Germline mutations in the MEN 1 gene. These mutations are distributed within the nine coding exons of the gene and include missense, nonsense, frameshift, etc. Above the depiction of the gene are five spicing defects and two missense mutations. Below the gene are seven nonsense and six frameshift mutations. Reproduced with permission from Mutch, M.G., et al., Germline mutations in the multiple endocrine neoplasia type 1 gene: Evidence for frequent splicing defects. Human Mutation, 1999. 13: 175–85
Given the autosomal dominant inheritance pattern, MEN 1 affects men and women equally, with a prevalence of 2–3 per 100,000 individuals . The syndrome includes three primary disorders: hyperparathyroidism, adenomas of the anterior pituitary glands, and neuroendocrine tumors of the gastropancreatic system, i.e. insulinomas, gastrinomas, and glucagonomas . Other tumors strongly associated with MEN 1 include lipomas, facial angiofibromas, collagenomas, thyroid and adrenal nodules, and foregut carcinoids. Endocrine neoplasms arising in the MEN 1 syndrome are generally characterized by earlier age of onset and are often multifocal. Hyperparathyroidism is the most common endocrine abnormality seen in patients with MEN 1, developing in greater than 90 % of individuals, and usually involves multiple glands. It often presents in the second to fourth decade of life, but has been reported as early as 5 years of age. This is in contrast to sporadic forms of hyperparathyroidism, which peak in the sixth decade . Additionally, MEN 1 HPT has a high rate of recurrent hyperparathyroidism after technically and biochemically successful subtotal parathyroidectomy. This is due to the involvement of multiple glands, with all parathyroid tissue predisposed to hyperplasia. Asymmetric glandular enlargement is characteristic of patients with MEN 1 (Fig. 6.2), while fewer than 15 % of patients with sporadic hyperparathyroidism have multiglandular disease . In one study, with a follow-up of 12 years, the recurrence rate was above 50 % .
Asymmetric parathyroid hyperplasia in MEN 1. Depicted are four parathyroid glands according to their in situ location within the neck along with the asymmetric hyperplasia commonly found in MEN 1 patients
Genetic testing and family counseling should be an integral part of the algorithm of treating patients with familial hyperparathyroidism, though ultimately clinical judgment and physician experience should dictate the type and timing of testing and treatment. Sequencing costs continue to be relatively expensive and insurance programs often do not cover genetic testing. Yearly screening of calcium, prolactin, pancreatic polypeptide, and gastrin levels is recommended in at-risk MEN 1 family members. Consensus guidelines have been published and contain expert recommendations for evaluation, imaging, treatment, and follow-up for patients with MEN 1 . Figure 6.3 contains a summary of recommendations for evaluation of these patients.
Consensus guidelines for the clinical evaluation, genetic testing, imaging , and surveillance of MEN 1 patients. Reproduced with permission from Whaley JG, Lairmore TC. Multiple Endocrine Neoplasia Type 1: Current diagnosis and management. In: McGraw-Hill’s manual of endocrine surgery, Morita SY, Dackiw APB, Zeiger MA (editors), McGraw-Hill Companies, Inc., New York, 2009
MEN 1: Treatment
In the biochemical evaluation of hyperparathyroidism, an elevated serum calcium level (hypercalcemia) is usually the first abnormality detected in patients with MEN 1. An inappropriately elevated parathyroid hormone (PTH) level in the setting of hypercalcemia confirms the diagnosis of hyperparathyroidism. Further evaluation may include measurement of elevated 24-h urine calcium if the diagnosis is still in question. One prospective study demonstrated that systematic screening of patients with MEN 1 showed a rapid rise in calcium levels between ages 10–15 years, before clinically evident disease , Fig. 6.4.
Serum calcium levels vs. age in genetically positive patients. Prospective data demonstrating different time points in age (years) and serum calcium levels (mg/dl) for each patient. A rapid rise in calcium levels is evidence between the ages of 10–15 years, often before clinically evident disease. The dotted line demonstrates the upper-limit of normal serum calcium levels. Reproduced with permission from Lairmore TC, Piersall L, DeBenedetti M, Dilley W, Mutch M, Whelan A. Clinical genetic testing and early surgical intervention in patients with multiple endocrine neoplasia type 1 (MEN 1). Ann Surg, 2004. 239(5): 637–45; discussion 645-7
Preoperative parathyroid imaging in patients with MEN 1 should take into account the fact that at initial surgery all four glands and thymic horns should be identified intraoperatively. This falls outside of the “minimally invasive” algorithm. We only perform an ultrasound of the neck, mainly to look for thyroid gland pathology that may need to be addressed. To demonstrate the limitations of preoperative imaging in patients with multi-gland parathyroid disease, one retrospective study evaluated preoperative imaging and intraoperative parathyroid hormone monitoring to detect multi-gland disease (MGD) with the objective to assess the best predictor for detecting MGD . Out of a cohort of 233 patients with hyperparathyroidism of all types, single gland disease (SGD) was found in 88 % and MGD in 10 %, with persistent hyperparathyroidism in 2.6 % of patients. For patients with operatively diagnosed MGD, preoperative sestamibi imaging correctly predicted MGD in only 2 of 23 patients, incorrectly showed SGD in 9 of 23 and was negative in 12 of 23. Ultrasound correctly predicting MGD in 6 of 23, incorrectly predicted SGD in 6 of 23, and was negative in 8 of 23 patients. Intraoperative PTH levels indicated MGD in 15 of 18 patients but falsely predicted cure after single gland excision in 3 of 18 patients. With all 3 modalities combined, the authors concluded MGD in 16 of 18 patients. In general, intra-op identification of all four parathyroid glands is standard in patients with MEN 1, along with serial measurement of intraoperative PTH levels.
There are two commonly utilized surgically procedures for the management of HPT in MEN 1: total parathyroidectomy with autotransplantation, and subtotal parathyroidectomy. Total parathyroidectomy is combined with heterotopic intramuscular autotransplantation, either in the sternocleidomastoid (SCM) or the brachioradialis muscle in the forearm . This approach appropriately reduces the volume of parathyroid tissue in an attempt to achieve normal calcium levels, while the auto-transplantation of parathyroid tissue in a vascular skeletal muscle bed allows simple access for further parathyroid tissue reduction (in the setting of recurrent hyperparathyroidism). The second approach involves performing a subtotal parathyroidectomy (3.5 glands), while leaving a viable parathyroid gland remnant on a vascular pedicle . This approach also reduces the volume of functional parathyroid tissue in the neck and results in normalization of calcium level, without the need for auto-transplantation, which entails a period of about 6 weeks for the transplanted parathyroid fragments to function adequately. Regardless of which approach utilized, the surgeon should make an effort to identify all four parathyroid glands as well as supernumerary or ectopic glands. The thymic horns should also be removed because additional parathyroid tissue may be present in these structures in MEN 1 patients. Multiple studies have demonstrated similar rates of recurrent hyperparathyroidism, and permanent postoperative hypoparathyroidism and associated hypocalcemia with either procedure [13–22]. One randomized prospective trial compared total parathyroidectomy with autotransplantation to subtotal parathyroidectomy in MEN 1 patients. No significant differences in rates of permanent hypoparathyroidism or recurrent hyperparathyroidism were noted .
Parathyroidectomy in MEN 1 has a higher risk of postoperative hypoparathyroidism and recurrent hyperparathyroidism when compared with parathyroidectomy for sporadic cases. To address the issue of postoperative hypoparathyroidism and symptomatic postoperative hypocalcemia, high volume centers with Good Medical Practice (GMP) capability utilize cryopreservation of autologous parathyroid tissue at the time of the index operation. This tissue can be transplanted back into the patient if transplanted autografts do not work, or if the viable parathyroid fragment fails. In one study that examined the functionality of delayed cryopreserved parathyroid autografts, however, the authors found that only 60 % of these delayed autografts showed evidence of graft function (based on venous PTH sampling) when comparing grafted versus nongrafted limbs. Additionally, 40 % of patients receiving delayed cryopreserved autografts resolved their postoperative hypocalcemia, and required no further calcium supplementation . It is best to do a successful operation the first time.
In cases of recurrent or persistent MEN1 hyperparathyroidism, it is extremely important to carefully review the previous operative notes and pathology reports to figure out exactly what was done at the initial operation. If the patient has parathyroid autografts in the forearm, parathyroid hormone gradients calculated from levels obtained from basilic vein blood draws from each arm, will help localize the source. If there is a large gradient in the grafted arm, then hyperplasia of the autografts is the likely source. If not, there may be hyperfunctioning parathyroid tissue left in the neck, and imaging with sestamibi scanning, ultrasound, and computed tomography of the neck and chest should be done. Sestamibi scanning should include the grafted forearm.
MEN 2: Introduction
MEN 2 syndromes include MEN 2A and MEN 2B. Familial non-MEN medullary thyroid carcinoma (FMTC) is now considered a sub-type of MEN 2A. The prevalence is approximately 1 per 30,000 . The hallmark disease of the MEN 2 syndromes is medullary thyroid carcinoma (MTC), which occurs in near total penetrance in affected families . MEN 2 syndromes are caused by activating mutations in the RET proto-oncogene , found on chromosome 10, and are autosomal dominant . The RET gene encodes a tyrosine kinase protein involved in multiple functions of cellular growth and differentiation of tissues, and is variably expressed in tissues of neural crest origin. These include the parafollicular C-cells of the thyroid, parathyroid glands, and adrenal enterochromaffin cells. The genetic and cellular basis for the MEN 2 phenotype is gain of function in the protein product of RET, rather than loss of function, as is seen in MEN 1.
The classic constellation of disease processes in MEN 2A includes medullary thyroid carcinoma (MTC) , adrenal medullary hyperplasia with pheochromocytoma, and hyperparathyroidism. MEN 2B includes medullary thyroid carcinoma, pheochromocytomas, and mucosal neuromas. Genetic testing is an important part of the workup in the assessment of patients with suspected MEN 2 syndrome, and the clinical features and tumor behavior are closely related to the specific RET germ-line mutation present. The mainstay for treatment in patients with MEN 2, with early identification of germ-line mutations in the RET gene, is prophylactic thyroidectomy to prevent medullary thyroid carcinoma. The role of surgery and management of hyperparathyroidism in the setting of MEN 2 is discussed below.
While virtually all patients who inherit a germ-line mutation in the RET proto-oncogene will develop MTC during their lifetime, primary hyperparathyroidism develops in only 10–25 % of MEN 2A patients [25, 27], and occurs mostly in patients with specific mutations. Mutations in codons 609, 611, 618, 620, 631, 634, 791, and 804 of RET are associated with hyperparathyroidism. As with MEN 1, multi-gland disease is common , and is found in 80 % of patients with hyperparathyroidism in MEN 2A. The most commonly associated mutation associated with hyperparathyroidism in MEN2A is a C634R mutation . Routine screening for hyperparathyroidism in patients with MEN 2A should include annual serum calcium levels, with an elevated level followed up with PTH measurement.
MEN 2A: Treatment
The goal of preventative surgery for patients with MEN 2A and 2B is well established, because the development of MTC is almost 100 % in carriers of MEN 2 germline mutations . Current evidence supports preventative surgery in the first year of life for patients with MEN 2B, and by the age of 5 or 6 or patients with MEN 2A, though there is controversy regarding this . Preservation of parathyroid glands in preventative thyroidectomy in children can be very difficult given their small size, appearance, and prominent thymic and nodal tissue (Fig. 6.5). These procedures should only be done by experienced surgeons. Additionally, the pursuit of an appropriate central node dissection compromises the blood supply to the parathyroid glands (inferior thyroid artery). Preservation of parathyroid function may be accomplished by either careful preservation on an intact vascular pedicle, or autotransplantation of minced devascularized glands. Parathyroid glands should be minced into 1 × 1 mm fragments and fragments transplanted into multiple individual muscle pockets, with ~2–3 fragments per pocket. This exposes the fragmented parathyroid glands to a bed of well-vascularized skeletal muscle, with an increase in available surface area . Experiences at high volume centers in patients with MEN 2A have demonstrated that total thyroidectomy, central node dissection, and total parathyroidectomy with auto-transplantation of parathyroid tissue into the nondominant forearm is safe, and long term disease control was excellent, with normal parathyroid function in 47/50 patients with no need for supplementation . Follow-up studies demonstrated that nodal metastases is rare in MEN 2A < 8 years of age and in patients with basal calcitonin levels less than 40 pg/ml [29, 30]—compelling a change in practice to perform total thyroidectomies and leave parathyroid glands in-situ if possible if the above conditions are met, assuming that there are no PTH abnormalities at the time of surgery. Interestingly, one study demonstrated that hyperparathyroidism did not develop in any of their 27 patients treated with early thyroidectomy , though the reasons for this currently remain unclear.
Post-procedure operative bed in an MEN 2A patient at 2.5 years of age. Depicted here is relationship between the recurrent laryngeal nerve (RLN) and the left upper and left lower parathyroid glands. Note the diminutive size of the glands, as well as the size of the RLN
If the parathyroid glands are left in-situ and the patient develops subsequent hyperparathyroidism, imaging with sestamibi scan, ultrasound, and computed tomography should be done to localize the hyperfunctioning gland or glands. The approach to these patients is similar to MEN 1 patients, described previously. Bilateral neck exploration with identification of all remaining parathyroid glands may be necessary, and intraoperative parathyroid hormone monitoring should be used to ensure correction. As with MEN 1, surgical options include a subtotal parathyroidectomy (3.5 gland), total parathyroidectomy, or removal of only abnormal appearing glands . The optimal surgical management remains controversial , however, as some specialist argue for the removal of only abnormal glands, while others advocate for a subtotal parathyroidectomy and leave a ½ gland remnant on a well vascularized pedicle. Other experts prefer total parathyroidectomy with auto-transplantation into the nondominant forearm muscle, even in the presence of normal appearing parathyroid tissue. This is due to the assumption that eventual parathyroid hyperplasia in normal appearing glands is high and provides the advantage that the forearm autograft is theoretically more easily accessible in cases recurrent hyperparathyroidism. Transplantation to the forearm theoretically prevents a reexploration of the neck. A recently published study by our group examined total parathyroidectomy with autotransplantation vs. an in situ preservation approach. Patients in the in situ group had parathyroid autotransplantation only if parathyroids were devasularized during surgery. Follow-up results demonstrated permanent hypoparathyroidism in 3/50 (6 %) patients in the total parathyroidectomy/forearm transplant group, and 1 of 102 (<1 %) patients in the in situ group. The authors therefore concluded that successful preservation of parathyroids in situ during preventative thyroidectomy (the authors performed central neck dissection only if the serum calcitonin > 40 pg/ml) was a safe and effective alternative . Irrespective of the surgical treatment, the general consensus is that institutional preference should be followed, as recurrence rates are generally low, whether in performing subtotal parathyroidectomy, or total parathyroidectomy [29, 32].
Hyperparathyroidism-Jaw Tumor Syndrome: Introduction
HPT-JT is an autosomal dominant disorder caused by mutations in the HRPT2 gene, found on chromosome 1 . HRPT2 encodes a 531 amino acid protein and is thought to act as a tumor-suppressor gene. Mutations in the HRPT2 gene reduce expression and/or function of the nuclear protein parafibromin (aka cell division cycle 73—CDC73), a regulator of gene expression and inhibitor of cellular proliferation [35, 36]. Further studies demonstrated that a high number of these mutations resulted in a premature truncated protein with loss of function . Currently, there are 111 recognized mutations: 68 germline, 38 somatic, and 5 with an origin that is not yet defined . Of these, germline frameshift mutations and nonsense mutations account for the majority (88 %) of identified mutations in HRPT2 HPT-JT .
One of the earliest reports of HPT-JT came from a case report in 1958  that described a multigenerational family with hyperparathyroidism in which four of five affected first generation members developed jaw tumors. Additionally, three members of the third generation (with HPT) also developed jaw tumors, which appeared after parathyroidectomy. These jaw tumors were histologically distinct from the classic hyperparathyroid-associated “brown tumors”. Brown tumors generally represent a reparative process secondary to heavy osteoclast activity. Histology usually demonstrates fibrous tissue, woven bone, evidence of angiogenesis, granulation tissue, giant cells, osteoblasts and osteoclasts, and deposition of hemosiderin . The lesions seen in the family were fibro-osseous appearing, lacked giant cells, and appeared histologically different from brown tumors.
The clinical presentation of HPT-JT includes parathyroid tumors (adenomas and carcinomas), uterine tumors, ossifying jaw tumors, and renal abnormalities [36, 42]. The most common initial presentation in HPT-JT is primary hyperparathyroidism, with a penetrance of 80–90 %, and often manifests in the third decade of life . Parathyroid adenomas often occur asynchronously in HPT-JT  and while most tumors are benign, the risk of malignant transformation is higher than in nonfamilial HPT adenomas. With a reported incidence of 15 %, parathyroid carcinoma is of clinical concern in patients with HPT-JT  compared to <1 % in other forms of primary HPT. One study examining germline and somatic mutations in HRPT2 in the setting of sporadic parathyroid carcinomas found that 10 of 15 patients had HRPT2 mutations, and while they did not specifically examine the linkage between these mutations and known mutations in HPT-JT, they concluded that patients with apparently sporadic parathyroid carcinoma, who carry germline mutations in HRPT2 may have evidence of HPT-JT syndrome, or phenotypic variants . This is supported by another study that demonstrated that a small minority of patients (2 of 7) with apparently sporadic parathyroid carcinoma, carried a germline HRPT2 mutation—suggesting they may have occult HPT-JT . Unlike the high level of penetrance of hyperparathyroidism in HPT-JT, renal abnormalities are only seen in approximately 5–15 % of patients, with cystic kidney disease being the most common . Unlike sporadic forms of hyperparathyroidism or familial HPT in MEN 1 or 2A, patients with HPT-JT can also develop renal anomalies including renal cysts, adult onset Wilms’ tumor, and hamartomas . Another feature of HPT-JT is the development of uterine tumors. These have been described as affecting up to 75 % of females with HPT-JT . Uterine tumors in HPT-JT may be malignant or benign, and include adenosarcomas (2/15), adenofibromas (5/15), leiomyomas (4/15), adenomyosis (8/15), and endometrial hyperplasia, (4/15). Some women had more than one uterine pathology .