An overview of 20 years of genetic studies in pheochromocytoma and paraganglioma.

Paragangliomas and pheochromocytomas (PPGL) are rare neuroendocrine tumours characterized by a strong genetic determinism. Over the past 20 years, evolution of PPGL genetics has revealed that around 40% of PPGL are genetically determined, secondary to a germline mutation in one of more than twenty susceptibility genes reported so far. More than half of the mutations occur in one of the SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), which encode the different subunits and assembly protein of a mitochondrial enzyme, succinate dehydrogenase. These susceptibility genes predispose to early forms (VHL, RET, SDHD, EPAS1, DLST), syndromic (RET, VHL, EPAS1, NF1, FH), multiple (SDHD, TMEM127, MAX, DLST, MDH2, GOT2) or malignant (SDHB, FH, SLC25A11) PPGL. The discovery of a germline mutation in one of these genes changes the patient's follow-up and allows genetic screening of affected families and the presymptomatic follow-up of relatives carrying a mutation.

Pheochromocytoma.

Pheochromocytomas are rare tumors originating in the adrenal medulla. They may be sporadic or in the context of a hereditary syndrome. A considerable number of pheochromocytomas carry germline or somatic gene mutations, which are inherited in the autosomal dominant way. All patients should undergo genetic testing. Symptoms are due to catecholamines over production or to a mass effect. Diagnosis is confirmed by raised plasma or urine metanephrines or normetanephrines. Radiology assists in the tumor location and any local invasion or metastasis. All the patients should have preoperative preparation with α-blockers and/or other medications to control hypertension, arrhythmia, and volume expansion. Surgery is the definitive treatment. Follow up should be life-long.

An update on adrenal endocrinology: significant discoveries in the last 10 years and where the field is heading in the next decade.

The last 10 years have produced an amazing number of significant discoveries in the field of adrenal endocrinology. The development of the adrenal gland was linked to specific molecules. Cortisol-producing lesions were associated mostly with defects of the cyclic AMP (cAMP) signaling pathway, whereas aldosterone-producing lesions were found to be the result of defects in aldosterone biosynthesis or the potassium channel KCNJ5 and related molecules. Macronodular adrenal hyperplasia was linked to ARMC5 defects and new genes were found to be involved in adrenocortical cancer (ACC). The succinate dehydrogenase (SDH) enzyme was proven to be the most important molecular pathway involved in pheochromocytomas, along with several other genes. Adrenomedullary tumors are now largely molecularly elucidated. Unfortunately, most of these important discoveries have yet to produce new therapeutic tools for our patients with adrenal diseases: ACC in its advanced stages remains largely an untreatable disorder and malignant pheochromocytomas are equally hard to treat. Thus, the challenge for the next 10 years is to translate the important discoveries of the previous decade into substantial advances in the treatment of adrenal disorders and tumors.

Who was Dr. William C. Baum?

The first discovery of primary hyperaldosteronism secondary to an aldosterone-secreting adrenal adenoma has been credited solely to Dr. Jerome Conn, an endocrinologist at the University of Michigan and for whom, Conn syndrome was named. Dr. William Baum, a urologist at the University of Michigan, however, was instrumental in the appropriate operation and historical aldosteronoma resection. Despite Dr. Baum's important role in this discovery, he was never included as an author in any of the subsequent papers describing Conn syndrome and, few today would recognize his name. So, who was Dr. Baum and what happened? This historical article aims to revisit the history surrounding the discovery of aldosteronoma as a cause of Conn's syndrome and to catalog the life and involvement of Dr. William C. Baum in that discovery.

15 YEARS OF PARAGANGLIOMA: Pheochromocytoma, paraganglioma and genetic syndromes: a historical perspective.

The last decades have elucidated the genetic basis of pheochromocytoma (PC) and paraganglioma (PGL) (PCPGL)-associated hereditary syndromes. However, the history of these syndromes dates back at least another 150 years. Detailed descriptions by clinicians and pathologists in the 19th and 20th centuries led to the recognition of the PCPGL-associated syndromes von Hippel-Lindau disease, neurofibromatosis type 1, and multiple endocrine neoplasia type 2. In the beginning of the current millennium the molecular basis of the hereditary PGL syndrome was elucidated by the discovery of mutations in genes encoding enzymes of the Krebs cycle, such as succinate dehydrogenase genes (SDHx) and other mutations, causing 'pseudo-hypoxia' signaling. These recent developments also marked a paradigm shift. It reversed the traditional order of genetic research that historically aimed to define the genetic basis of a known hereditary syndrome but now is challenged with defining the full clinical phenotype associated with a newly defined genetic basis. This challenge underscores the importance to learn from medical history, continue providing support for clinical research, and train physicians with regards to their skills to identify patients with PCPGL-associated syndromes to extend our knowledge of the associated phenotype. This historical overview provides details on the history of the paraganglial system and PCPGL-associated syndromes. As such, it hopefully will not only be an interesting reading for the physician with a historical interest but also emphasize the necessity of ongoing astute individual clinical observations and clinical registries to increase our knowledge regarding the full phenotypic spectrum of these conditions.

The adrenal medulla and extra-adrenal paraganglia: then and now.

The past 25 years have witnessed revolutionary changes in the care of patients with pheochromocytomas and extra-adrenal paragangliomas. Germline mutations of at least 13 genes are now associated with tumor development, a greater degree of hereditary susceptibility than for any other human neoplasm. Somatic mutations, either of the same genes or of several additional ones with closely related functions, are also increasingly recognized. Clinicians are now aware of the genetic implications of a pheochromocytoma or paraganglioma. All patients are therefore offered genetic testing and receive lifelong surveillance. Almost all of the mutated genes have well-described correlations with clinical and biochemical phenotypes. Tumors arising in patients with mutations of the SDHB gene have at least a 30 % chance of metastasizing and typically produce norepinephrine and/or dopamine. Assay of plasma-free metanephrines serves as a highly sensitive and specific biochemical screen for the presence of catecholamine-producing tumors, and the dopamine metabolite methoxytyramine serves as a useful marker for detecting minimally functional tumors or their metastases. New functional imaging techniques provide highly sensitive tumor localization. In addition to differential diagnosis, pathologists play new roles in helping to identify hereditary disease and guiding the sequence of genetic testing.

Evidence of MEN-2 in the original description of classic pheochromocytoma.

The first description of pheochromocytoma in 1886 has been attributed to Felix Fränkel, who described an 18-year-old woman with bilateral adrenal "sarcoma and angio-sarcoma." We reviewed the publication and then approached and assessed relatives of the patient to update the findings with the use of current technology. In-depth review revealed that the histopathological findings were consistent with pheochromocytoma. Because the proband was young and had bilateral disease at diagnosis, we hypothesized that she had an inherited condition. The presence of germ-line RET mutations in four living relatives demonstrates that the original patient and her family had multiple endocrine neoplasia type 2 and provides molecular evidence that she had pheochromocytoma.

The president and the pheochromocytoma.

President Eisenhower experienced an acute heart attack in September 1955 and died of ischemic cardiomyopathy 14 years later. The autopsy revealed, unexpectedly, a 1.5-cm pheochromocytoma in the left adrenal gland. In view of these hitherto unreported findings, the investigators analyzed the blood pressure pattern of the president throughout his life. Although hypertension was documented on and off from 1930 until his death, it is unknown whether the pheochromocytoma was present during his presidency. During the later part of President Eisenhower's life, excessive systolic and diastolic blood pressure spikes were documented, although he concomitantly had severe ischemic cardiomyopathy. In conclusion, most likely, the pheochromocytoma was the underlying cause of this erratic blood pressure pattern and may have worsened the course of the president's ischemic cardiomyopathy.