Rudolph's Pediatrics, 22nd Ed.

CHAPTER 537. Endocrine Neoplasia Syndromes

Steven D. Chernausek and Constantine A. Stratakis

INTRODUCTION

Most endocrine tumors in children occur in the context of genetic conditions predisposing to multiple neoplasias: multiple endocrine neoplasia types 1 and 2 (MEN-1 and MEN-2), Mc-Cune Albright syndrome, Carney complex, Von Hippel-Lindau (VHL) disease, Peutz-Jeghers syndrome (PJS), Cowden disease (CD), hereditary hyperparathyroidism and jaw tumor syndrome (HPJTS), and other extraordinarily rare conditions such as the isolated paraganglioma and Carney-Stratakis syndromes, Carney triad, Burt-Hogg-Dubé, and others. Therefore, it is now essential that the evaluation and management of these patients involves experts in cancer genetics and includes formal genetic counseling. Gene testing may be offered but performed in the setting of a cancer genetic consultation which includes pretest and posttest counseling. If a family-specific mutation is found, the genetics consultant can offer mutation-specific predictive testing to relatives. A list of endocrine neoplasia syndromes and their genetic causes is provided in Table 537-1. Disease associations in the multiple endocrine neoplasia syndromes are shown in Table 537-2. In this chapter we will discuss only the MEN conditions and the related Carney complex. Pheochromocytoma is also discussed as an endocrine tumor common in a number of endocrine neoplasia syndromes.

MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES

Multiple endocrine neoplasia (MEN) syndromes as well as related conditions (such as Carney complex) are autosomal dominant disorders in which specific endocrine glands and other organs develop hyperplasia or neoplasia.1,2Though more often seen in adults, these conditions may present in childhood. For MEN 2 and the familial pheochromocytomas, it is extremely important to diagnose these genetic conditions during childhood in order to provide periodic screening for the development of neoplasia and to offer timely prophylactic surgery.3,4

Table 537-1. Endocrine and Other Tumors in Childhood and Young Adulthood and Their Genetic Causes

MULTIPLE ENDOCRINE NEOPLASIA 1 (MEN 1)

Pathophysiology

MEN 1 is caused by germline mutations in MEN1. MEN1 encodes MENIN, which functions as a tumor suppressor.2,5 The principal glands affected in MEN 1 are the parathyroid, pituitary, and pancreatic islets.6 Nearly all individuals who harbor mutations characteristic of MEN 1 develop clinically significant disease at some point in their lifetime.7

Clinical Features

Hyperparathyroidism is the most common endocrine abnormality and is characterized by disease in multiple glands.1,2 Once manifest, it typically progresses slowly and steadily over time. The next most common is intrapancreatic islet cell tumors (gastrinomas and β cell tumors). Carcinoid tumors, adrenal cortical hyperplasia, and lipomas are also found in these individuals. Collagenomas and facial angiomata have been found in up to 90% of the patients with MEN 1 (Fig. 537-1A, B). These cutaneous features can suggest carrier status within affected families.1

Genetic Screening

Because of a nearly inevitable appearance of serious endocrine abnormalities, affected families should undergo screening to detect clinical manifestations before complications occur from hormone excess or tumors metastasis. Genetic testing should be offered to individuals with familial endocrinopathies typical for MEN 1 and should also be considered in sporadic cases where 2 or more MEN-1-type tumors occur. An abnormality in the MEN1 gene can be found in approximately 70% of cases of typical MEN 1. These include a wide variety of point mutations and deletions that result in inactivation of the MEN1gene (eFig. 537.1C ). If a specific mutation is identified, molecular genetic methods can determine carrier status. Most of the other cases probably also have defects that affect MENIN expression but were undetected by genetic analysis.7 Genetic testing should be offered to individuals with familial endocrinopathies typical for MEN 1. It should also be considered in sporadic cases where there are 2 or more MEN-1-type tumors.

Management

Current recommendations for carriers include annual biochemical monitoring for hyperparathyroidism, hyperinsulinism, and anterior pituitary disease beginning at age 5 years, accompanied by less frequent imaging studies. Testing for gastrinoma (which manifests as ulcers in the Zollinger-Ellison syndrome), carcinoid, and other intrapancreatic tumors should begin after age 20 years. This periodic screening will hopefully increase the early detection of tumors and will likely improve long-term survival, but this has yet to be proven effective.

Treatment of the hyperparathyroidism of MEN 1 involves subtotal parathyroidectomy with removal of 3.5 glands or a total parathyroidectomy with reimplantation.1 Similarly, when dealing with β-cell disease, the likelihood of multiple insulinomas is high and partial pancreatectomy might be required.

MULTIPLE ENDOCRINE NEOPLASIA 2 (MEN 2)

Pathophysiology

The MEN 2 syndromes include MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC) (eFig. 537.2A ). MEN 2 is caused by gain of function mutations in the RET proto-oncogene (eFig. 537.2B ). The RETproto-oncogene encodes RET protein, which is a cell surface growth factor receptor.8,9 It mediates the actions of the glial-derived neurotrophic factor family of peptide growth factors.10These factors regulate neural tissue development in peripheral and enteric nervous systems.11 In contrast to the situation in MEN 1 where a wide variety of specific mutations cause disease, a much smaller number of genetic mutations cause MEN 2.1 This is because these are activating mutations as opposed to inactivating mutations. Furthermore, the specific mutations observed correlate with the phenotype of the patients and with forms and aggressiveness of the associated neoplasms.12 For example, codon 634 mutations almost always produce MEN 2A, whereas mutations more toward the N-terminus of the protein typically produce FMTC. For MEN 2B, 95% of the patients have a mutation in the intracellular tyrosine kinase domain (M918T).

Table 537-2. Disease Associations in the Multiple Endocrine Neoplasia Syndromes

Multiple Endocrine Neoplasia Type 1

Parathyroid hyperplasia or adenoma

Islet cell hyperplasia, adenoma, or carcinoma

Pituitary hyperplasia or adenoma

Less common: carcinoid, pheochromocytoma, subcutaneous or visceral lipomas, cutaneous lichen amyloidosis

Multiple Endocrine Neoplasia Type 2

Type 2a

Medullary thyroid carcinoma

Pheochromocytoma

Parathyroid hyperplasia or adenoma

Familial medullary carcinoma

Type 2b

Medullary thyroid carcinoma

Pheochromocytoma

Mucosal and gastrointestinal neuromas

Intestinal neuronal dysplasia (presents like Hirschsprung disease)

Marfanoid features

Mixed Syndromes

Carney complex

Myxomas of heart, skin, and breast

Spotty cutaneous pigmentation

Testicular, adrenal, and GH producing pituitary tumors

Peripheral nerve schwannomas

Von Hippel–Lindau syndrome

Pheochromocytoma

Islet cell tumor

Renal cell carcinoma

Hemangioblastoma of central nervous system

Retinal angiomas

Neurofibromatosis with features of MEN1 or 2

FIGURE 537-1. A: Collagenomas and angiomas are present in most patients with MEN 1 starting around puberty; they can progress with age (as in the picture) but they can serve as a good diagnostic clinical marker for affected relatives of newly identified patients. B: Lipomas are also frequent in patients with MEN 1.

Clinical Features

Medullary carcinoma of the thyroid is found in all MEN 2 subtypes.6,8 It begins as C-cell hyperplasia and progresses to multicentric medullary thyroid carcinoma (Fig. 537-2A ). Individuals with familial medullary thyroid carcinoma develop the thyroid neoplasm as their sole manifestation. MEN 2A (Sipple syndrome) is characterized by medullary carcinoma of the thyroid, pheochromocytoma, and occasional hyperparathyroidism. Patients with MEN 2B have medullary carcinoma of the thyroid and pheochromocytomas as well, but also have an unusual somatic phenotype with a Marfanoid body habitus, multiple mucosal neuromas occurring throughout the gastrointestinal tract, and a characteristic facial appearance with thickened lips.12 The gastrointestinal tract neuromas are associated with gastrointestinal symptoms and poor intestinal function. MEN 2B is occasionally diagnosed when neuromas are found on rectal biopsy during evaluation for possible Hirschsprung disease. Interestingly, inactivating RET mutations cause approximately 15% to 20% of sporadic cases of Hirschsprung disease and up to 50% of familial cases.13

Management

Prophylactic thyroidectomy is proven to decrease morbidity and mortality among individuals with MEN 2.6,13 Measurement of circulating calcitonin, the product of C-cells, has been used to screen individuals with MEN 2 for medullary thyroid carcinoma.14 If calcitonin is high, further stimulation testing should not be performed. In familial MEN 2, calcitonin measurement following bolus pentagastrin administration can be used to screen for C-cell abnormalities. This was generally performed at around age 15 years of age, but now calcitonin measurements are only used for monitoring patients following thyroidectomy or as marker of tumor burden in patients with metastatic medullary thyroid carcinoma.

Because the penetrance of medullary thyroid carcinoma is nearly 100% for most RET mutations, prophylactic thyroidectomy in childhood is indicated.13 Molecular genetic testing not only allows identification of affected individuals, but it also permits stratification according to risk level. This information guides the timing of prophylactic thyroidectomy. The most aggressive forms of MCT are found in MEN 2B (codon 883, 918, and 922 mutations). Thyroidectomy in infancy is recommended for those individuals.6,13 For those with intermediate risk (codon 611, 619, 620, or 634 mutations), thyroidectomy should be performed before age 5. Those at lowest risk (ie, with mutations associated with familial MCT only) should have thyroidectomy performed by 5 to 10 years of age.

Serum calcium levels should be monitored to detect hyperparathyroidism. Those with mutations predisposing to pheochromocytoma should have periodic biochemical screening as described later in this chapter.

CARNEY COMPLEX

Carney complex was first reported in 1985; the syndrome described the association of heart myxomas and lentigines (Fig. 537-3 ) with pituitary-independent Cushing syndrome caused by an unusual adrenal pathology.15 The latter was characterized by multiple, small, pigmented, adrenocortical nodules, a disease that is now known as primary pigmented nodular adrenocortical disease (PPNAD).16

PATHOPHYSIOLOGY AND SCREENING

Carney complex and PPNAD are inherited in an autosomal dominant manner. The PRKARIA gene coding for the type IA regulatory subunit of protein kinase A (PKA) is the gene responsible for Carney complex in most patients.17Almost all Carney complex-responsible mutations lead to truncation of the protein. A defective cyclic nucleotide-dependent pathway had long been considered a candidate mechanism for the various manifestations of CNC including tumors similar to those of Mc-Cune Albright syndrome and paradoxical responses to hormonal stimuli. An overresponsive PKA enzyme is now considered the most likely mechanism underlying tumorigenesis in CNC.21,22 Clinical and biochemical screening for CNC remains the gold standard for the diagnosis of Carney complex. Molecular testing for PRKAR1A mutations is not recommended at present for all patients with Carney complex but may be advised for detection of affected patients in families with known mutations of that gene to avoid unnecessary medical surveillance of noncarriers.16

CLINICAL FEATURES

Cushing syndrome is the most common endocrine manifestation in Carney complex.15,16 Patients often present with atypical manifestations15,18; these patients tend to have normal or near-normal 24-hour cortisol production, but with absence of the normal circadian rhythmicity of this hormone. Occasionally, patients present with “periodic Cushing syndrome,” a variant of Cushing syndrome that is frequently found in children with PPNAD and related adrenal pathology.18,19 These patients also respond to dexamethasone with a paradoxical rise of cortisol production. The test may be used diagnostically for the identification of PPNAD, even in patients who have normal baseline cortisol levels. Some patients with Carney complex (10% to 15%) have a growth hormone (GH)-secreting pituitary adenoma that results in acromegaly. Abnormal 24-hour GH and prolactin secretion can precede the development of a pituitary tumor.20 Endocrine involvement in Carney complex also includes 3 types of testicular tumors16—large cell, calcifying Sertoli cell tumor (LCCSCT), adrenocortical rests, and Leydig cell tumor. More than 75% of affected male patients have 1 or more of these masses. LCCSCT may secrete estrogens and cause precocious puberty, gynecomastia, or both. Thyroid follicular neoplasms, both benign and malignant, have also been found in a number of patients. Nonendocrine tumors include psammomatous melanotic schwannoma, epithelioid blue nevus, and ductal adenoma of the breast.

MANAGEMENT

The recommended clinical surveillance of patients with Carney complex differs per age group.16 For postpubertal pediatric and adult patients, annual echocardiogram is necessary; this study should be obtained biannually for young patients with a history of excised myxoma. Other studies include testicular and thyroid ultrasound, and urinary free cortisol (UFC) and serum insulin-like growth factor-1 (IGF-1) levels. For prepubertal pediatric patients, annual echocardiogram is recommended (biannually for patients with a history of excised myxoma), as well as testicular ultrasound for boys. If close monitoring of growth rate and pubertal staging indicates other abnormalities, such as possible Cushing syndrome, appropriate testing should be done as needed. Dexamethasone-stimulation test and imaging of the adrenals may be necessary for the diagnosis of PPNAD. For gigantism, acromegaly, in addition to serum IGF-1 levels, pituitary magnetic resonance imaging and a 3-hour oral glucose tolerance test (oGTT) may be obtained. For psammomatous melanotic schwannoma, magnetic resonance imaging of the brain, spine, chest, abdomen, retroperitoneum, or pelvis may be necessary.

PHEOCHROMOCYTOMA

PATHOPHYSIOLOGY

Pheochromocytomas are chromaffin cell tumors that produce, store, metabolize, and secrete catecholamines.21-24 The metabolism of catecholamines is a more consistent process than that of catecholamine secretion. Nearly 80% to 85% of pheochromocytomas arise from the adrenal medulla; the remaining are derived from extra-adrenal chromaffin tissue, and they are called paragangliomas. MEN2A, neurofibromatosis type 1, and Von Hippel-Lindau disease predispose to the development of pheochromocytomas and paragangliomas.3,4,23 Familial nonsyndromic pheochromocytoma and paraganglioma are associated with germ-line mutations of genes encoding succinate dehydrogenase subunits B, C, and D (SDHBSDHC, and SDHD).3,23 In general, the traits are inherited in an autosomal dominant pattern and can be associated with other tumors in the context of Carney triad and Carney-Stratakis syndrome23SDHB defects have also been associated with renal cancer and thyroid tumors. In recent studies, it has been found that about 4% to 12% of apparently sporadic pheochromocytomas and in up to 50% of familial pheochromocytomas have either SDHD or SDHB mutation.3,25

CLINICAL FEATURES

Patients with MEN-2-related pheochromocytoma often lack hypertension or symptoms (occurs only in about 50%).4,24 MEN-2-related pheochromocytomas are characterized by production of epinephrine only or epinephrines together with norepinephrine and are therefore best detected by elevations of plasma or urinary metanephrine, normetanephrine, and related catecholamines. MEN-2-related pheochromocytomas are almost always intra-adrenal, often bilateral, and they are rarely malignant (< 5%). In addition, as with most epinephrine-secreting pheochromocytomas, hypertension when present is more likely to be paroxysmal than sustained. For these reasons, the diagnosis is easy to miss.

Less than 30% of patients with Von Hippel-Lindau disease (VHL germline mutations) develop a pheochromocytoma. These are exclusively of the noradrenergic phenotype, reflecting lack of production of epinephrine.4 These tumors are mainly located intra-adrenally and are in about 50% of patients bilateral with a less than 5% incidence of metastases. They do not express glucagon receptors so a glucagon test is not useful for diagnosis. These tumors are commonly found based on periodic annual screening or during searches for other tumors that are part of this syndrome. Therefore, when detected, these tumors are commonly small and often cannot be detected by nuclear imaging methods. Furthermore, about 80% of pheochromocytomas found in Von Hippel-Lindau disease patients are asymptomatic and not associated with hypertension.

Malignant pheochromocytoma is relatively rare,24 but patients with SDHB mutations have a particularly high incidence of metastatic pheochromocytoma. Malignant disease has an overall 5-year survival rate of approximately 50%.3

DIAGNOSIS

The diagnosis of pheochromocytoma depends on biochemical evidence of excessive catecholamine (norepinephrine, epinephrine, and dopamine) production by the tumor.24 Plasma metanephrine testing has the highest sensitivity (96%) for detecting a pheochromocytoma, but it has a low specificity (85%). Twenty-four-hour urinary collection for catecholamines and metanephrines has a sensitivity of 87.5% and a specificity of 99.7%. Therefore, high-risk patients such as those who have a genetic syndrome that predisposes them to pheochromocytoma should be screened with plasma metanephrine testing because it has a higher sensitivity. A fractionated plasma free metanephrine level may be measured in a seated, ambulatory patient with a standard venipuncture. Patients at lower risk such as those with flushing spells, adrenal incidentalomas, or uncontrolled hypertension may be screened with a 24-hour urine collection for catecholamines, vanniylmandelic acid, and metanephrines (and creatinine), because the specificity is greater, and sensitivity is relatively high. The most sensitive test for a pheochromocytoma is to obtain plasma metanephrine levels, and vanillylmandelic acid is the least specific test and has a false-positive rate greater than 15%.

Imaging tests that are useful include computerized tomography (CT) or magnetic resonance imaging (MRI). MRI is preferred due to the high sensitivity for adrenal tumors and better ability to localize extra-adrenal pheochromocytomas. Metaiodobenzylguanidine scintigraphy (MIBG scan) is used to locate and confirm pheochromocytoma and rule out metastatic disease. The specificity of MIBG is about 95% to 100%, but this technique offers suboptimal sensitivity (78% to 83%) with the 131I-labeled agent compared with 123I-MIBG scintigraphy that provides superior image quality and is especially useful for detecting recurrent or metastatic pheochromocytoma. Recently, positron emission tomography (PET) scanning, using 6-[18F]fluorodopamine or 6-[18F]fluorodopa, was shown to be superior to [123I]-MIBG and Octreoscan, especially for the localization of metastatic lesions or those tumors that are very difficult to localize (eg, previous surgical procedure).

Laparoscopic surgery is now the technique of first choice for resection adrenal and extra-adrenal pheochromocytomas.24 Due to the high incidence of bilateral adrenal disease in hereditary pheochromocytoma, partial adrenalectomies are advocated in these patients, thereby avoiding morbidity associated with medical adrenal replacement. Exposure to high levels of circulating catecholamines during surgery may cause hypertensive crises and arrhythmias, which can occur even when patients are preoperatively normotensive and asymptomatic. All patients with pheochromocytoma should therefore receive appropriate preoperative medical management to block the effects of released catecholamines. Phenoxybenzamine (Dibenzyline), an alpha-adrenoceptor blocker, is most commonly used for preoperative control of blood pressure. The drug is administered orally at a dose of 10 to 20 mg twice daily for 10 to 14 days before surgery (higher doses may be necessary to control symptoms of catecholamine overproduction). At some centers, a supplemental dose (0.5 to 1.0 mg/kg) is administered at midnight before surgery, in which case appropriate safeguards are required to avoid orthostatic hypotension. Intravenous fluids are usually administered to adequately replaced blood volume.