MEN 2A is also known as Sipple syndrome named after John Sipple, a pulmonary physician who first reported this endocrinopathy [1, 2]. This syndrome includes MTC , pheochromocytoma, and primary hyperparathyroidism. MTC is the most common clinical presentation of MEN 2A, with nearly 100 % of patients affected. The average age of presentation of a patient with sporadic MTC is in the sixth decade. In contrast, the average age of presentation for a patient with MEN 2A syndrome is 20–40 years, with some more aggressive forms presenting by age 5 [6].

Less commonly, patients present with symptoms due to pheochromocytomas. Pheochromocytomas are present in approximately 50 % of patients with MEN 2A and cause various symptoms including palpitations, headaches, hypertension, and flushing. Hyperparathyroidism occurs in 15–30 % of MEN 2A patients, with the peak incidence in the third or fourth decade. Multiglandular hyperplasia is the most common histologic finding, although single gland adenomas are present in some patients [4, 5, 7]. In addition, rare variants of MEN 2A exist, which include the above-listed endocrine tumors, along with either cutaneous lichen amyloidosis or Hirschsprung’s disease [8, 9].

Like MEN 2A, MEN 2B patients have MTC and pheochromocytomas, but they do not present with parathyroid disease. Instead, MEN 2B patients exhibit various unique physical features, most commonly mucosal neuromas and a marfan-like physical constitution.

MTC in MEN 2B also manifests in nearly 100 % of patients. MTC develops earlier and more aggressively than in MEN 2A. Metastatic disease has been reported before age 1, and death may occur in the second or third decade of life [4, 5]. Pheochromocytomas occur in more than half of MEN 2B patients with similar presentations as in MEN 2A. There are no well-documented examples of parathyroid disease in MEN 2B patients.

The mucosal neuromas and marfanoid body habitus are the most distinctive features of MEN 2B and are recognizable in childhood. Patients can have prominent lips and prognathic jaws (Fig. 1). The corneal nerves can also be quite enlarged. The marfanoid habitus combined with facial features is unique, and often unrelated affected individuals look strikingly similar. Neuromas are present on the tip of the tongue, buccal mucosa, under the eyelids, and throughout the gastrointestinal (GI) tract. The most common presentation in children relates to GI symptomatology, including intermittent colic, pseudo-obstruction, and diarrhea. Some children present with failure to thrive secondary to these persistent GI symptoms [5, 10]. Almost 75 % of patients will have skeletal abnormalities that give them a marfanoid body habitus [11]. Mucosal neuromas or GI gangliomas are present in nearly 100 % of MEN 2B patients [12]. Confirmation of these various clinical features can be made by biopsy of the mucosal neuromas, rectal biopsy, or slit-lamp examination for medullated corneal nerves [6].

Once thought to be a distinct entity, first described by John Farndon, FMTC is now considered a common subvariant of MEN 2A, in which MTC is the only manifestation. The clinical diagnosis of FMTC is established by the presence of MTC in greater than four family members over multiple generations without any evidence of pheochromocytoma or hyperparathyroidism. The clinical course of MTC in FMTC patients is more benign than in MEN2A and MEN2B, with a late onset or no clinical manifestation of disease. Thus, the overall prognosis is relatively good and better than the other MEN 2 subtypes [8, 9].

Since the penetrance of pheochromocytoma is 50 % in MEN 2A, it is possible that MEN 2A could masquerade as FMTC in small kindreds. It is important to consider this, because failure to recognize this scenario could lead to serious morbidity and mortality from an undiagnosed pheochromocytoma in an affected family member [4, 5].

Pheochromocytomas are present in about 50 % of both MEN 2A and MEN 2B patients. The characteristics of the tumors and clinical manifestations are similar in the two subvariants. Pheochromocytomas arise in the adrenal medulla from neural crest-derived chromaffin cells which primarily secrete the catecholamines epinephrine and norepinephrine. Tumors tend to be benign with metastasis being uncommon. Tumors are commonly bilateral. If they do not present simultaneously, more than 50 % of patients who have had unilateral adrenalectomy later develop a pheochromocytoma in the contralateral gland within a decade. A distinguishing feature from hereditary paraganglioma syndromes is that the pheochromocytomas in MEN 2 are almost always found within the adrenal gland, not as extra-adrenal tumors [4, 5, 7]. Clinical presentation is similar to sporadic forms with patients having symptoms from catecholamine excess such as headaches, palpitations, hypertension, tachycardia, and flushing.

Screening for pheochromocytoma involves measuring plasma or 24-h urinary levels of metanephrines and normetanephrines. If the biochemical diagnosis is confirmed, the patient should get imaging to localize the tumor with either computed tomography (CT) or magnetic resonance imaging (MRI) [4]. Further localization and staging for metastatic disease is performed with radiolabeled metaiodobenzylguanidine (MIBG) scintigraphy and positron emission tomography (PET) with different radiotracers such as fluorine-18-dopamine ([¹⁸F]DA), fluorine-18-dihydroxyphenylalanine ([¹⁸F]DOPA) or fluorine-18-fluorodeoxyglucose ([¹⁸F]FDG). MIBG scans have historically been the most widespread functional imaging technique used for localization of pheochromocytomas and paragangliomas with high sensitivity and specificity [14, 15]. However, recent studies have shown that MIBG has lower sensitivity for certain conditions such as familial pheochromocytoma and paraganglioma syndromes and malignant disease. Increasing evidence suggests that fluorine dopamine (FDA)-PET, fluorodeoxyglucose (FDG)-PET, and dihydroxyphenylalanine (DOPA)-PET are superior localization studies for pheochromocytoma and are helpful in the above scenarios when MIBG fails to demonstrate disease, though suspicion for disease is high (Fig. 2). MIBG is still the most widely used functional imaging technique and has the added advantage of selecting for patients with metastatic disease who are suitable for MIBG nuclear therapy [14, 15].

Because of the possible coexistence of pheochromocytoma, it is essential to screen for these tumors before thyroidectomy for MTC. There is significant morbidity and mortality from an undiagnosed pheochromocytoma. Before the association of pheochromocytomas and MTC in MEN 2 was recognized, many patients died from a hypertensive crisis during or after thyroidectomy secondary to unrecognized disease [1]. In fact, before advances in screening, pheochromocytoma, not MTC, was the leading cause of death in MEN 2A patients. If a patient has both a pheochromocytoma and MTC, adrenalectomy should be performed first to avoid an intraoperative adrenal crisis during thyroidectomy [4].