Primary HPT is the most common clinical manifestation in individuals with MEN-1. Studies have shown that by 40 years of age, approximately 95 % of patients with MEN-1 mutations have parathyroid disease [27, 30]. HPT is also the most common initial presentation of MEN-1, accounting for 60–90 % of presenting complaints. The rate of symptomatic hypercalcemia is markedly decreased to 30 % in those patients within a known MEN-1 kindred who are known to be at risk and are undergoing regular biochemical surveillance. MEN-1 HPT accounts for only 2–4 % of all HPT cases in the community and 10 % of those with multiglandular disease [38]. MEN-1-related HPT differs from sporadic cases, and these differences have implications for the surgical management of this disease. First, the typical age of presentation is approximately 20–25 years of age, which is in marked contrast to sporadic HPT, which most commonly occurs during the fifth decade of life [27, 30]. Second, the sex distribution for MEN-1-related HPT is equal with males just as likely to have HPT as females [30, 32]. In contrast, sporadic HPT is three times more common in females. Thirdly, the pattern of parathyroid enlargement differs between MEN-1 and sporadic HPT. In sporadic HPT, approximately 90 % of cases are due to a single adenoma, while, in comparison, HPT in MEN-1 presents with multiglandular disease [39, 40]. The development of parathyroid hyperplasia in MEN-1 is asynchronous in nature with all four glands ultimately involved but at varying times. This gives rise to a pattern of asymmetrical disease with some glands showing significant growth, while others appear initially to be macroscopically normal [40, 41]. MEN-1 parathyroid disease is associated with supernumerary glands and ectopic glands in up to 15 % [42–44]. This pattern of multiglandular involvement and frequent occurrence of extra glands supports the traditional surgical approach of four-gland parathyroid exploration with cervical thymectomy. This approach has been challenged more recently with some groups advocating focused parathyroidectomy in selected cases [45]. Histopathologically, the enlarged glands show multiple monoclonal tumors, which have developed from polyclonal hyperplasia [46]. MEN-1 patients appear to demonstrate markedly increased levels of parathyroid mitogenic factor found within the serum of MEN1 patients. This mitogenic factor is similar to fibroblast growth factor and influences growth of the endothelial component of parathyroid glands [47]. Despite this mitogenic influence, it is unusual for HPT cases in MEN-1 to progress to parathyroid cancer [48–52].

Aside from the differences in age and sex distribution at presentation, the symptoms of MEN-1-associated HPT do not differ significantly from those seen in the sporadic form of the disease. In the past, up to 50 % of MEN-1 cases have presented with symptomatic renal calculi; however, with the advent of genetic testing and aggressive screening protocols, more patients are being managed with subclinical disease. The typical symptoms of HPT including bone abnormalities, musculoskeletal complaints, fatigue, and change in mental state are also seen. MEN-1 patients with HPT may complain of fatigue, polydipsia, polyuria, joint pain, bone pain, constipation, and sometimes depression.

Inappropriately elevated intact serum parathyroid hormone levels in conjunction with hypercalcemia (raised ionized or total-albumin corrected serum calcium) are the principal biochemical characteristic in the diagnosis of HPT. Biochemical confirmation of HPT should always include measurement of 24-h urinary calcium to exclude benign familial hypocalciuric hypercalcemia. Determination of 1,25-dihydroxyvitamin D3 levels and serum blood urea and nitrogen and glomerular filtration rate (GFR) are important to rule out secondary causes of HPT. Screening for other elements of the MEN-1syndrome in patients considered a risk such as gastrin, insulin, Chromogranin A, pancreatic polypeptide (PP), IGF-1, VIP, glucagon, and prolactin can be obtained. Screening also includes cross-sectional imaging of the pancreas, adrenal glands, thymus, and pituitary. With the advent of minimally invasive surgery and focused parathyroid exploration for sporadic HPT, localization studies with ultrasound, sestamibi scintigraphy, or 4-D CT (four-dimensional computerized tomography) are now well established in the preoperative workup of sporadic cases. However, the role of localization studies for parathyroid tumors in MEN-1 is more controversial. This is because HPT in MEN-1 is multiglandular and traditional surgical approaches have required bilateral exploration. Parathyroid imaging for preoperative localization has not traditionally been advocated as a thorough four-gland exploration is the most widely adopted surgical approach [26, 53, 54]. However, the frequency of supernumerary glands and ectopic parathyroid locations challenges this view, and our practice more recently has been to routinely perform ultrasound and sestamibi scintigraphy prior to parathyroid surgery in MEN-1. This approach may also provide the surgeon and patient with the option of undertaking focused or minimally invasive parathyroid surgery if the imaging points to enlarged parathyroid glands confined to just one side of the neck [45]. Careful preoperative imaging is very important in planning surgery for patients with recurrent or persistent HPT, and in this setting concordant functional and anatomical imaging should be sought.

The indications for parathyroid surgery generally follow the guidelines suggested for the management of asymptomatic HPT [55]. MEN-1 patients with Zollinger–Ellison syndrome should be considered for early parathyroid surgery as hypercalcemia is a potent stimulus for gastrin secretion, and normalizing parathyroid hormone levels improves control of hypergastrinemia [56, 57]. With the advent of easily available hormone assays, DNA analysis, improved imaging modalities, and surveillance of known MEN-1 kindreds, patients are increasingly presenting with mild HPT and are often asymptomatic. The question in these cases is when to initiate surgical intervention.

The ideal surgical approach to parathyroid disease in MEN-1 should strike a balance between minimizing the incidence of persistent or recurrent disease and avoiding permanent hypoparathyroidism. Surgery should be initiated in a timely fashion prior to the development of significant renal or skeletal complications. Prophylactic parathyroidectomy is generally not supported, and it is important that the surgeon understands that the outcome of permanent hypoparathyroidism may be worse than the disease itself considering there is rarely any malignant potential to parathyroid tumors in MEN-1 HPT. The timing of surgery and the specific surgical approaches are important and debatable. Some groups have suggested that delaying surgery until hypercalcemia worsens or symptoms develop allows the pathological glands to enlarge making success at the first operation greater and reduces the need for subsequent reoperations. However, proponents for early surgical intervention argue that normalization of hypercalcemia may not only decrease gastrin production but also help to avoid the skeletal and renal complications of HPT [57–62].

The main operative approaches at initial surgery are total parathyroidectomy with autotransplantation of a portion of parathyroid tissue (total parathyroidectomy; tPTX) or subtotal parathyroidectomy (sPTX; Fig. 1). In both procedures, cervical thymectomy is recommended to allow inspection of the thymus for supernumerary glands as well as potentially reducing the chance of thymic carcinoid tumors developing. In a small number of cases where preoperative imaging suggests asymmetric parathyroid disease, and parathyroid enlargement is confined to one side of the neck, we have undertaken unilateral parathyroid exploration with removal of the ipsilateral thymus via a small cervical incision [45]. This approach certainly avoids the problem of hypoparathyroidism; however, its long-term durability requires longer follow-up.

The operative approach requires a delicate balance between avoiding recurrence and preventing hypoparathyroidism. The two main surgical approaches for MEN-1 HPT are tPTX or sPTX (Fig. 1). Procedures which involve a lesser approach to parathyroidectomy (< sPTX) than tPTX or sPTX are associated with higher (> 50 %) persistent or recurrent rates and lower disease-free intervals (7 years for < sPTX vs. 16.5 years for tPTX or sPTX) [63]. However, in selected cases, we have undertaken unilateral minimally invasive parathyroidectomy (MIP) with a resulting improvement in the complication profile and acceptable control of HPT [45]. Figure 2 illustrates a case in which unilateral parathyroidectomy has been performed with thymectomy.

The technique for total parathyroidectomy involves removing all visible parathyroid glands with autotransplantation of small fragments of parathyroid tissue from the most normal-appearing gland either into the brachioradialis muscle of the forearm or into the sternocleidomastoid muscle of the neck. Once all four parathyroids have been located, cervical thymectomy is undertaken and a portion of the most normal-appearing gland weighing approximately 50 mg is transplanted into the brachioradilais muscle of the nondominant upper limb via a longitudinal incision placed over the forearm [64]. This autotransplantation site is marked with titanium clips to facilitate excision in the event of graft hyperfunction. The remaining glands are removed and sent for histological assessment with a portion of tissue also saved for cryopreservation. The benefits of using cryopreserved tissue in hypoparathyroid patients have also been questioned by other groups who have demonstrated poor success rates after transplantation of cryopreserved tissue [65–69].

sPTX (Fig. 1), in which three and a half glands are removed with a small parathyroid remnant equal to approximately 50 mg left in situ on a vascularized pedicle, is utilized by many especially in the younger patients. Once the viability of the retained gland is established, the remaining glands are removed and the in situ parathyroid is marked with a nonabsorbable Prolene suture. At this point, a cervical thymectomy is performed. Cervical thymectomy has the theoretical advantage of decreasing the rate of MEN-1-associated thymic carcinoid tumors as well as increasing the disease-free survival rates [70–72]. However, it should be noted that cases of thymic carcinoid have been documented in patients with prior cervical thymectomy [73–76].

sPTX is associated with lower rates of hypoparathyroidism on the order of 1–10 % compared with rates of 10–30 % seen in tPTX. However, MEN-1 patients treated with sPTX have been shown to have recurrence rates within 10–12 years between 40 and 60 % of patients, in comparison to sporadic HPT with rates of < 5 % [41, 77–84].

Persistent HPT in MEN-1 is typically due to the failure to identify and resect supernumerary or ectopic glands at the first procedure [85]. In addition, the development of hyperfunction in autotransplanted tissue or parathyroids which were retained at sPTX is a frequent cause of recurrence [85]. Index cases of MEN-1 who undergo surgery for what appears at initial presentation to be sporadic disease are at risk of recurrence as a result of the widespread use of minimally invasive techniques for parathyroidectomy and because hyperplasia may not have been appreciated at the initial procedure. As such, screening patients who present with HPT at a young age, < 40 years for MEN-1, is appropriate. Imaging studies are essential for planning reoperative surgery in contrast to primary cases and having two concordant imaging modalities are ideal prior to proceeding to reoperative parathyroidectomy. Useful modalities include two or more of the following: CT, sestamibi, cervical ultrasonography, MRI with sensitivities of 70–85, 70–85, 25–90, and 60–80 %, respectively [86–90] (Fig. 3). In cases where forearm autotransplantation has been performed, graft hyperfunction can be demonstrated by drawing blood from both arms, while a tourniquet is applied to the side which carries the autotransplanted tissue. Known as the Casanova test, this approach can confirm differential PTH readings between the grafted forearm and peripheral blood and can direct the surgeon to either repeat cervical surgery or removal of the forearm graft. In difficult cases of recurrent disease, where ultrasound, sestamibi, 4-D CT, and MRI are unhelpful, we undertake selective venous sampling (SVS). This modality requires an experienced interventional radiologist and the mapping of PTH gradients from multiple sites along the internal jugular and mediastinal veins. SVS has been shown to correctly localize hyperfunctioning parathyroids in 60–85 % of cases [91–94]. In cases where imaging has failed to confidently localize the site of recurrence, undirected cervical reoperation is usually best avoided, and we prefer to observe the patient for a period of 6 months before repeating our imaging algorithm.

After adequate preoperative imaging, reoperation for HPT in MEN-1 can often be undertaken as a focused procedure without the need for extensive dissection. The majority of recurrent intrathymic parathyroid tumors sit within the upper anterior mediastinum and can be successfully removed via cervical exploration. For tumors located deeper in the middle and posterior mediastinum and aorticopulmonary window, minimally invasive thoracic approaches and even formal sternotomy is necessary to establish safe surgical access.

Achieving normocalcemia after revision surgery for HPT in MEN-1 has been described in up to 70 % of cases [72, 95]. Recurrences following reoperation are frequent and occur in 30–60 % of patients with 10–30 % of patients acquiring permanent hypoparathyroidism and 1–5 % with permanent recurrent laryngeal nerve injury. In cases where surgery is not feasible or the patient is not a suitable operative candidate, ethanol ablation and angiographic embolization have been used with some success. Medical therapy with the calcimimetic agent Cinacalcet can be used to manage refractory cases where operative intervention is not appropriate.

The prevalence of nonfunctioning PNETs in MEN-1 is around 20–35 % and clinical presentation has been detected as early as 12 and 14 years of age [26, 27, 108]. Despite its asymptomatic nature, they have a high-malignant potential and subsequently need to be monitored and resected before malignant progression. The 10-year survival rate for patients with nonfunctioning PNETs has been found to be around 62 % [108, 141]. Furthermore, the rate of survival can be correlated to tumor size and metastasis. Tumors with diameters of < 1, 1–3, and > 3 cm had metastasized in 4, 28, and 43 % of patients, respectively. This correlated with 8-year survival rates of approximately 100, 80, and 40 %, respectively [108]. Studies by Triponez and colleagues have recommended surgical excision in those that are ≥ 2 cm. However, in their study, 4 % of patients with tumors, less than 1 cm had metastasis [108, 109]. Due to this, some have called for earlier intervention on lesions > 1 cm. Whether preventing metastasis by more aggressive and earlier surgical intervention is improving survival has yet to be elucidated.

Carcinoid tumors in MEN-1 patients are found predominately in the foregut (gastric, thymic, and bronchial). Carcinoids occur in about 15 % of MEN-1 patients [26, 27, 29]. MEN-1 carcinoid tumors also have strong gender-specific distribution; thymic carcinoids are found predominantly in males and bronchial carcinoids in females [24, 71, 144, 145]. Furthermore, unlike other MEN-1 associated tumors, the average age of onset is much later in the 40s [146]. This reflects the lack of hormonal oversecretion and compression-induced symptoms. These tumors have malignant potential and represent the second most common case of tumor-related deaths. Thymic carcinoids are more often malignant than bronchial carcinoids (70 vs. 20 %, respectively).

Thymic carcinoids are usually found at an advanced stage as a large invasive mass as can be seen in Fig. 7. Patients with MEN-1 thymic carcinoid have a poor prognosis with reported median survival of 28 months and 5-year survival rate of less than 30 %. As such, it has been suggested that routine transcervical thymectomy should be performed as part of procedures for parathyroid disease [70–72]. However, resection does not prevent development of thymic carcinoids as there have been many reported cases of post-cervical thymectomized patients with thymic carcinoids [73–76]. It seems rational therefore to carefully monitor for progression of thymic disease. Bronchial carcinoids on the other hand are more indolent. Gastric carcinoids are tumors of enterochromaffin-like cells, and they occur in 10 % of MEN-1 patients. They can be found either as an incidental finding on endoscopy or cause hormonal sequelae by its excessive secretion of serotonin and histamine. Also known as type II gastric neuroendocrine tumours, they have a 5-year disease free survival rate of 78%. Lesions smaller than 2 cm are recommended for endoscopic removal; however, larger ones require surgical excision.