ost common

TABLE 388-2 Multiple Endocrine and Other Organ Neoplasia (MEON)

Syndromes

DISEASEa GENE PRODUCT

CHROMOSOMAL

LOCATION

Hyperparathyroidism-jaw

tumor (HPT-JT)

Parafibromin 1q31.2

Carney complex

CNC1 PRAKAR1A 17q24.2

CNC2 ?b 2p16

von Hippel–Lindau

disease (VHL)

pVHL (elongin) 3p25

Neurofibromatosis

type 1 (NF1)

Neurofibromin 17q11.2

Cowden’s syndrome

(CWS)

CWS1 PTEN 10q23.31

CWS2 SDHB 1p36.13

CWS3 SDHD 11q23.1

CWS4 KLLN 10q23.31

CWS5 PIK3CA 3q26.32

CWS6 AKT1 14q32.33

CWS7 SEC23B 20p11.23

McCune-Albright

syndrome (MAS)

Gs

α 20q13.32

a

The 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 Gs

α. b

?, unknown.

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 388-3). 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 vs 55 years) and an equal maleto-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.

TREATMENT

Parathyroid Tumors

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 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. 84) 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

388-1) 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

2985 Multiple Endocrine Neoplasia Syndromes CHAPTER 388

nonsecretory. These pancreatic islet cell tumors have an earlier age at

onset in patients with MEN 1 than in patients without MEN 1.

Gastrinoma Gastrin-secreting tumors (gastrinomas) are associated with marked gastric acid production and recurrent peptic

ulcerations, a combination referred to as Zollinger-Ellison syndrome.

Gastrinomas occur more often in patients with MEN 1 who are aged

>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 388-3). However, the diagnosis of

Zollinger-Ellison syndrome may be difficult in hypercalcemic MEN

1 patients because hypercalcemia can also cause hypergastrinemia.

Ultrasonography, endoscopic ultrasonography, computed tomography

(CT), nuclear magnetic resonance imaging (MRI), selective abdominal

angiography, venous sampling, and somatostatin receptor scintigraphy

(SRS) are helpful in localizing the tumor prior to surgery. Gastrinomas

represent >50% of all pancreatic NETs in patients with MEN 1, and

~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.

TREATMENT

Gastrinoma

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 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 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 (SSAs);

selected internal radiation therapy (SIRT); radiofrequency ablation;

peptide radio receptor therapy (PRRT); hepatic artery embolization; administration of human leukocyte interferon; and removal of

all resectable tumor have been successful in some patients.

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 388-3). 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 388-3). 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

aged <40 years, and some arise in individuals aged <20 years. In contrast, in patients without MEN 1, insulinomas generally occur in those

aged >40 years. Insulinomas may be the first manifestation of MEN 1 in

10% of patients, and ~4% of patients with insulinomas will have MEN 1.

TREATMENT

Insulinoma

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

TABLE 388-3 Biochemical and Radiologic Screening in Multiple Endocrine Neoplasia Type 1

TUMOR AGE TO BEGIN (YEARS) BIOCHEMICAL TEST (PLASMA OR SERUM) ANNUALLY IMAGING TEST (TIME INTERVAL)

Parathyroid 8 Calcium, PTH None

Pancreatic NETs

Gastrinoma 20 Gastrin (± gastric pH) None

Insulinoma 5 Fasting glucose, insulin None

Other pancreatic NET <10 Chromogranin A; pancreatic polypeptide, glucagon,

vasoactive intestinal peptide

MRI, CT, or EUS (annually)

Anterior pituitary 5 Prolactin, IGF-I MRI (every 3 years)

Adrenal <10 None unless symptoms or signs of functioning tumor and/or

tumor >1 cm identified on imaging

MRI or CT (annually with pancreatic imaging)

Thymic and bronchial

carcinoid

15 None CT or MRI (every 1–2 years)

Abbreviations: CT, computed tomography; EUS, endoscopic ultrasound; IGF-I, insulin-like growth factor I; MRI, magnetic resonance imaging; PTH, parathyroid hormone.

Source: Data from PJ Newey, RV Thakker: Role of multiple endocrine neoplasia type 1 mutational analysis in clinical practice. Endocr Pract 17, 2011 and RV Thakker:

Multiple endocrine neoplasia type 1 (MEN1). Translational Endocrinology and Metabolism, Vol 2. Chevy Chase, MD: The Endocrine Society; 2011.

2986 PART 12 Endocrinology and Metabolism

(streptozotocin, 5-fluorouracil, and doxorubicin), PRRT (e.g., with

177Lu-DOTATATE), or hepatic artery embolization has been used

for metastatic disease.

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 intolerance and hyperglucagonemia.

TREATMENT

Glucagonoma

Surgical removal of the glucagonoma is the treatment of choice.

However, treatment may be difficult because ~50–80% of patients

have metastases at the time of diagnosis. Medical treatment with

SSAs (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.

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 (WDHA syndrome), which is also referred to as the

Verner-Morrison syndrome, or the VIPoma syndrome. The diagnosis

is established by excluding laxative and diuretic abuse, confirming a

stool volume in excess of 0.5–1.0 L/d during a fast, and documenting a

markedly increased plasma VIP concentration.

TREATMENT

VIPomas

Surgical management of VIPomas, which are mostly located in

the tail of the pancreas, can be curative. However, in patients with

unresectable tumor, SSAs, 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.

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. 388-1). 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 SRS is the most reliable method

for detecting metastatic disease (Table 388-3).

TREATMENT

PPomas and Nonfunctioning Pancreatic NETs

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

is complete. Alternatively, other experts recommend surgery based

on tumor size, using either >1 cm or >2 cm at different centers. Pancreatoduodenal surgery is successful in removing the tumors in 80%

of patients, but >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 NET metastases and in doubling the progression-free survival time. Additional

treatments for metastatic disease include PRRT using 177Lu-DOTATATE, chemotherapy, radiofrequency ablation, transarterial chemoemobilization, and SIRT.

FIGURE 388-1 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 nonsecreting NET due to loss

of menin expression. (Part A reproduced with permission from PJ Newey et al:

Asymptomatic children with multiple endocrine neoplasia type 1 mutations may

harbor nonfunctioning pancreatic neuroendocrine tumors. J Clin Endocrinol Metab

94:3640, 2009.)

A

B

2987 Multiple Endocrine Neoplasia Syndromes CHAPTER 388

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.

Pituitary Tumors (See also Chap. 380) Pituitary tumors occur

in 15–50% of patients with MEN 1 (Table 388-1), and ~75% of these are

microadenomas (<1 cm diameter). The tumors 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, in whom they are often macroadenomas (>1 cm diameter). There are no specific histologic parameters

that 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 388-1). 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 aged >40 years. 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 asymptomatic patients

with MEN 1, periodic biochemical monitoring of serum prolactin and

insulin-like growth factor 1 (IGF-1) levels, as well as MRI of the pituitary, can lead to early identification of pituitary tumors (Table 388-3). 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.

TREATMENT

Pituitary Tumors

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.

Associated Tumors Patients with MEN 1 may also develop carcinoid tumors, adrenal cortical tumors, facial angiofibromas, collagenomas, thyroid tumors, and lipomatous tumors.

Carcinoid Tumors (See also Chap. 84) Carcinoid tumors

occur in >3% of patients with MEN 1 (Table 388-1). The carcinoid

tumor may be located in the bronchi, gastrointestinal tract, pancreas,

or 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 388-3), 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 gastric enterochromaffinlike (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 sized <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 aggressive. The presence of thymic tumors

in patients with MEN 1 is associated with a median survival after

diagnosis of ~9.5 years, with 70% of patients dying as a direct result

of the tumor.

TREATMENT

Carcinoid Tumors

If resectable, surgical removal of carcinoid tumors is the treatment of choice. For patients with unresectable tumors and those

with metastatic disease, treatment with SSAs, radiotherapy, chemotherapeutic agents (e.g., fluorouracil, temozolomide, cisplatin,

etoposide), mTOR inhibitors (e.g., everolimus), or PRRT therapy

has resulted in symptom improvement and regression of some

tumors. Little is known about the malignant potential of gastric

type II ECLomas, but treatment with SSAs has resulted in regression of these ECLomas.

Adrenocortical Tumors (See also Chap. 386) Asymptomatic adrenocortical tumors occur in 20–70% of patients with MEN 1

depending on the radiologic screening methods used (Table 388-1).

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 ~1% of MEN 1 patients but increases to >10% for adrenal

tumors >1 cm.

TREATMENT

Adrenocortical Tumors

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

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.

2988 PART 12 Endocrinology and Metabolism

Meningioma Central nervous system (CNS) tumors, including

ependymomas, schwannomas, and meningiomas, have been reported

in MEN 1 patients (Table 388-1). 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 388-1) 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.

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 388-1). 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.

Genetics and Screening The MEN1 gene is located on chromosome 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 388-1). 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 HPT-JT 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 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 in all index cases

(e.g., patients) with two or more endocrine tumors, is advisable. If a

MEN1 mutation is not identified in the index case with two or more

endocrine tumors, clinical and genetic tests for other disorders such as

HPT-JT syndrome, FBHH, FIPA, MEN 2, or MEN 4 should be considered because these patients may represent phenocopies for MEN 1.

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 who have been identified to harbor

a MEN1 mutation, will require biochemical and radiologic screening

(Table 388-3). 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.

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 388-3)

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 1- to 3-year intervals (Table 388-3). 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 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-1 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.

■ 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 388-1). 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 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 FMTC and MEN 2A is

difficult and should only be considered if there are at least four family

members aged >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