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InternalMed_Harrison. A single adrenal pheochromocytoma in a patient with an otherwise unremarkable history may still be associated with mutations of VHL, RET, SDHB, or SDHD (in decreasing order of frequency). Two-thirds of extra-adrenal tumors are associated with one of these syndromes, and multifocal tumors occur with decreasing frequency in carriers of RET, SDHD, VHL, and SDHB mutations. About 30% of head and neck paragangliomas are associated with germ-line mutations of one of the SDH subunit genes (most often SDHD) and are rare in carriers of VHL, RET, and TMEM127 mutations (Fig. 407-6F). Immunohistochemistry is helpful in the preselection of hereditary pheochromocytoma. Negative immunostaining with antibodies to SDHB, TMEM127, and MAX may predict mutations of the SDH, TMEM127, and MAX genes, respectively.


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InternalMed_Harrison. Once the underlying syndrome is diagnosed, the benefit of genetic testing can be extended to relatives. For this purpose, it is necessary to identify the germ-line mutation in the proband and, after genetic counseling, to perform DNA sequence analyses of the responsible gene in relatives to determine whether they are affected (Chap. 84). Other family members may benefit when individuals who carry a germ-line mutation are biochemically screened for paraganglial tumors.


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InternalMed_Harrison. Asymptomatic paraganglial tumors, now often detected in patients with hereditary tumors and their relatives, are challenging to manage. Watchful waiting strategies have been introduced. Head and neck paragangliomas—mainly carotid body, jugular, and vagal tumors—are increasingly treated by radiation, since surgery is frequently associated with permanent palsy of cranial nerves II, VII, IX, X, XI, and XII. Nevertheless, tympanic paragangliomas are symptomatic early, and most of these tumors can easily be resected, with subsequent improve- Rajesh V. Thakker


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InternalMed_Harrison. Multiple endocrine neoplasia (MEN) is characterized by a predilection for tumors involving two or more endocrine glands. Four major forms of MEN are recognized and referred to as MEN types 1–4 (MEN 1–4) (Table 408-1). Each type of MEN is inherited as an autosomal dominant syndrome or may occur sporadically; that is, without a family history. However, this distinction between familial and sporadic forms is often difficult because family members with the disease may have died before symptoms developed. In addition to MEN 1–4, at least six other syndromes are associated with multiple endocrine and other organ neoplasias (MEONs) (Table 408-2). These MEONs include the hyperparathyroidism-jaw tumor syndrome, Carney complex, von Hippel-Lindau disease (Chap. 407), neurofibromatosis type 1 (Chap. 118), Cowden’s syndrome, and McCune-Albright syndrome (Chap. 426e); all of these are inherited as autosomal dominant disorders, except for McCune-Albright syndrome, which is caused by mosaic


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InternalMed_Harrison. 1 (Chap. 118), Cowden’s syndrome, and McCune-Albright syndrome (Chap. 426e); all of these are inherited as autosomal dominant disorders, except for McCune-Albright syndrome, which is caused by mosaic expression of a postzygotic somatic cell mutation (Table 408-2).


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InternalMed_Harrison. A diagnosis of a MEN or MEON syndrome may be established in an individual by one of three criteria: (1) clinical features (two or more of the associated tumors [or lesions] in an individual); (2) familial pattern (one of the associated tumors [or lesions] in a first-degree relative of a patient with a clinical diagnosis of the syndrome); and (3) genetic analysis (a germline mutation in the associated gene in an individual, who may be clinically affected or asymptomatic). Mutational analysis in MEN and MEON syndromes is helpful in clinical practice to: (1) confirm the clinical diagnosis; (2) identify family members who harbor the mutation and require screening for relevant tumor detection and early/appropriate treatment; and (3) identify the ~50% of family members who do not harbor the germline mutation and can, therefore, 2335 be alleviated of the anxiety of developing associated tumors. This latter aspect also helps to reduce health care costs by reducing the need for unnecessary


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InternalMed_Harrison. germline mutation and can, therefore, 2335 be alleviated of the anxiety of developing associated tumors. This latter aspect also helps to reduce health care costs by reducing the need for unnecessary biochemical and radiologic investigations.


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InternalMed_Harrison. MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 Clinical Manifestations MEN type 1 (MEN 1), which is also referred to as Wermer’s syndrome, is characterized by the triad of tumors involving the parathyroids, pancreatic islets, and anterior pituitary. In addition, adrenal cortical tumors, carcinoid tumors usually of the foregut, meningiomas, facial angiofibromas, collagenomas, and lipomas may also occur in some patients with MEN 1. Combinations of the affected glands and their pathologic features (e.g., hyperplastic adenomas of the parathyroid glands) may differ in members of the same family and even between identical twins. In addition, a nonfamilial (e.g., sporadic) form occurs in 8–14% of patients with MEN 1, and molecular genetic studies have confirmed the occurrence of de novo mutations of the MEN1 gene in approximately 10% of patients with MEN 1. The prevalence of MEN 1 is approximately 0.25% based on randomly chosen postmortem studies but is 1–18% among patients with primary


InternalMed_Harrison

InternalMed_Harrison. of the MEN1 gene in approximately 10% of patients with MEN 1. The prevalence of MEN 1 is approximately 0.25% based on randomly chosen postmortem studies but is 1–18% among patients with primary hyperparathyroidism, 16–38% among patients with pancreatic islet tumors, and <3% among patients with pituitary tumors. The disorder affects all age groups, with a reported age range of 5 to 81 years, with clinical and biochemical manifestations developing in the vast majority by the fifth decade. The clinical manifestations of MEN 1 are related to the sites of tumors and their hormonal products. In the absence of treatment, endocrine tumors are associated with an earlier mortality in patients with MEN 1, with a 50% probability of death by the age of 50 years. The cause of death is usually a malignant tumor, often from a pancreatic neuroendocrine tumor (NET) or foregut carcinoid. In addition, the treatment outcomes of patients with MEN 1–associated tumors are not as successful as those in


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InternalMed_Harrison. tumor, often from a pancreatic neuroendocrine tumor (NET) or foregut carcinoid. In addition, the treatment outcomes of patients with MEN 1–associated tumors are not as successful as those in patients with non–MEN 1 tumors. This is because MEN 1–associated tumors, with the exception of pituitary NETs, are usually multiple, making it difficult to achieve a successful surgical cure. Occult metastatic disease is also more prevalent in MEN 1, and the tumors may be larger, more aggressive, and resistant to treatment.


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InternalMed_Harrison. Parathyroid Tumors (See also Chap. 424) Primary hyperparathyroidism occurs in approximately 90% of patients and is the most common feature of MEN 1. Patients may have asymptomatic hypercalcemia or vague symptoms associated with hypercalcemia (e.g., polyuria, polydipsia, constipation, malaise, or dyspepsia). Nephrolithiasis and osteitis fibrosa cystica (less commonly) may also occur. Biochemical investigations reveal hypercalcemia, usually in association with elevated circulating parathyroid hormone (PTH) (Table 408-3). The hypercalcemia is usually mild, and severe hypercalcemia or parathyroid cancer is a rare occurrence. Additional differences in the primary hyperparathyroidism of patients with MEN 1, as opposed to those without MEN 1, include an earlier age at onset (20–25 years vs 55 years) and an equal male-to-female ratio (1:1 vs 1:3). Preoperative imaging (e.g., neck ultrasound with 99mTc-sestamibi parathyroid scintigraphy) is of limited benefit because all parathyroid glands may


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InternalMed_Harrison. and an equal male-to-female ratio (1:1 vs 1:3). Preoperative imaging (e.g., neck ultrasound with 99mTc-sestamibi parathyroid scintigraphy) is of limited benefit because all parathyroid glands may be affected, and neck exploration may be required irrespective of preoperative localization studies.


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InternalMed_Harrison. Surgical removal of the abnormally overactive parathyroids in patients with MEN 1 is the definitive treatment. However, it is controversial whether to perform subtotal (e.g., removal of 3.5 glands) or total parathyroidectomy with or without autotransplantation of parathyroid tissue in the forearm, and whether surgery should be performed at an early or late stage. Minimally invasive parathyroidectomy is not recommended because all four parathyroid glands are usually affected with multiple adenomas or hyperplasia. Surgical experience should be taken into account given the variability in pathology in MEN 1. Calcimimetics (e.g., cinacalcet), which act via MEN 2 (10 cen-10q11.2) MEN 2A MTC only MEN 2B (also known as MEN 3)


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InternalMed_Harrison. MEN 2 (10 cen-10q11.2) MEN 2A MTC only MEN 2B (also known as MEN 3) Parathyroid adenomaa Pituitary adenomaa Reproductive organ tumorsa (e.g., testicular cancer, neuroendocrine cervical carcinoma) ?Adrenal + renal tumorsa 83/84, 4-bp del (≈4%) 119, 3-bp del (≈3%) 209-211, 4-bp del (≈8%) 418, 3-bp del (≈4%) 514-516, del or ins (≈7%) Intron 4 ss (≈10%) 634, e.g., Cys → Arg (~85%) RET 618, missense (>50%) RET 918, Met → Thr (>95%) CDKN1B; no common mutations identified to date aInsufficient numbers reported to provide prevalence information. Note: Autosomal dominant inheritance of the MEN syndromes has been established. Abbreviations: del, deletion; ins, insertion; MTC, medullary thyroid cancer; NET, neuroendocrine tumor; PPoma, pancreatic polypeptide–secreting tumor; VIPoma, vasoactive intestinal polypeptide–secreting tumor. Source: Reproduced from RV Thakker et al: J Clin Endocrinol Metab 97:2990, 2012.


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InternalMed_Harrison. Source: Reproduced from RV Thakker et al: J Clin Endocrinol Metab 97:2990, 2012. the calcium-sensing receptor, have been used to treat primary hyperparathyroidism in some patients when surgery is unsuccessful or contraindicated. Pancreatic Tumors (See also Chap. 113) The incidence of pancreatic islet cell tumors, which are NETs, in patients with MEN 1 ranges from 30 to 80% in different series. Most of these tumors (Table 408-1) produce excessive amounts of hormone (e.g., gastrin, insulin, glucagon, vasoactive intestinal polypeptide [VIP]) and are associated with distinct clinical syndromes, although some are nonfunctioning or non-secretory. These pancreatic islet cell tumors have an earlier age at onset in patients with MEN 1 than in patients without MEN 1.


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InternalMed_Harrison. Gastrinoma Gastrin-secreting tumors (gastrinomas) are associated with marked gastric acid production and recurrent peptic ulcerations, a combination referred to as the Zollinger-Ellison syndrome. Gastrinomas occur more often in patients with MEN 1 who are older than age 30 years. Recurrent severe multiple peptic ulcers, which may perforate, and cachexia are major contributors to the high mortality. Patients with Zollinger-Ellison syndrome may also suffer from diarrhea and steatorrhea. The diagnosis is established by demonstration of an elevated fasting serum gastrin concentration in association with increased basal gastric acid secretion (Table 408-3). However, the diagnosis of Zollinger-Ellison syndrome may be difficult in hypercalcemic MEN 1 patients, because hypercalcemia can also cause hypergastrinemia.


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InternalMed_Harrison. aThe inheritance for these disorders is autosomal dominant, except MAS, which is due to mosaicism that results from the postzygotic somatic cell mutation of the GNAS1 gene, encoding Gsα. b?, unknown. Ultrasonography, endoscopic ultrasonography, computed tomography (CT), nuclear magnetic resonance imaging (MRI), selective abdominal angiography, venous sampling, and somatostatin receptor scintigraphy are helpful in localizing the tumor prior to surgery. Gastrinomas represent more than 50% of all pancreatic NETs in patients with MEN 1, and approximately 20% of patients with gastrinomas will be found to have MEN 1. Gastrinomas, which may also occur in the duodenal mucosa, are the major cause of morbidity and mortality in patients with MEN 1. Most MEN 1 gastrinomas are malignant and metastasize before a diagnosis is established.


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InternalMed_Harrison. Medical treatment of patients with MEN 1 and Zollinger-Ellison syndrome is directed toward reducing basal acid output to <10 mmol/L. Parietal cell H+-K+-adenosine triphosphatase (ATPase) inhibitors (e.g., omeprazole or lansoprazole) reduce acid output and are the drugs of choice for gastrinomas. Some patients may also require additional treatment with the histamine H2 receptor antagonists, cimetidine or ranitidine. The role of surgery in the treatment of gastrinomas in patients with MEN 1 is controversial. The goal of surgery is to reduce the risk of distant metastatic disease and improve survival. For a nonmetastatic gastrinoma situated in the pancreas, surgical excision is often effective. However, the risk of hepatic metastases increases with tumor size, such that 25–40% of patients with pancreatic NETs >4 cm develop hepatic metastases, and 2337 50–70% of patients with tumors 2–3 cm in size have lymph node metastases. Survival in MEN 1 patients with gastrinomas <2.5 cm in size is


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InternalMed_Harrison. pancreatic NETs >4 cm develop hepatic metastases, and 2337 50–70% of patients with tumors 2–3 cm in size have lymph node metastases. Survival in MEN 1 patients with gastrinomas <2.5 cm in size is 100% at 15 years, but 52% at 15 years, if metastatic disease is present. The presence of lymph node metastases does not appear to adversely affect survival. Surgery for gastrinomas that are >2–2.5 cm has been recommended, because the disease-related survival in these patients is improved following surgery. In addition, duodenal gastrinomas, which occur more frequently in patients with MEN 1, have been treated successfully with surgery. However, in most patients with MEN 1, gastrinomas are multiple or extrapancreatic, and with the exception of duodenal gastrinomas, surgery is rarely successful. For example, the results of one study revealed that only ~15% of patients with MEN 1 were free of disease immediately after surgery, and at 5 years, this number had decreased to ~5%; the respective


InternalMed_Harrison

InternalMed_Harrison. For example, the results of one study revealed that only ~15% of patients with MEN 1 were free of disease immediately after surgery, and at 5 years, this number had decreased to ~5%; the respective outcomes in patients without MEN 1 were better, at 45% and 40%. Given these findings, most specialists recommend a nonsurgical management for gastrinomas in MEN 1, except as noted earlier for smaller, isolated lesions. Treatment of disseminated gastrinomas is difficult. Chemotherapy with streptozotocin and 5-fluorouracil; hormonal therapy with octreotide or lanreotide, which are human somatostatin analogues; hepatic artery embolization; administration of human leukocyte interferon; and removal of all resectable tumor have been successful in some patients.


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InternalMed_Harrison. Insulinoma These β islet cell insulin-secreting tumors represent 10–30% of all pancreatic tumors in patients with MEN 1. Patients with an insulinoma present with hypoglycemic symptoms (e.g., weakness, headaches, sweating, faintness, seizures, altered behavior, weight gain) that typically develop after fasting or exertion and improve after glucose intake. The most reliable test is a supervised 72-h fast. Biochemical investigations reveal increased plasma insulin concentrations in association with hypoglycemia (Table 408-3). Circulating concentrations of C peptide and proinsulin, which are also increased, are useful in establishing the diagnosis. It also is important to demonstrate the absence of sulfonylureas in plasma and urine samples obtained during the investigation of hypoglycemia (Table 408-3). Surgical success is greatly enhanced by preoperative localization by endoscopic ultrasonography, CT scanning, or celiac axis angiography. Additional localization methods may include


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InternalMed_Harrison. (Table 408-3). Surgical success is greatly enhanced by preoperative localization by endoscopic ultrasonography, CT scanning, or celiac axis angiography. Additional localization methods may include preoperative and perioperative percutaneous transhepatic portal venous sampling, selective intraarterial stimulation with hepatic venous sampling, and intraoperative direct pancreatic ultrasonography. Insulinomas occur in association with gastrinomas in 10% of patients with MEN 1, and the two tumors may arise at different times. Insulinomas occur more often in patients with MEN 1 who are younger than 40 years, and some arise in individuals younger than 20 years. In contrast, in patients without MEN 1, insulinomas generally occur in those older than 40 years. Insulinomas may be the first manifestation of MEN 1 in 10% of patients, and approximately 4% of patients with insulinomas will have MEN 1.


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InternalMed_Harrison. Abbreviations: CT, computed tomography; EUS, endoscopic ultrasound; IGF-I, insulin-like growth factor I; MRI, magnetic resonance imaging; PTH, parathyroid hormone. Source: Reproduced from RV Thakker et al: J Clin Endocrinol Metab 97:2990, 2012. Medical treatment, which consists of frequent carbohydrate meals and diazoxide or octreotide, is not always successful, and surgery is the optimal treatment. Surgical treatment, which ranges from enucleation of a single tumor to a distal pancreatectomy or partial pancreatectomy, has been curative in many patients. Chemotherapy may include streptozotocin, 5-fluorouracil, and doxorubicin. Hepatic artery embolization has been used for metastatic disease.


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InternalMed_Harrison. Glucagonoma These glucagon-secreting pancreatic NETs occur in <3% of patients with MEN 1. The characteristic clinical manifestations of a skin rash (necrolytic migratory erythema), weight loss, anemia, and stomatitis may be absent. The tumor may have been detected in an asymptomatic patient with MEN 1 undergoing pancreatic imaging or by the finding of glucose intolerence and hyperglucagonemia. Surgical removal of the glucagonoma is the treatment of choice. However, treatment may be difficult because approximately 50–80% of patients have metastases at the time of diagnosis. Medical treatment with somatostatin analogues (e.g., octreotide or lanreotide) or chemotherapy with streptozotocin and 5-fluorouracil has been successful in some patients, and hepatic artery embolization has been used to treat metastatic disease.


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InternalMed_Harrison. Vasoactive Intestinal Peptide (VIP) Tumors (VIPomas) VIPomas have been reported in only a few patients with MEN 1. This clinical syndrome is characterized by watery diarrhea, hypokalemia, and achlorhydria and is also referred to as the Verner-Morrison syndrome, the WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome, or the VIPoma syndrome. The diagnosis is established by excluding laxative and diuretic abuse, by confirming a stool volume in excess of 0.5–1.0 L/d during a fast, and by documenting a markedly increased plasma VIP concentration. Surgical management of VIPomas, which are mostly located in the tail of the pancreas, can be curative. However, in patients with unresectable tumor, somatostatin analogues, such as octreotide and lanreotide, may be effective. Streptozotocin with 5-fluorouracil may be beneficial, along with hepatic artery embolization for the treatment of metastases.


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InternalMed_Harrison. Pancreatic Polypeptide-Secreting Tumors (Ppomas) and Nonfunctioning Pancreatic NETs PPomas are found in a large number of patients with MEN 1. No pathologic sequelae of excessive polypeptide (PP) secretion are apparent, and the clinical significance of PP is unknown. Many PPomas may have been unrecognized or classified as nonfunctioning pancreatic NETs, which likely represent the most common enteropancreatic NET associated with MEN 1 (Fig. 408-1). The absence of both a clinical syndrome and specific biochemical abnormalities may result in a delayed diagnosis of nonfunctioning pancreatic NETs, which are associated with a worse prognosis than other functioning tumors, including insulinoma and gastrinoma. The optimum screening method and its timing interval for nonfunctioning pancreatic NETs remain to be established. At present, endoscopic ultrasound likely represents the most sensitive method of detecting small pancreatic tumors, but somatostatin receptor scintography is the most


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InternalMed_Harrison. NETs remain to be established. At present, endoscopic ultrasound likely represents the most sensitive method of detecting small pancreatic tumors, but somatostatin receptor scintography is the most reliable method for detecting metastatic disease (Table 408-3).


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InternalMed_Harrison. The management of nonfunctioning pancreatic NETs in the asymptomatic patient is controversial. One recommendation is to undertake surgery irrespective of tumor size after biochemical


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InternalMed_Harrison. FIGURE 408-1 Pancreatic nonfunctioning neuroendocrine tumor (NET) in a 14-year-old patient with multiple endocrine neoplasia type 1 (MEN 1). A. An abdominal magnetic resonance imaging scan revealed a low-intensity >2.0 cm (anteroposterior maximal diameter) tumor within the neck of pancreas. There was no evidence of invasion of adjacent structures or metastases. The tumor is indicated by white dashed circle. B. The pancreatic NET was removed by surgery, and macroscopic examination confirmed the location of the tumor (white dashed circles) in the neck of the pancreas. Immunohistochemistry showed the tumor to immunostain for chromogranin A, but not gastrointestinal peptides or menin, thereby confirming that it was a non-secreting NET due to loss of menin expression. (Part A adapted with permission from PJ Newey et al: J Clin Endocrinol Metab 10:3640, 2009.) assessment is complete. Alternatively, other experts recommend surgery based on tumor size, using either >1 cm or >3 cm at different


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InternalMed_Harrison. from PJ Newey et al: J Clin Endocrinol Metab 10:3640, 2009.) assessment is complete. Alternatively, other experts recommend surgery based on tumor size, using either >1 cm or >3 cm at different centers. Pancreatoduodenal surgery is successful in removing the tumors in 80% of patients, but more than 40% of patients develop complications, including diabetes mellitus, frequent steatorrhea, early and late dumping syndromes, and other gastrointestinal symptoms. However, ~50–60% of patients treated surgically survive >5 years. When considering these recommendations, it is important to consider that occult metastatic disease (e.g., tumors not detected by imaging investigations) is likely to be present in a substantial proportion of these patients at the time of presentation. Inhibitors of tyrosine kinase receptors (TKRs) and of the mammalian target of rapamycin (mTOR) signaling pathway have been reported to be effective in treating pancreatic NETs and in doubling the progression-free


InternalMed_Harrison

InternalMed_Harrison. tyrosine kinase receptors (TKRs) and of the mammalian target of rapamycin (mTOR) signaling pathway have been reported to be effective in treating pancreatic NETs and in doubling the progression-free survival time.


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InternalMed_Harrison. Other Pancreatic NETs NETs secreting growth hormone–releasing hormone (GHRH), GHRHomas, have been reported rarely in patients with MEN 1. It is estimated that ~33% of patients with GHRHomas have other MEN 1–related tumors. GHRHomas may be diagnosed by demonstrating elevated serum concentrations of growth hormone and GHRH. More than 50% of GHRHomas occur in the lung, 30% occur in the pancreas, and 10% are found in the small intestine. Somatostatinomas secrete somatostatin, a peptide that inhibits the secretion of a variety of hormones, resulting in hyperglycemia, cholelithiasis, low acid output, steatorrhea, diarrhea, abdominal pain, anemia, and weight loss. Although 7% of pancreatic NETs secrete somatostatin, the clinical features of somatostatinoma syndrome are unusual in patients with MEN 1.


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InternalMed_Harrison. Pituitary Tumors (See also Chap. 403) Pituitary tumors occur in 15–50% of patients with MEN 1 (Table 408-1). These occur as early as 5 years of age or as late as the ninth decade. MEN 1 pituitary adenomas are more frequent in women than men and significantly are macroadenomas (i.e., diameter >1 cm). Moreover, about one-third of these pituitary tumors show invasive features such as infiltration of tumor cells into surrounding normal juxtatumoral pituitary tissue. However, no specific histologic parameters differentiate between MEN 1 and non–MEN 1 pituitary tumors. Approximately 60% of MEN 1–associated pituitary tumors secrete prolactin, <25% secrete growth hormone, 5% secrete adrenocorticotropic hormone (ACTH), and the remainder appear to be nonfunctioning, with some secreting glycoprotein subunits (Table 408-1). However, pituitary tumors derived from MEN 1 patients may exhibit immunoreactivity to several hormones. In particular, there is a greater frequency of somatolactotrope tumors.


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InternalMed_Harrison. subunits (Table 408-1). However, pituitary tumors derived from MEN 1 patients may exhibit immunoreactivity to several hormones. In particular, there is a greater frequency of somatolactotrope tumors. Prolactinomas are the first manifestation of MEN 1 in ~15% of patients, whereas somatotrope tumors occur more often in patients older than 40 years of age. Fewer than 3% of patients with anterior pituitary tumors will have MEN 1. Clinical manifestations are similar to those in patients with sporadic pituitary tumors without MEN 1 and depend on the hormone secreted and the size of the pituitary tumor. Thus, patients may have symptoms of hyperprolactinemia (e.g., amenorrhea, infertility, and galactorrhea in women, or impotence and infertility in men) or have features of acromegaly or Cushing’s disease. In addition, enlarging pituitary tumors may compress adjacent structures such as the optic chiasm or normal pituitary tissue, causing visual disturbances and/or hypopituitarism. In


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InternalMed_Harrison. Cushing’s disease. In addition, enlarging pituitary tumors may compress adjacent structures such as the optic chiasm or normal pituitary tissue, causing visual disturbances and/or hypopituitarism. In asymptomatic patients with MEN 1, periodic biochemical monitoring of serum prolactin and insulin-like growth factor I (IGF-I) levels, as well as MRI of the pituitary, can lead to early identification of pituitary tumors (Table 408-3). In patients with abnormal results, hypothalamic-pituitary testing should characterize the nature of the pituitary lesion and its effects on the secretion of other pituitary hormones.


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InternalMed_Harrison. Treatment of pituitary tumors in patients with MEN 1 consists of therapies similar to those used in patients without MEN 1 and includes appropriate medical therapy (e.g., bromocriptine or cabergoline for prolactinoma; or octreotide or lanreotide for somatotrope tumors) or selective transsphenoidal adenomectomy, if feasible, with radiotherapy reserved for residual unresectable tumor tissue. Pituitary tumors in MEN 1 patients may be more aggressive and less responsive to medical or surgical treatments. Associated Tumors Patients with MEN 1 may also develop carcinoid tumors, adrenal cortical tumors, facial angiofibromas, collagenomas, thyroid tumors, and lipomatous tumors.


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InternalMed_Harrison. Carcinoid Tumors (See also Chap. 113) Carcinoid tumors occur in more than 3% of patients with MEN 1 (Table 408-1). The carcinoid tumor may be located in the bronchi, gastrointestinal tract, pancreas, or 2339 thymus. At the time of diagnosis, most patients are asymptomatic and do not have clinical features of the carcinoid syndrome. Importantly, no hormonal or biochemical abnormality (e.g., plasma chromogranin A) is consistently observed in individuals with thymic or bronchial carcinoid tumors. Thus, screening for these tumors is dependent on radiologic imaging. The optimum method for screening has not been established. CT and MRI are sensitive for detecting thymic and bronchial tumors (Table 408-3), although repeated CT scanning raises concern about exposure to repeated doses of ionizing radiation. Octreotide scintigraphy may also reveal some thymic and bronchial carcinoids, although there is insufficient evidence to recommend its routine use. Gastric carcinoids, of which the type II


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InternalMed_Harrison. radiation. Octreotide scintigraphy may also reveal some thymic and bronchial carcinoids, although there is insufficient evidence to recommend its routine use. Gastric carcinoids, of which the type II gastric enterochromaffin-like (ECL) cell carcinoids (ECLomas) are associated with MEN 1 and Zollinger-Ellison syndrome, may be detected incidentally at the time of gastric endoscopy for dyspeptic symptoms in MEN 1 patients. These tumors, which may be found in >10% of MEN 1 patients, are usually multiple and smaller than 1.5 cm. Bronchial carcinoids in patients with MEN 1 occur predominantly in women (male-to-female ratio, 1:4). In contrast, thymic carcinoids in European patients with MEN 1 occur predominantly in men (male-to-female ratio, 20:1), with cigarette smokers having a higher risk for these tumors; thymic carcinoids in Japanese patients with MEN 1 have a less marked sex difference (male-to-female ratio 2:1). The course of thymic carcinoids in MEN 1 appears to be particularly


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InternalMed_Harrison. for these tumors; thymic carcinoids in Japanese patients with MEN 1 have a less marked sex difference (male-to-female ratio 2:1). The course of thymic carcinoids in MEN 1 appears to be particularly aggressive. The presence of thymic tumors in patients with MEN 1 is associated with a median survival after diagnosis of approximately 9.5 years, with 70% of patients dying as a direct result of the tumor.


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InternalMed_Harrison. If resectable, surgical removal of carcinoid tumors is the treatment of choice. For unresectable tumors and those with metastatic disease, treatment with radiotherapy or chemotherapeutic agents (e.g., cisplatin, etoposide) may be used. In addition, somatostatin analogues, such as octreotide or lanreotide, have resulted in symptom improvement and regression of some tumors. Little is known about the malignant potential of gastric type II ECLomas, but treatment with somatostatin analogues, such as octreotide or lanreotide, has resulted in regression of these ECLomas.


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InternalMed_Harrison. Adrenocortical Tumors (See also Chap. 406) Asymptomatic adrenocortical tumors occur in 20–70% of patients with MEN 1 depending on the radiologic screening methods used (Table 408-1). Most of these tumors, which include cortical adenomas, hyperplasia, multiple adenomas, nodular hyperplasia, cysts, and carcinomas, are nonfunctioning. Indeed, <10% of patients with enlarged adrenal glands have hormonal hypersecretion, with primary hyperaldosteronism and ACTH-independent Cushing’s syndrome being encountered most commonly. Occasionally, hyperandrogenemia may occur in association with adrenocortical carcinoma. Pheochromocytoma in association with MEN 1 is rare. Biochemical investigation (e.g., plasma renin and aldosterone concentrations, low-dose dexamethasone suppression test, urinary catecholamines, and/or metanephrines) should be undertaken in those with symptoms or signs suggestive of functioning adrenal tumors or in those with tumors >1 cm. Adrenocortical carcinoma occurs in


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InternalMed_Harrison. catecholamines, and/or metanephrines) should be undertaken in those with symptoms or signs suggestive of functioning adrenal tumors or in those with tumors >1 cm. Adrenocortical carcinoma occurs in approximately 1% of MEN 1 patients but increases to >10% for adrenal tumors larger than 1 cm.


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InternalMed_Harrison. Consensus has not been reached about the management of MEN 1–associated nonfunctioning adrenal tumors, because the majority are benign. However, the risk of malignancy increases with size, particularly for tumors with a diameter >4 cm. Indications for surgery for adrenal tumors include: size >4 cm in diameter; atypical or suspicious radiologic features (e.g., increased Hounsfield unit on unenhanced CT scan) and size of 1–4 cm in diameter; or significant 2340 measurable growth over a 6-month period. The treatment of functioning (e.g., hormone-secreting) adrenal tumors is similar to that for tumors occurring in non–MEN 1 patients.


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InternalMed_Harrison. Meningioma Central nervous system (CNS) tumors, including ependymomas, schwannomas, and meningiomas, have been reported in MEN 1 patients (Table 408-1). Meningiomas are found in <10% of patients with other clinical manifestations of MEN 1 (e.g., primary hyperparathyroidism) for >15 years. The majority of meningiomas are not associated with symptoms, and 60% do not enlarge. The treatment of MEN 1–associated meningiomas is similar to that in non–MEN 1 patients. Lipomas Subcutaneous lipomas occur in >33% of patients with MEN 1 (Table 408-1) and are frequently multiple. In addition, visceral, pleural, or retroperitoneal lipomas may occur in patients with MEN 1. Management is conservative. However, when surgically removed for cosmetic reasons, they typically do not recur.


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InternalMed_Harrison. Facial Angiofibromas and Collagenomas The occurrence of multiple facial angiofibromas in patients with MEN 1 may range from >20 to >90%, and occurrence of collagenomas may range from 0 to >70% (Table 408-1). These cutaneous findings may allow presymptomatic diagnosis of MEN 1 in the relatives of a patient with MEN 1. Treatment for these cutaneous lesions is usually not required. Thyroid Tumors Thyroid tumors, including adenomas, colloid goiters, and carcinomas, have been reported to occur in >25% of patients with MEN 1. However, the prevalence of thyroid disorders in the general population is high, and it has been suggested that the association of thyroid abnormalities in patients with MEN 1 may be incidental. The treatment of thyroid tumors in MEN 1 patients is similar to that for non–MEN 1 patients.


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InternalMed_Harrison. Genetics and Screening The MEN1 gene is located on chromo some 11q13 and consists of 10 exons, which encode a 610– amino acid protein, menin, that regulates transcription, genome stability, cell division, and proliferation. The pathophysiology of MEN 1 follows the Knudson two-hit hypothesis with a tumor-suppressor role for menin. Inheritance of a germline MEN1 mutation predisposes an individual to developing a tumor that arises following a somatic mutation, which may be a point mutation or more commonly a deletion, leading to loss of heterozygosity (LOH) in the tumor DNA. The germline mutations of the MEN1 gene are scattered throughout the entire 1830-bp coding region and splice sites, and there is no apparent correlation between the location of MEN1 mutations and clinical manifestations of the disorder, in contrast with the situation in patients with MEN 2 (Table 408-1). More than 10% of MEN1 germline mutations arise de novo and may be transmitted to subsequent generations. Some


InternalMed_Harrison

InternalMed_Harrison. of the disorder, in contrast with the situation in patients with MEN 2 (Table 408-1). More than 10% of MEN1 germline mutations arise de novo and may be transmitted to subsequent generations. Some families with MEN 1 mutations develop parathyroid tumors as the sole endocrinopathy, and this condition is referred to as familial isolated hyperparathyroidism (FIHP). However, between 5 and 25% of patients with MEN 1 do not harbor germline mutations or deletions of the MEN1 gene. Such patients with MEN 1–associated tumors but without MEN1 mutations may represent phenocopies or have mutations involving other genes. Other genes associated with MEN 1–like features include: CDC73, which encodes parafibromin, whose mutations result in the hyperparathyroid-jaw tumor syndrome; the calcium-sensing receptor gene (CaSR), whose mutations result in familial benign hypocalciuric hypercalcemia (FBHH); and the aryl hydrocarbon receptor interacting protein gene (AIP), a tumor suppressor located on


InternalMed_Harrison

InternalMed_Harrison. receptor gene (CaSR), whose mutations result in familial benign hypocalciuric hypercalcemia (FBHH); and the aryl hydrocarbon receptor interacting protein gene (AIP), a tumor suppressor located on chromosome 11q13 whose mutations are associated with familial isolated pituitary adenomas (FIPA). Genetic testing to determine the MEN1 mutation status in symptomatic family members within a MEN 1 kindred, as well as to all index cases (e.g., patients) with two or more endocrine tumors, is advisable. If an MEN1 mutation is not identified in the index case with two or more endocrine tumors, then clinical and genetic tests for other disorders such as hyperparathyroid-jaw tumor syndrome, FBHH, FIPA, MEN 2, or MEN 4 should be considered, because these patients may represent phenocopies for MEN 1.


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InternalMed_Harrison. The current guidelines recommend that MEN1 mutational analysis should be undertaken in: (1) an index case with two or more MEN 1– associated endocrine tumors (e.g., parathyroid, pancreatic, or pituitary tumors); (2) asymptomatic first-degree relatives of a known MEN1 mutation carrier; and (3) first-degree relatives of a MEN1 mutation carrier with symptoms, signs, or biochemical or radiologic evidence for one or more MEN 1–associated tumors. In addition, MEN1 mutational analysis should be considered in patients with suspicious or atypical MEN 1. This would include individuals with parathyroid adenomas before the age of 30 years or multigland parathyroid disease; individuals with gastrinoma or multiple pancreatic NETs at any age; or individuals who have two or more MEN 1–associated tumors that are not part of the classical triad of parathyroid, pancreatic islet, and anterior pituitary tumors (e.g., parathyroid tumor plus adrenal tumor). Family members, including asymptomatic individuals


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InternalMed_Harrison. are not part of the classical triad of parathyroid, pancreatic islet, and anterior pituitary tumors (e.g., parathyroid tumor plus adrenal tumor). Family members, including asymptomatic individuals who have been identified to harbor a MEN1 mutation, will require biochemical and radiologic screening (Table 408-3). In contrast, relatives who do not harbor the MEN1 mutation have a risk of developing MEN 1–associated endocrine tumors that is similar to that of the general population; thus, relatives without the MEN1 mutation do not require repeated screening.


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InternalMed_Harrison. Mutational analysis in asymptomatic individuals should be undertaken at the earliest opportunity and, if possible, in the first decade of life because tumors have developed in some children by the age of 5 years. Appropriate biochemical and radiologic investigations (Table 408-3) aimed at detecting the development of tumors should then be undertaken in affected individuals. Mutant gene carriers should undergo biochemical screening at least once per annum and also have baseline pituitary and abdominal imaging (e.g., MRI or CT), which should then be repeated at 1to 3-year intervals (Table 408-3). Screening should commence after 5 years of age and should continue for life because the disease may develop as late as the eighth decade. The screening history and physical examination elicit the symptoms and signs of hypercalcemia, nephrolithiasis, peptic ulcer disease, neuroglycopenia, hypopituitarism, galactorrhea and amenorrhea in women, acromegaly, Cushing’s disease, and visual field loss


InternalMed_Harrison

InternalMed_Harrison. and signs of hypercalcemia, nephrolithiasis, peptic ulcer disease, neuroglycopenia, hypopituitarism, galactorrhea and amenorrhea in women, acromegaly, Cushing’s disease, and visual field loss and the presence of subcutaneous lipomas, angiofibromas, and collagenomas. Biochemical screening should include measurements of serum calcium, PTH, gastrointestinal hormones (e.g., gastrin, insulin with a fasting glucose, glucagon, VIP, PP), chromogranin A, prolactin, and IGF-I in all individuals. More specific endocrine function tests should be undertaken in individuals who have symptoms or signs suggestive of a specific clinical syndrome. Biochemical screening for the development of MEN 1 tumors in asymptomatic members of families with MEN 1 is of great importance to reduce morbidity and mortality from the associated tumors.


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InternalMed_Harrison. MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 AND TYPE 3 Clinical Manifestations MEN type 2 (MEN 2), which is also called Sipple’s syndrome, is characterized by the association of medullary thyroid carcinoma (MTC), pheochromocytomas, and parathyroid tumors (Table 408-1). Three clinical variants of MEN 2 are recognized: MEN 2A, MEN 2B, and MTC only. MEN 2A, which is often referred to as MEN 2, is the most common variant. In MEN 2A, MTC is associated with pheochromocytomas in 50% of patients (may be bilateral) and with parathyroid tumors in 20% of patients. MEN 2A may rarely occur in association with Hirschsprung’s disease, caused by the absence of autonomic ganglion cells in the terminal hindgut, resulting in colonic dilatation, severe constipation, and obstruction. MEN 2A may also be associated with cutaneous lichen amyloidosis, which is a pruritic lichenoid lesion that is usually located on the upper back. MEN 2B, which is also referred to as MEN 3, represents 5% of all cases of MEN 2 and is


InternalMed_Harrison

InternalMed_Harrison. cutaneous lichen amyloidosis, which is a pruritic lichenoid lesion that is usually located on the upper back. MEN 2B, which is also referred to as MEN 3, represents 5% of all cases of MEN 2 and is characterized by the occurrence of MTC and pheochromocytoma in association with a Marfanoid habitus; mucosal neuromas of the lips, tongue, and eyelids; medullated corneal fibers; and intestinal autonomic ganglion dysfunction leading to multiple diverticulae and megacolon. Parathyroid tumors do not usually occur in MEN 2B. MTC only (FMTC) is a variant in which MTC is the sole manifestation of the syndrome. However, the distinction between aAdapted from American Thyroid Association Guidelines, RT Kloos et al: Thyroid 6:565, 2009. bRisk for early development of metastasis and aggressive growth of medullary thyroid cancer: ++++, highest; +++, high; ++, intermediate; and +, lowest. cMutations associated with MEN 2A (or medullary thyroid carcinoma only). dConsider surgery at 5 years or later if


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InternalMed_Harrison. medullary thyroid cancer: ++++, highest; +++, high; ++, intermediate; and +, lowest. cMutations associated with MEN 2A (or medullary thyroid carcinoma only). dConsider surgery at 5 years or later if serum calcitonin is normal, neck ultrasound is normal, and there is a less aggressive family history and family preference. eConsider surgery before 5 years or later if serum calcitonin is normal, neck ultrasound is normal, and there is a less aggressive family history and family preference. fMutations associated with MEN 2B (MEN 3). gNot required because PHPT is not a feature of MEN 2B (MEN 3).


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InternalMed_Harrison. Abbreviations: ASAP, as soon as possible; MEN, multiple endocrine neoplasia; PHPT, primary hyperparathyroidism. FMTC and MEN 2A is difficult and should only be considered if there are at least four family members above the age of 50 years who are affected by MTC but not pheochromocytomas or primary hyperparathyroidism. All of the MEN 2 variants are due to mutations of the rearranged during transfection (RET) protooncogene, which encodes a TKR. Moreover, there is a correlation between the locations of RET mutations and MEN 2 variants. Thus, ~95% of MEN 2A patients have mutations involving the cysteine-rich extracellular domain, with mutations of codon 634 accounting for ~85% of MEN 2A mutations; FMTC patients also have mutations of the cysteine-rich extracellular domain, with most mutations occurring in codon 618. In contrast, ~95% of MEN 2B/MEN 3 patients have mutations of codon 918 of the intracellular tyrosine kinase domain (Table 408-1 and Table 408-4).


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InternalMed_Harrison. Medullary Thyroid Carcinoma MTC is the most common feature of MEN 2A and MEN 2B and occurs in almost all affected individuals. MTC represents 5–10% of all thyroid gland carcinomas, and 20% of MTC patients have a family history of the disorder. The use of RET mutational analysis to identify family members at risk for hereditary forms of MTC has altered the presentation of MTC from that of symptomatic tumors to a preclinical disease for which prophylactic thyroidectomy (Table 408-4) is undertaken to improve the prognosis and ideally result in cure. However, in patients who do not have a known family history of MEN 2A, FMTC, or MEN 2B, and therefore have not had RET mutational analysis, MTC may present as a palpable mass in the neck, which may be asymptomatic or associated with symptoms of pressure or dysphagia in >15% of patients. Diarrhea occurs in 30% of patients and is associated either with elevated circulating concentrations of calcitonin or tumor-related secretion of serotonin and


InternalMed_Harrison

InternalMed_Harrison. or dysphagia in >15% of patients. Diarrhea occurs in 30% of patients and is associated either with elevated circulating concentrations of calcitonin or tumor-related secretion of serotonin and prostaglandins. Some patients may also experience flushing. In addition, ectopic ACTH production by MTC may cause Cushing’s syndrome. The diagnosis of MTC relies on the demonstration of hypercalcitoninemia (>90 pg/mL in the basal state); stimulation tests using IV pentagastrin (0.5 mg/kg) and or calcium infusion (2 mg/kg) are rarely used now, reflecting improvements in the assay for calcitonin. Neck ultrasonography with fine-needle aspiration of the nodules can confirm the diagnosis. Radionucleotide thyroid scans may reveal MTC tumors as “cold” nodules. Radiography may reveal dense irregular calcification within the involved portions of the thyroid gland and in lymph nodes involved with metastases. Positron emission tomography (PET) may help to identify the MTC and metastases (Fig. 408-2).


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InternalMed_Harrison. within the involved portions of the thyroid gland and in lymph nodes involved with metastases. Positron emission tomography (PET) may help to identify the MTC and metastases (Fig. 408-2). Metastases of MTC usually occur to the cervical lymph nodes in the early stages and to the mediastinal nodes, lung, liver, trachea, adrenal, esophagus, and bone in later stages. Elevations in serum calcitonin concentrations are often the first sign of recurrence or persistent disease, and the serum calcitonin doubling time is useful for determining prognosis. MTC can have an aggressive clinical course, with early metastases and death in approximately 10% of patients. A family history of aggressive MTC or MEN 2B may be elicited.


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InternalMed_Harrison. Individuals with RET mutations who do not have clinical manifestations of MTC should be offered prophylactic surgery between the ages of <1 and 5 years. The timing of surgery will depend on the type of RET mutation and its associated risk for early development, metastasis, and aggressive growth of MTC (Table 408-4). Such patients should have a total thyroidectomy with a systematic central neck dissection to remove occult nodal metastasis, although FIGURE 408-2 Fluorodeoxyglucose (FDG) positron emission tomography scan in a patient with multiple endocrine neoplasia type 2A, showing medullary thyroid cancer (MTC) with hepatic and skeletal (left arm) metastasis and a left adrenal pheochromocytoma. Note the presence of excreted FDG compound in the bladder.


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InternalMed_Harrison. (Reproduced with permission from A Naziat et al: Clin Endocrinol [Oxf] 78:966, 2013.) 2342 the value of undertaking a central neck dissection has been subject to debate. Prophylactic thyroidectomy, with life-long thyroxine replacement, has dramatically improved outcomes in patients with MEN 2 and MEN 3, such that ~90% of young patients with RET mutations who had a prophylactic thyroidectomy have no evidence of persistent or recurrent MTC at 7 years after surgery. In patients with clinically evident MTC, a total thyroidectomy with bilateral central resection is recommended, and an ipsilateral lateral neck dissection should be undertaken if the primary tumor is >1 cm in size or there is evidence of nodal metastasis in the central neck. Surgery is the only curative therapy for MTC. The 10-year survival in patients with metastatic MTC is ~20%. For inoperable MTC or metastatic disease, the tyrosine kinase inhibitors, vandetanib and cabozantinib, have improved the progression-free survival


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InternalMed_Harrison. survival in patients with metastatic MTC is ~20%. For inoperable MTC or metastatic disease, the tyrosine kinase inhibitors, vandetanib and cabozantinib, have improved the progression-free survival times. Other types of chemotherapy are of limited efficacy, but radiotherapy may help to palliate local disease.


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InternalMed_Harrison. Pheochromocytoma (See also Chap. 407) These noradrenalineand adrenaline-secreting tumors occur in >50% of patients with MEN 2A and MEN 2B and are a major cause of morbidity and mortality. Patients may have symptoms and signs of catecholamine secretion (e.g., headaches, palpitations, sweating, poorly controlled hypertension), or they may be asymptomatic with detection through biochemical screening based on a history of familial MEN 2A, MEN 2B, or MTC. Pheochromocytomas in patients with MEN 2A and MEN 2B differ significantly in distribution when compared with patients without MEN 2A and MEN 2B. Extra-adrenal pheochromocytomas, which occur in 10% of patients without MEN 2A and MEN 2B, are observed rarely in patients with MEN 2A and MEN 2B. Malignant pheochromocytomas are much less common in patients with MEN 2A and MEN 2B. The biochemical and radiologic investigation of pheochromocytoma in patients with MEN 2A and MEN 2B is similar to that in non– MEN 2 patients and includes the


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InternalMed_Harrison. in patients with MEN 2A and MEN 2B. The biochemical and radiologic investigation of pheochromocytoma in patients with MEN 2A and MEN 2B is similar to that in non– MEN 2 patients and includes the measurement of plasma (obtained from supine patients) and urinary free fractionated metanephrines (e.g., normetanephrine and metanephrines measured separately), CT or MRI scanning, radionuclide scanning with meta-iodo-(123I or 131I)-benzyl guanidine (MIBG), and PET using (18F)-fluorodopamine or (18F)-fluoro-2-dexoxy-d-glucose (Fig. 408-2).


InternalMed_Harrison

InternalMed_Harrison. Surgical removal of pheochromocytoma, using α and β adrenoreceptor blockade before and during the operation, is the recommended treatment. Endoscopic adrenal-sparing surgery, which decreases postoperative morbidity, hospital stay, and expense, as opposed to open surgery, has become the method of choice. Parathyroid Tumors (See also Chap. 424) Parathyroid tumors occur in 10–25% of patients with MEN 2A. However, >50% of these patients do not have hypercalcemia. The presence of abnormally enlarged parathyroids, which are unusually hyperplastic, is often seen in the normocalcemic patient undergoing thyroidectomy for MTC. The biochemical investigation and treatment of hypercalcemic patients with MEN 2A is similar to that of patients with MEN 1.


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InternalMed_Harrison. Genetics and Screening To date, approximately 50 different RET mutations have been reported, and these are located in exons 5, 8, 10, 11, 13, 14, 15, and 16. RET germline mutations are detected in >95% of MEN 2A, FMTC, and MEN 2B families, with Cys634Arg being most common in MEN 2A, Cys618Arg being most common in FMTC, and Met918Thr being most common in MEN 2B (Tables 408-1 and 408-4). Between 5 and 10% of patients with MTC or MEN 2A– associated tumors have de novo RET germline mutations, and ~50% of patients with MEN 2B have de novo RET germline mutations. These de novo RET germline mutations always occur on the paternal allele. Approximately 5% of patients with sporadic pheochromocytoma have a germline RET mutation, but such germline RET mutations do not appear to be associated with sporadic primary hyperparathyroidism.


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InternalMed_Harrison. Thus, RET mutational analysis should be performed in: (1) all patients with MTC who have a family history of tumors associated with MEN 2, FMTC, or MEN 3, such that the diagnosis can be confirmed and genetic testing offered to asymptomatic relatives; (2) all patients with MTC and pheochromocytoma without a known family history of MEN 2 or MEN 3; (3) all patients with MTC, but without a family history of MEN 2, FMTC, or MEN 3, because these patients may have a de novo germline RET mutations; (4) all patients with bilateral pheochromocytoma; and (5) patients with unilateral pheochromocytoma, particularly if this occurs with increased calcitonin levels.


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InternalMed_Harrison. Screening for MEN 2/MEN 3–associated tumors in patients with RET germline mutations should be undertaken annually and include serum calcitonin measurements, a neck ultrasound for MTC, plasma and 24-h urinary fractionated metanephrines for pheochromocytoma, and albumin-corrected serum calcium or ionized calcium with PTH for primary hyperparathyroidism. In patients with MEN 2–associated RET mutations, screening for MTC should begin by 3 to 5 years; for pheochromocytoma by 20 years; and for primary hyperparathyroidism by 20 years of age (Table 408-4).


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InternalMed_Harrison. MULTIPLE ENDOCRINE NEOPLASIA TYPE 4 Clinical Manifestations Patients with MEN 1–associated tumors, such as parathyroid adenomas, pituitary adenomas, and pancreatic NETs, occurring in association with gonadal, adrenal, renal, and thyroid tumors have been reported to have mutations of the gene encoding the 196–amino acid cyclin-dependent kinase inhibitor (CK1) p27 kip1 (CDNKIB). Such families with MEN 1–associated tumors and CDNKIB mutations are designated to have MEN 4 (Table 408-1). The investigations and treatments for the MEN 4–associated tumors are similar to those for MEN 1 and non–MEN 1 tumors.


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InternalMed_Harrison. Genetics and Screening To date, eight different MEN 4–associ ated mutations of CDNKIB, which is located on chromosome 12p13, have been reported, and all of these are associated with a loss of function. These MEN 4 patients may represent ~3% of the 5–10% of patients with MEN 1 who do not have mutations of the MEN1 gene. Germline CDNKIB mutations may rarely be found in patients with sporadic (i.e., nonfamilial) forms of primary hyperparathyroidism.


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InternalMed_Harrison. HYPERPARATHYROIDISM-JAW TUMOR SYNDROME (SEE ALSO CHAP. 424) Clinical Manifestations Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder characterized by the development of parathyroid tumors (15% are carcinomas) and fibroosseous jaw tumors. In addition, some patients may also develop Wilms’ tumors, renal cysts, renal hematomas, renal cortical adenomas, papillary renal cell carcinomas, pancreatic adenocarcinomas, uterine tumors, testicular mixed germ cell tumors with a major seminoma component, and Hürthle cell thyroid adenomas. The parathyroid tumors may occur in isolation and without any evidence of jaw tumors, and this may cause confusion with other hereditary hypercalcemic disorders, such as MEN 1. However, genetic testing to identify the causative mutation will help to establish the correct diagnosis. The investigation and treatment for HPT-JT-associated tumors are similar to those in non-HPT-JT patients, except that early parathyroidectomy is


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InternalMed_Harrison. mutation will help to establish the correct diagnosis. The investigation and treatment for HPT-JT-associated tumors are similar to those in non-HPT-JT patients, except that early parathyroidectomy is advisable because of the increased frequency of parathyroid carcinoma.


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InternalMed_Harrison. Genetics and Screening The gene that causes HPT-JT is located on chromosome 1q31.2 and encodes a 531–amino acid protein, parafibromin (Table 408-2). Parafibromin is also referred to as cell division cycle protein 73 (CDC73) and has a role in transcription. Genetic testing in families helps to identify mutation carriers who should be periodically screened for the development of tumors (Table 408-5). VON HIPPEL-LINDAU DISEASE (SEE ALSO CHAP. 407) Clinical Manifestations von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by hemangioblastomas of the retina and CNS; cysts involving the kidneys, pancreas, and epididymis; renal cell carcinomas; pheochromocytomas; and pancreatic islet cell tumors. The retinal and CNS hemangioblastomas are benign vascular tumors that may be multiple; those in the CNS may cause symptoms Parathyroid Serum Ca, PTH 6–12 months Ossifying jaw fibroma Panoramic jaw x-ray with neck 5 years shieldingc


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InternalMed_Harrison. Parathyroid Serum Ca, PTH 6–12 months Ossifying jaw fibroma Panoramic jaw x-ray with neck 5 years shieldingc Renal Abdominal MRIc,d 5 years aScreening for most common HPT-JT–associated tumors is considered. Assessment for other reported tumor types may be indicated (e.g., pancreatic, thyroid, testicular tumors). bFrequency of repeating test after baseline tests performed. cX-rays and imaging involving ionizing radiation should ideally be avoided to minimize risk of generating subsequent mutations. dUltrasound scan recommended if MRI unavailable. eSuch selective pelvic imaging should be considered after obtaining a detailed menstrual history. Abbreviations: Ca, calcium; D&C, dilatation and curettage; HPT-JT, hyperparathyroidismjaw tumor syndrome; MRI, magnetic resonance imaging; PTH, parathyroid hormone. Source: Reproduced from PJ Newey et al: Hum Mutat 31:295, 2010.


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InternalMed_Harrison. by compressing adjacent structures and/or increasing intracranial pressure. In the CNS, the cerebellum and spinal cord are the most frequently involved sites. The renal abnormalities consist of cysts and carcinomas, and the lifetime risk of a renal cell carcinoma (RCC) in VHL is 70%. The endocrine tumors in VHL consist of pheochromocytomas and pancreatic islet cell tumors. The clinical presentation of pheochromocytoma in VHL disease is similar to that in sporadic cases, except there is a higher frequency of bilateral or multiple tumors, which may involve extra-adrenal sites in VHL disease. The most frequent pancreatic lesions in VHL are multiple cyst-adenomas, which rarely cause clinical disease. However, nonsecreting pancreatic islet cell tumors occur in <10% of VHL patients, who are usually asymptomatic. The pancreatic tumors in these patients are often detected by regular screening using abdominal imaging. Pheochromocytomas should be investigated and treated as described earlier


InternalMed_Harrison

InternalMed_Harrison. asymptomatic. The pancreatic tumors in these patients are often detected by regular screening using abdominal imaging. Pheochromocytomas should be investigated and treated as described earlier for MEN 2. The pancreatic islet cell tumors frequently become malignant, and early surgery is recommended.


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InternalMed_Harrison. Genetics and Screening The VHL gene, which is located on chro mosome 3p26-p25, is widely expressed in human tissues and encodes a 213–amino acid protein (pVHL) (Table 408-2). A wide variety of germline VHL mutations have been identified. VHL acts as a tumor-suppressor gene. A correlation appears to exist between the type of mutation and the clinical phenotype; large deletions and protein-truncating mutations are associated with a low incidence of pheochromocytomas, whereas some missense mutations in VHL patients are associated with pheochromocytoma (referred to as VHL type 2C). Other missense mutations may be associated with hemangioblastomas and RCC but not pheochromocytoma (referred to as VHL type 1), whereas distinct missense mutations are associated with hemangioblastomas, RCC, and pheochromocytoma (VHL type 2B). VHL type 2A, which refers to the occurrence of hemangioblastomas and pheochromocytoma without RCC, is associated with rare missense mutations. The basis for these complex


InternalMed_Harrison

InternalMed_Harrison. (VHL type 2B). VHL type 2A, which refers to the occurrence of hemangioblastomas and pheochromocytoma without RCC, is associated with rare missense mutations. The basis for these complex genotype-phenotype relationships remains to be elucidated. One major function of pVHL, which is also referred to as elongin, is to downregulate the expression of vascular endothelial growth factor (VEGF) and other hypoxia-inducible mRNAs. Thus, pVHL, in complex with other proteins, regulates the expression of hypoxia-inducible factors (HIF-1 and HIF-2) such that loss of functional pVHL leads to a stabilization of the HIF protein complexes, resulting in VEGF overexpression and tumor angiogenesis. Screening for the development of pheochromocytomas and pancreatic islet cell tumors is as described earlier for MEN 2 and MEN 1, respectively (Tables 408-3 and 408-4).


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InternalMed_Harrison. NEUROFIBROMATOSIS Clinical Manifestations Neurofibromatosis type 1 (NF1), which is also referred to as von Recklinghausen’s disease, is an autosomal dominant disorder characterized by the following manifestations: neurologic (e.g., peripheral and spinal neurofibromas); ophthalmologic (e.g., optic gliomas and iris hamartomas such as Lisch nodules); dermatologic 2343 (e.g., café au lait macules); skeletal (e.g., scoliosis, macrocephaly, short stature, and pseudoarthrosis); vascular (e.g., stenoses of renal and intra-cranial arteries); and endocrine (e.g., pheochromocytoma, carcinoid tumors, and precocious puberty). Neurofibromatosis type 2 (NF2) is also an autosomal dominant disorder but is characterized by the development of bilateral vestibular schwannomas (acoustic neuromas) that lead to deafness, tinnitus, or vertigo. Some patients with NF2 also develop meningiomas, spinal schwannomas, peripheral nerve neurofibromas, and café au lait macules. Endocrine abnormalities are not found in


InternalMed_Harrison

InternalMed_Harrison. deafness, tinnitus, or vertigo. Some patients with NF2 also develop meningiomas, spinal schwannomas, peripheral nerve neurofibromas, and café au lait macules. Endocrine abnormalities are not found in NF2 and are associated solely with NF1. Pheochromocytomas, carcinoid tumors, and precocious puberty occur in about 1% of patients with NF1, and growth hormone deficiency has been also reported. The features of pheochromocytomas in NF1 are similar to those in nonNF1 patients, with 90% of tumors being located within the adrenal medulla and the remaining 10% at an extra-adrenal location, which often involves the para-aortic region. Primary carcinoid tumors are often periampullary and may also occur in the ileum but rarely in the pancreas, thyroid, or lungs. Hepatic metastases are associated with symptoms of the carcinoid syndrome, which include flushing, diarrhea, bronchoconstriction, and tricuspid valve disease. Precocious puberty is usually associated with the extension of an optic glioma


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InternalMed_Harrison. symptoms of the carcinoid syndrome, which include flushing, diarrhea, bronchoconstriction, and tricuspid valve disease. Precocious puberty is usually associated with the extension of an optic glioma into the hypothalamus with resultant early activation of gonadotropin-releasing hormone secretion. Growth hormone deficiency has also been observed in some NF1 patients, who may or may not have optic chiasmal gliomas, but it is important to note that short stature is frequent in the absence of growth hormone deficiency in patients with NF1. The investigation and treatment for tumors are similar to those undertaken for each respective tumor type in non-NF1 patients. Genetics and Screening The NF1 gene, which is located on chro mosome 17q11.2 and acts as a tumor suppressor, consists of 60 exons that span more than 350 kb of genomic DNA (Table 408-2). Mutations in NF1 are of diverse types and are scattered throughout the exons. The NF1 gene product is the protein neurofibromin, which has


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InternalMed_Harrison. that span more than 350 kb of genomic DNA (Table 408-2). Mutations in NF1 are of diverse types and are scattered throughout the exons. The NF1 gene product is the protein neurofibromin, which has homologies to the p120GAP (GTPase activating protein) and acts on p21ras by converting the active GTP bound form to its inactive GDP form. Mutations of NF1 impair this downregulation of the p21ras signaling pathways, which in turn results in abnormal cell proliferation. Screening for the development of pheochromocytomas and carcinoid tumors is as described earlier for MEN 2 and MEN 1, respectively (Tables 408-3 and 408-4).


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InternalMed_Harrison. CARNEY COMPLEX Clinical Manifestations Carney complex (CNC) is an autosomal dominant disorder characterized by spotty skin pigmentation (usually of the face, labia, and conjunctiva), myxomas (usually of the eyelids and heart, but also the tongue, palate, breast, and skin), psammomatous melanotic schwannomas (usually of the sympathetic nerve chain and upper gastrointestinal tract), and endocrine tumors that involve the adrenals, Sertoli cells, somatotropes, thyroid, and ovary. Cushing’s syndrome, the result of primary pigmented nodular adrenal disease (PPNAD), is the most common endocrine manifestation of CNC and may occur in one-third of patients. Patients with CNC and Cushing’s syndrome often have an atypical appearance by being thin (as opposed to having truncal obesity). In addition, they may have short stature, muscle and skin wasting, and osteoporosis. These patients often have levels of urinary free cortisol that are normal or increased only marginally. Cortisol production may


InternalMed_Harrison

InternalMed_Harrison. they may have short stature, muscle and skin wasting, and osteoporosis. These patients often have levels of urinary free cortisol that are normal or increased only marginally. Cortisol production may fluctuate periodically with days or weeks of hypercortisolism; this pattern is referred to as “periodic Cushing’s syndrome.” Patients with Cushing’s syndrome usually have loss of the circadian rhythm of cortisol production. Acromegaly, the result of a somatotrope tumor, affects ~10% of patients with CNC. Testicular tumors may also occur in one-third of patients with CNC. These may either be large-cell calcifying Sertoli cell tumors, adrenocortical rests, or Leydig cell tumors. The Sertoli cell tumors occasionally may be estrogen-secreting and lead to precocious puberty or gynecomastia. Some patients with CNC have been reported to develop thyroid follicular tumors, ovarian cysts, or breast duct adenomas.


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InternalMed_Harrison. Genetics and Screening CNC type 1 (CNC1) is due to mutations of the protein kinase A (PKA) regulatory subunit 1 α (R1α) (PPKAR1A), a tumor suppressor, whose gene is located on chromosome 17q.24.2 (Table 408-2). The gene causing CNC type 2 (CNC2) is located on chromosome 2p16 and has not yet been identified. It is interesting to note, however, that some tumors do not show LOH of 2p16 but instead show genomic instability, suggesting that this CNC gene may not be a tumor suppressor. Screening and treatment of these endocrine tumors are similar to those described earlier for patients with MEN 1 and MEN 2 (Tables 408-3 and 408-4).


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InternalMed_Harrison. COWDEN’S SYNDROME Clinical Manifestations Multiple hamartomatous lesions, especially of the skin, mucous membranes (e.g., buccal, intestinal, and colonic), breast, and thyroid are characteristic of Cowden’s (CWD) syndrome, which is an autosomal dominant disorder. Thyroid abnormalities occur in two-thirds of patients with CWD syndrome, and these usually consist of multinodular goiters or benign adenomas, although <10% of patients may have a follicular thyroid carcinoma. Breast abnormalities occur in >75% of patients and consist of either fibrocystic disease or adenocarcinomas. The investigation and treatment for CWD tumors are similar to those undertaken for non-CWD patients.


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InternalMed_Harrison. Genetics and Screening CWD syndrome is genetically heterogenous, and six types (CWD1–6) are recognized (Table 408-2). CWD is due to mutations of the phosphate and tensin homologue deleted on chromosome 10 (PTEN) gene, located on chromosome 10q23.31. CWD2 is caused by mutations of the succinate dehydrogenase subunit B (SDHB) gene, located on chromosome 1p36.13; and CWD3 is caused by mutations of the SDHD gene, located on chromosome 11q13.1. SDHB and SDHD mutations are also associated with pheochromocytoma. CWD4 is caused by hypermethylation of the Killin (KLLN) gene, the promoter of which shares the same transcription site as PTEN on chromosome 10q23.31. CWD5 is caused by mutations of the phosphatidylinositol 3-kinase catalytic alpha (PIK3CA) gene on chromosome 3q26.32, and CWD6 is caused by mutations of the V-Akt murine thymoma viral oncogene homolog 1 (AKT1) gene on chromosome 14q32.33. Screening for thyroid abnormalities entails neck ultrasonography and fine-needle aspiration with


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InternalMed_Harrison. by mutations of the V-Akt murine thymoma viral oncogene homolog 1 (AKT1) gene on chromosome 14q32.33. Screening for thyroid abnormalities entails neck ultrasonography and fine-needle aspiration with analysis of cell cytology.


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InternalMed_Harrison. MCCUNE-ALBRIGHT SYNDROME (SEE ALSO CHAP. 426e) Clinical Manifestations McCune-Albright syndrome (MAS) is characterized by the triad of polyostotic fibrous dysplasia, which may be associated with hypophosphatemic rickets; café au lait skin pigmentation; and peripheral precocious puberty; other endocrine abnormalities include thyrotoxicosis, which may be associated with a multinodular goiter, somatotrope tumors, and Cushing’s syndrome (due to adrenal tumors). Investigation and treatment for each endocrinopathy are similar to those used in patients without MAS.


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InternalMed_Harrison. Genetics and Screening MAS is a disorder of mosaicism that results from postzygotic somatic cell mutations of the G protein α stimulating subunit (Gsα), encoded by the GNAS1 gene, located on chromosome 20q13.32 (Table 408-2). The Gsα mutations, which include Arg201Cys, Arg201His, Glu227Arg, or Glu227His, are activating and are found only in cells of the abnormal tissues. Screening for hyperfunction of relevant endocrine glands and development of hypophosphatemia, which may be associated with elevated serum fibroblast growth factor 23 (FGF23) concentrations, is undertaken in MAS patients. The author is grateful to the Medical Research Council (UK) for support and to Mrs. Tracey Walker for typing the manuscript. Peter A. Gottlieb


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InternalMed_Harrison. Polyglandular deficiency syndromes have been given many different names, reflecting the wide spectrum of disorders that have been associated with these syndromes and the heterogeneity of their clinical presentations. The name used in this chapter for this group of disorders is autoimmune polyendocrine syndrome (APS). In general, these disorders are divided into two major categories, APS type 1 (APS-1) and APS type 2 (APS-2). Some groups have further subdivided APS-2 into APS type 3 (APS-3) and APS type 4 (APS-4) depending on the type of autoimmunity involved. For the most part, this additional classification does not clarify our understanding of disease pathogenesis or prevention of complications in individual patients. Importantly, there are many nonendocrine disease associations included in these syndromes, suggesting that although the underlying autoimmune disorder predominantly involves endocrine targets, it does not exclude other tissues. The disease associations found in APS-1


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InternalMed_Harrison. in these syndromes, suggesting that although the underlying autoimmune disorder predominantly involves endocrine targets, it does not exclude other tissues. The disease associations found in APS-1 and APS-2 are summarized in Table 409-1. Understanding these syndromes and their disease manifestations can lead to early diagnosis and treatment of additional disorders in patients and their family members.


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InternalMed_Harrison. Abbreviations: DIDMOAD, diabetes insipidus, diabetes mellitus, progressive bilateral optic atrophy, and sensorineural deafness; POEMS, polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes. Note: Italics denote less common disorders.


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InternalMed_Harrison. APS-1 (Online Mendelian Inheritance in Man [OMIM] 240300) has also been called autoimmune polyendocrinopathy–candidiasis– ectodermal dystrophy (APECED). Mucocutaneous candidiasis, hypoparathyroidism, and Addison’s disease form the three major components of this disorder. However, as summarized in Table 409-1, many other organ systems can be involved over time. APS-1 is rare, with fewer than 500 cases reported in the literature. It is an autosomal recessive disorder caused by mutations in the AIRE gene (autoimmune regulator gene) found on chromosome 21. This gene is most highly expressed in thymic medullary epithelial cells (mTECs) where it appears to control the expression of tissue-specific self-antigens (e.g., insulin). Deletion of this regulator leads to decreased expression of tissue-specific self-antigens and is hypothesized to allow autoreactive T cells to avoid clonal deletion, which normally occurs during T cell maturation in the thymus. The AIRE gene is also expressed in


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InternalMed_Harrison. self-antigens and is hypothesized to allow autoreactive T cells to avoid clonal deletion, which normally occurs during T cell maturation in the thymus. The AIRE gene is also expressed in epithelial cells found in peripheral lymphoid organs, but its role in these extrathymic cells remains controversial. A number of mutations have been described in this gene, and there is a higher frequency within certain ethnic groups including Iranian Jews, Sardinians, Finns, Norwegians, and Irish.


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InternalMed_Harrison. Clinical Manifestations APS-1 develops very early in life, often in infancy (Table 409-2). Chronic mucocutaneous candidiasis without signs of systemic disease is often the first manifestation. It affects the mouth and nails more frequently than the skin and esophagus. Chronic oral candidiasis can result in atrophic disease with areas suggestive of leukoplakia, which can pose a risk for future carcinoma. The etiology is associated with anticytokine autoantibodies (anti-IL-17A, -IL-17F, and -IL-22) related to T helper (TH) 17 T cells and depressed production of these cytokines by peripheral blood mononuclear cells. Hypoparathyroidism usually develops next, followed by adrenal insufficiency. The time from development of one component of the disorder to the next can be many years, and the order of disease appearance is variable.


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InternalMed_Harrison. Chronic candidiasis is nearly always present and is not very responsive to treatment. Hypoparathyroidism is found in >85% of cases, and Addison’s disease is found in nearly 80%. Gonadal failure appears to affect women more than men (70% vs 25%, respectively), and hypoplasia of the dental enamel also occurs frequently (77% of patients). Other endocrine disorders that occur less frequently include type 1 diabetes (23%) and autoimmune thyroid disease (18%). Nonendocrine manifestations that present less frequently include alopecia (40%), vitiligo (26%), intestinal malabsorption (18%), pernicious anemia (31%), chronic active hepatitis (17%), and nail dystrophy. An unusual and debilitating manifestation of the disorder is the development of refractory diarrhea/obstipation that may be related to autoantibody-mediated destruction of enterochromaffin or enterochromaffin-like cells.


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InternalMed_Harrison. Early onset: infancy Later onset Siblings often affected and at risk Multigenerational Equivalent sex distribution Females > males affected Monogenic: AIRE gene, chromo-Polygenic: HLA, MICA, PTNP22, CTLA4 some 21, autosomal recessive Not HLA associated for entire syn-DR3/DR4 associated; other HLA class III drome, some specific component gene associations noted risk Autoantibodies to type 1 interfer-No autoantibodies to cytokines Autoantibodies to specific target Autoantibodies to specific target organs organs Asplenism No defined immunodeficiency Mucocutaneous candidiasis Association with other nonendocrine Abbreviations: APS, autoimmune polyendocrine syndrome; IL, interleukin. The incidence rates for many of these disorders peak in the first or 2345 second decade of life, but the individual disease components continue to emerge over time. Therefore, prevalence rates may be higher than originally reported.


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InternalMed_Harrison. Diagnosis The diagnosis of APS-1 is usually made clinically when two of the three major component disorders are found in an individual patient. Siblings of individuals with APS-1 should be considered affected even if only one component disorder has been detected due to the known inheritance of the syndrome. Genetic analysis of the AIRE gene should be undertaken to identify mutations. Initial sequencing may detect the common mutations, but rare mutations are continually being noted, and an initial negative genetic analysis should not dissuade one from the clinical diagnosis until more extensive DNA sequencing can be performed. Detection of anti–interferon α and anti–interferon ο antibodies can identify nearly 100% of cases with APS-1. The autoantibody arises independent of the type of AIRE gene mutation and is not found in other autoimmune disorders.


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InternalMed_Harrison. Diagnosis of each underlying disorder should be done based on their typical clinical presentations (Table 409-3). Mucocutaneous candidiasis may present throughout the gastrointestinal tract, and it may be detected in the oral mucosa or from stool samples. Evaluation by a gastroenterologist to examine the esophagus for candidiasis or secondary stricture may be merited based on symptoms. Other gastrointestinal manifestations of APS-1, including malabsorption and obstipation, may also bring these young patients to the attention of gastroenterologists for first evaluation. Specific physical examination findings of hyperpigmentation, vitiligo, alopecia, tetany, and signs of hyperor hypothyroidism should be considered as signs of development of component disorders.


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InternalMed_Harrison. The development of disease-specific autoantibody assays can help confirm disease and also detect risk for future disease. For example, where possible, detection of anticytokine antibodies to interleukin (IL) 17 and IL-22 would confirm the diagnosis of mucocutaneous candidiasis due to APS-1. The presence of anti-21-hydroxylase antibody or anti-17-hydroxylase antibody (which may be found more commonly in adrenal insufficiency associated with APS-1) would confirm the presence or risk for Addison’s disease. Other autoantibodies found in type 1 diabetes (e.g., anti-GAD65), pernicious anemia, and other component conditions should be screened for on a regular basis (6to 12-month intervals depending on the age of the subject).


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InternalMed_Harrison. Laboratory tests, including a complete metabolic panel, phosphorous and magnesium, thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH; morning), hemoglobin A1c, plasma vitamin B12 level, and complete blood count with peripheral smear looking for Howell-Jolly bodies (asplenism), should also be performed at these time points. Detection of abnormal physical findings or test results should prompt subsequent examinations of the relevant organ system (e.g., presence of Howell-Jolly bodies indicates need for ultrasound of spleen).


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InternalMed_Harrison. Therapy of individual disease components is carried out as outlined in other relevant chapters. Replacement of deficient hormones (e.g., adrenal, pancreas, ovaries/testes) will treat most of the endocrinopathies noted. Several unique issues merit special emphasis. Adrenal insufficiency can be masked by primary hypothyroidism by prolonging the half-life of cortisol. The caveat therefore is that replacement therapy with thyroid hormone can precipitate an adrenal crisis in an undiagnosed individual. Hence, all patients with hypothyroidism and the possibility of APS should be screened for adrenal insufficiency to allow treatment with glucocorticoids prior to the initiation of thyroid hormone replacement. Treatment of mucocutaneous candidiasis with ketoconazole in an individual with subclinical adrenal insufficiency may also precipitate adrenal crisis. Furthermore, mucocutaneous candidiasis may be difficult to eradicate entirely. Severe cases of disease involvement may require systemic


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InternalMed_Harrison. adrenal insufficiency may also precipitate adrenal crisis. Furthermore, mucocutaneous candidiasis may be difficult to eradicate entirely. Severe cases of disease involvement may require systemic immunomodulatory therapy, but this is not commonly needed.


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InternalMed_Harrison. Addison’s disease Sodium, potassium, ACTH, cortisol, 21and 17-hydroxylase autoantibodies Hypoparathyroidism Serum calcium, phosphate, PTH Male hypogonadism FSH/LH, testosterone Malabsorption Physical examination, anti-IL-17 and anti-IL-22 autoantibodies Mucocutaneous Physical examination, mucosal swab, stool samples Ovarian failure FSH/LH, estradiol Pernicious anemia CBC, vitamin B12 levels Type 1 diabetes Glucose, hemoglobin A1c, diabetes-associated autoantibodies (insulin, GAD65, IA-2, ZnT8) Addison’s disease 21-Hydroxylase autoantibodies, ACTH stimulation testing if positive or hypothyroidism autoantibodies, anti-TSH receptor Ab Cerebellar ataxia Dictated by signs and symptoms of disease Chronic inflamma-Dictated by signs and symptoms of disease tory demyelinating polyneuropathy Hypophysitis Dictated by signs and symptoms of disease, anti-Pit1 Idiopathic heart Dictated by signs and symptoms of disease Myasthenia gravis Dictated by signs and symptoms of disease,


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InternalMed_Harrison. Hypophysitis Dictated by signs and symptoms of disease, anti-Pit1 Idiopathic heart Dictated by signs and symptoms of disease Myasthenia gravis Dictated by signs and symptoms of disease, Myocarditis Dictated by signs and symptoms of disease CBC, vitamin B12 levels if positive Serositis Dictated by signs and symptoms of disease Stiff man syndrome Dictated by signs and symptoms of disease Vitiligo Physical examination, NALP-1 polymorphism Abbreviations: Ab, antibody; ACTH, adrenocorticotropic hormone; APS, autoimmune polyendocrine syndrome; CBC, complete blood count; FSH, follicle-stimulating hormone; IL, interleukin; LH, luteinizing hormone; PTH, parathyroid hormone; TSH, thyroid-stimulating hormone.


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InternalMed_Harrison. APS-2 (OMIM 269200) is more common than APS-1 with a prevalence of 1 in 100,000. It has a gender bias and occurs more often in female patients with a ratio of at least 3:1 compared to male patients. In contrast to APS-1, APS-2 often has its onset in adulthood with a peak incidence between 20 and 60 years of age. It shows a familial, multigenerational heritage (Table 409-2). The presence of two or more of the following endocrine deficiencies in the same patient defines the presence of APS-2: primary adrenal insufficiency (Addison’s disease; 50–70%), Graves’ disease or autoimmune thyroiditis (15–69%), type 1 diabetes mellitus (T1D; 40–50%), and primary hypogonadism. Frequently associated autoimmune conditions include celiac disease (3–15%), myasthenia gravis, vitiligo, alopecia, serositis, and pernicious anemia. These conditions occur with increased frequency in affected patients but are also are found in their family members (Table 409-3).


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InternalMed_Harrison. Genetic Considerations The overwhelming risk factor for APS-2 has been localized to the genes in the human lymphocyte antigen complex on chromosome 6. Primary adrenal insufficiency in APS-2, but not APS-1, is strongly associated with both HLA-DR3 and HLA-DR4. Other class I and class II genes and alleles, such as HLA-B8, HLA-DQ2 and HLA-DQ8, and HLA-DR subtype such as DRB1*0404, appear to contribute to organ-specific disease susceptibility (Table 409-4). HLA-B8and HLA-DR3-associated illnesses include selective IgA deficiency, juvenile dermatomyositis, dermatitis herpetiformis, alopecia, scleroderma, autoimmune thrombocytopenia purpura, hypophysitis, metaphyseal osteopenia, and serositis.


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InternalMed_Harrison. Several other immune genes have been proposed to be associated with Addison’s disease and therefore with APS-2 (Table 409-3). The “5.1” allele of a major histocompatibility complex (MHC) gene is an atypical class I HLA molecule MIC-A. The MIC-A5.1 allele has a very strong association with Addison’s disease that is not accounted for by linkage disequilibrium with DR3 or DR4. Its role is complicated because certain HLA class I genes can offset this effect. PTPN22 codes for a polymorphism in a protein tyrosine phosphatase, which acts on intracellular signaling pathways in both T and B lymphocytes. It has been implicated in T1D, Addison’s disease, and other autoimmune conditions. CTLA4 is a receptor on the T cell surface that modulates the activation state of the cell as part of the signal 2 pathway. Polymorphisms of this gene appear to cause downregulation of the cell surface expression of the receptor, leading to decreased T cell activation and proliferation. This appears to contribute


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InternalMed_Harrison. pathway. Polymorphisms of this gene appear to cause downregulation of the cell surface expression of the receptor, leading to decreased T cell activation and proliferation. This appears to contribute to disease in Addison’s disease and potentially other components of APS-2. Allelic variants of the IL-2Rα are linked to development of T1D and autoimmune thyroid disease and could contribute to the phenotype of APS-2 in certain individuals.


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InternalMed_Harrison. Diagnosis When one of the component disorders is present, a second associated disorder occurs more commonly than in the general population (Table 409-3). There is controversy as to which tests to use and how often to screen individuals for disease. A strong family history of autoimmunity should raise suspicion in an individual with an initial component diagnosis. The development of a rarer form of autoimmunity, such as Addison’s disease, should prompt more extensive screening for other linked disorders compared to the diagnosis of autoimmune thyroid disease, which is relatively common.


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InternalMed_Harrison. Circulating autoantibodies, as previously discussed, can precede the development of disease by many years but would allow the clinician to follow the patient and identify the disease onset at its earliest time point (Tables 409-3 and 409-4). For each of the endocrine components of the disorder, appropriate autoantibody assays are listed and, if positive, should prompt physiologic testing to diagnose clinical or subclinical disease. For Addison’s disease, antibodies to 21-hydroxylase antibodies are highly diagnostic for risk of adrenal insufficiency. However, individuals may take many years to develop overt hypoadrenalism. Screening of 21-hydroxylase antibody–positive patients can be performed measuring morning ACTH and cortisol on a yearly basis. Rising ACTH values over time or low morning cortisol in association with signs or symptoms of adrenal insufficiency should prompt testing via the cosyntropin stimulation test (Chap. 406). T1D can be screened for by measuring autoantibodies


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InternalMed_Harrison. cortisol in association with signs or symptoms of adrenal insufficiency should prompt testing via the cosyntropin stimulation test (Chap. 406). T1D can be screened for by measuring autoantibodies including anti-insulin, anti-GAD65, anti-IA-2, and anti-ZnT8. Risk for progression to disease can be based on the number of antibodies, and in some cases the titer (insulin autoantibody), as well as other metabolic factors (impaired oral glucose tolerance test). National Institutes of Health–sponsored trial groups such as Type 1 Diabetes TrialNet are screening firstand second-degree family members for these autoantibodies and identifying prediabetic individuals who may qualify for intervention trials to change the course of the disease prior to onset.


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InternalMed_Harrison. Abbreviations: APS, autoimmune polyendocrine syndrome; SLE, systemic lupus erythematosus; TSH, thyroid-stimulating hormone.


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InternalMed_Harrison. Screening tests for thyroid disease can include anti–thyroid peroxidase (TPO) or anti-thyroglobulin autoantibodies or anti-TSH receptor antibodies for Graves’ disease. Yearly measurements of TSH can then be used to follow these individuals. Celiac disease can be screened for using the anti–tissue transglutaminase (tTg) antibody test. For those <20 years of age, testing every 1–2 years should be performed, whereas less frequent testing is indicated after the age of 20 because the majority of individuals who develop celiac disease have the antibody earlier in life. Positive tTg antibody test results should be confirmed on repeat testing, followed by small-bowel biopsy to document pathologic changes of celiac disease. Many patients have asymptomatic celiac disease that is nevertheless associated with osteopenia and impaired growth. If left untreated, symptomatic celiac disease has been reported to be associated with an increased risk of gastrointestinal malignancy, especially lymphoma.


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InternalMed_Harrison. The knowledge of the particular disease associations should guide other autoantibody or laboratory testing. A complete history and physical examination should be performed every 1–3 years including CBC, metabolic panel, TSH, and vitamin B12 levels to screen for most of the possible abnormalities. More specific tests should be based on specific findings from the history and physical.


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InternalMed_Harrison. With the exception of Graves’ disease, the management of each of the endocrine components of APS-2 involves hormone replacement and is covered in detail in the chapters on adrenal (Chap. 406), thyroid (Chap. 405), gonadal (Chaps. 411 and 412), and parathyroid disease (Chap. 424). As noted for APS-1, adrenal insufficiency can be masked by primary hypothyroidism and should be considered and treated as discussed above. In patients with T1D, decreasing insulin requirements or hypoglycemia, without obvious secondary causes, may indicate the emergence of adrenal insufficiency. Hypocalcemia in APS-2 patients is more likely due to malabsorption than hypoparathyroidism.


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InternalMed_Harrison. Immunotherapy for autoimmune endocrine disease has been reserved for T1D, for the most part, reflecting the lifetime burden of the disease for the individual patient and society. Although several immunotherapies (e.g., modified anti-CD3, rituximab, abatacept) can prolong the honeymoon phase of T1D, none has achieved long-term success. Active research using new approaches and combination therapy may change the treatment of this disease or other autoimmune conditions that share similar pathways. Furthermore, treatment of subclinical disease diagnosed by the presence of autoantibodies may provide a mechanism to preempt the development of overt disease and is the subject of active basic and clinical research.


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InternalMed_Harrison. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked disease (IPEX; OMIM 304790) is a rare X-linked recessive disorder. The disease onset is in infancy and is characterized by severe enteropathy, T1D, and skin disease, as well as variable association with several other autoimmune disorders. Many infants die within the first days of life, but the course is variable, with some children surviving for 12–15 years. Early onset of T1D, often at birth, is highly suggestive of the diagnosis because nearly 80% of IPEX patients develop T1D. Although treatment of the individual disorders can temporarily improve the situation, treatment of the underlying immune deficiency is required and includes immunosuppressive therapy generally followed by hematopoietic stem cell transplantation. Transplantation is the only life-saving form of therapy and can be fully curative by normalizing the imbalanced immune system found in this disorder.


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InternalMed_Harrison. 2348 IPEX is caused by mutations in the FOXP3 gene, which is also mutated in the Scurfy mouse, an animal model that shares much of the phenotype of IPEX patients. The FOXP3 transcription factor is expressed in regulatory T cells designated CD4+CD25+FOXP3+ (Treg). Lack of this factor causes a profound deficiency of this Treg population and results in rampant autoimmunity due to the lack of peripheral tolerance normally provided by these cells. Certain mutations may lead to varying forms of expression of the full syndrome, and there are rare cases where the FOXP3 gene is intact but other genes involved in this pathway (e.g., CD25, IL-2Rα) may be causative.


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InternalMed_Harrison. Thymomas and thymic hyperplasia are associated with several autoimmune diseases, with the most common being myasthenia gravis (44%) and red cell aplasia (20%). Graves’ disease, T1D, and Addison’s disease may also be associated with thymic tumors. Patients with myasthenia gravis and thymoma may have unique anti–acetylcholine receptor autoantibodies. Many thymomas lack AIRE expression within the thymoma, and this could be a potential factor in the development of autoimmunity. In support of this concept, thymoma is the one other disease with “frequent” development of anticytokine antibodies and mucocutaneous candidiasis in adults. The majority of tumors are malignant, and temporary remissions of the autoimmune condition can occur with resection of the tumor.


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InternalMed_Harrison. This is a very rare disorder where severe insulin resistance (type B) is caused by the presence of anti-insulin receptor antibodies. It is associated with acanthosis nigricans, which can also be associated with other forms of less severe insulin resistance. About one-third of patients have an associated autoimmune illness such as systemic lupus erythematosus or Sjögren’s syndrome. Therefore, the presence of antinuclear antibodies, elevated erythrocyte sedimentation rate, hyperglobulinemia, leukopenia, and hypocomplementemia may accompany the presentation. The presence of anti-insulin receptor autoantibodies leads to marked insulin resistance, requiring more than 100,000 units of insulin to be given daily with only partial control of hyperglycemia. Patients can also have severe hypoglycemia due to partial activation of the insulin receptor by the antibody. The course of the disease is variable, and several patients have had spontaneous remissions. Therapy targeting B lymphocytes


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InternalMed_Harrison. due to partial activation of the insulin receptor by the antibody. The course of the disease is variable, and several patients have had spontaneous remissions. Therapy targeting B lymphocytes including rituximab, cyclophosphamide, and pulse steroids can induce remission of the disease.


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InternalMed_Harrison. The insulin autoimmune syndrome, associated with Graves’ disease and methimazole therapy (or other sulfhydryl-containing medications), is of particular interest due to a remarkably strong association with a specific HLA haplotype. Such patients with elevated titers of anti-insulin autoantibodies frequently present with hypoglycemia. In Japan, the disease is restricted to HLA-DR4-positive individuals with DRB1*0406. Curiously, a recent report demonstrated that five out of six Caucasian patients taking lipoic acid (sulfhydryl group) who developed insulin autoimmune syndrome were primarily DRB1*0403 (which is related to DRB1*0406); the sixth was DRB1*0406. In Hirata’s syndrome the anti-insulin autoantibodies are often polyclonal. Discontinuation of the medication generally leads to resolution of the syndrome over time.