with the sporadic form. Further, the latest advances in elucidating the cellular pathways involved in PCC and PGL development are discussed in detail. Finally, an algorithm for genetic testing in patients with PCC and PGL is proposed.

Context: The occurrence of multiple small pancreatic endocrine tumors in patients suffering from multiple endocrine neoplasia type 1 (MEN1) represents a unique possibility to study early neoplasms and their potential precursor lesions. To date, it is unknown whether small islet-like endocrine cell clusters found in MEN1 patients are neoplastic or rather hyperplastic. It is also unclear whether microadenomas develop from islets. Design: We hypothesized that monohormonal endocrine cell clusters observed in MEN1 patients are small neoplasms with loss of heterozygosity of the MEN1 locus. Using a technique combining fluorescence in situ hybridization of the MEN1 locus and the centromeric region of chromosome 11q with hormone immunostaining, we examined resection specimens from four MEN1 patients. We focused our investigations on the following: 1) typical microadenomas; 2) monohormonal endocrine cell clusters; 3) endocrine and exocrine structures entrapped in microadenomas; and 4) morphologically normal islets. Results: Loss of one MEN1 allele was found in all 27 microadenomas and 19 of 20 (95%) monohormonal endocrine cell clusters. By contrast, it was absent in islets and ductal or acinar structures. Our results indicate that monohormonal endocrine cell clusters represent a minute form of microadenomas. Conclusion: The frequent presence of single nonneoplastic insulin cells in microadenomas and the occurrence of microadenomas in islets suggest an islet origin of microadenomas. Islet hyperplasia does not seem to be an obligatory stage in pancreatic MEN1-associated tumor development.

Background Germline mutations are present in 20–30 per cent of patients with phaeochromocytoma. For patients who develop bilateral disease, complete removal of both adrenal glands (total adrenalectomy) will result in lifelong adrenal insufficiency with an increased risk of death from adrenal crisis. Unilateral/bilateral adrenal‐sparing surgery (subtotal adrenalectomy) offers preservation of cortical function and independence from steroids, but leaves the adrenal medulla in situ and thus at risk of developing new and possibly malignant disease. Here, present knowledge about how tumour genotype relates to clinical behaviour is reviewed, and application of this knowledge when choosing the extent of adrenalectomy is discussed. Methods A literature review was undertaken of the penetrance of the different genotypes in phaeochromocytomas, the frequency of bilateral disease and malignancy, and the underlying pathophysiological mechanisms, with emphasis on explaining the clinical phenotypes of phaeochromocytomas and their associated syndromes. Results Patients with bilateral phaeochromocytomas most often have multiple endocrine neoplasia type 2 (MEN2) or von Hippel–Lindau disease (VHL) with high‐penetrance mutations for benign disease, whereas patients with mutations in the genes encoding SDHB (succinate dehydrogenase subunit B) or MAX (myelocytomatosis viral proto‐oncogene homologue‐associated factor X) are at increased risk of malignancy. Conclusion Adrenal‐sparing surgery should be the standard approach for patients who have already been diagnosed with MEN2 or VHL when operating on the first side, whereas complete removal of the affected adrenal gland(s) is generally recommended for patients with SDHB or MAX germline mutations. Routine assessment of a patient's genotype, even after the first operation, can be crucial for adopting an appropriate strategy for follow‐up and future surgery.

Hypertension is a common medical condition and affects approximately 20% of the population in developed countries. Primary aldosteronism is the most common form of secondary hypertension and affects 8–13% of patients with hypertension. The two most common causes of primary aldosteronism are aldosterone-producing adenoma and bilateral adrenal hyperplasia. Familial hyperaldosteronism types I, II and III are the known genetic syndromes, in which both adrenal glands produce excessive amounts of aldosterone. However, only a minority of patients with primary aldosteronism have one of these syndromes. Several novel susceptibility genes have been found to be mutated in aldosterone-producing adenomas: KCNJ5, ATP1A1, ATP2B3, CTNNB1, CACNA1D, CACNA1H and ARMC5. This review describes the genes currently known to be responsible for primary aldosteronism, discusses the origin of aldosterone-producing adenomas and considers the future clinical implications based on these novel insights. Abstract Hypertension is a common medical condition and affects approximately 20% of the population in developed countries. Primary aldosteronism is the most common form of secondary hypertension and affects 8–13% of patients with hypertension. The two most common causes of primary aldosteronism are aldosterone-producing adenoma and bilateral adrenal hyperplasia. Familial hyperaldosteronism types I, II and III are the known genetic syndromes, in which both adrenal glands produce excessive amounts of aldosterone. However, only a minority of patients with primary aldosteronism have one of these syndromes. Several novel susceptibility genes have been found to be mutated in aldosterone-producing adenomas: KCNJ5, ATP1A1, ATP2B3, CTNNB1, CACNA1D, CACNA1H and ARMC5. This review describes the genes currently known to be responsible for primary aldosteronism, discusses the origin of aldosterone-producing adenomas and considers the future clinical implications based on these novel insights.