CHAPTER 81 Gastrinomas 476 Biochemical investigations The diagnosis rests on \201 nding an inappropriately elevated fasting plasma gastrin in the presence of increased gastric acid secretion. Patients should have antisecretory treatment stopped prior to the test (3 days for H 2 bloc kers and 2 weeks for PPIs), since these drugs are associ- ated with hypergastrinemia. Howev er, gastrin levels above 1000 pg/mL in the presence of elevated gastric acid production, ar e virtually diagnostic of a gastrinoma. The secretin stimulation test is the most sensitive and speci \201 c stimula- tion test. A dose of 2 mcg/kg of secretin is given intravenously and blood samples are drawn for gastri n at 2, 5, 10, 20, and 30 minutes. A rise of >150 pg/mL is highly suggestive of gastrinoma. A gut hormone pro \201 le may identify elevated plasma levels of pancreatic polypeptide or other gut hormones. The tumor localization techniques described for insulinomas are also relevant for gastrinom as ( b Tumor localization, p. 473). Very small tumors or duodenal tumors can be very hard t o localize and even small tumors are frequently associated with local lymph node disease. Selective arterial angiography may be combined with a provocative test for gastrin release using a bolus of calcium gluconate or secretin for elusive small tumors. For causes of hypergastrinemia, see Box 81.1. Box 81.1 Causes of hypergastrinemia Low or normal gastric acid production \200 H 2 blocke rs \200 PPIs \200 Vagotomy \200 Hypochlorhydria \200 Short gut syndrome \200 Rena l failure \200 Hypercalcemia Elevated gastric acid production \200 Gastrinoma \200 G- cell hyperplasia 81-Draznin-Chap81.indd 476 3/31/2011 8:47:54 PM TREATMENT 477 Treatment The treatment of choice is complete surgical tumor removal, although this is usua lly only considered after the tumor has been identi \201 ed preopera- tively. Surgery is r arely justi \201 ed in patients with known hepatic metastases, but some small studies have raised the possibility of bene \201 t from tumor debulking. Where preoperative imaging has failed to identify a tumor, the patient is often best mainta ined on medical therapy with regular imaging to reas- sess (PPIs need to be given less freq uently than H 2 antagonists). Check B 12 annually. Somatostatin analogs do not appear to be more effective at control- ling gastric acid hyper secretion and relieving symptoms than PPIs or H 2 blockers. The data are currently limited, but as for insulinomas, radiolabeled somatostatin analogs may be a future treatment option for gastrinomas. In patients with MEN1, management is more controversial. The usual policy is to operate when a well-de \201 ned tumor can be identi \201 ed. Table 81.1 Treatment options for gastrinomas Medical treatment \200 H 2 blockers \200 PPIs \200 Octreotide Surgery \200 Tumor resection \200 Tumor debulking \200 Liver transplant Palliation \200 Chemotherapy \200 Hepatic artery embolization 81-Draznin-Chap81.indd 477 3/31/2011 8:47:54 PM CHAPTER 82 Glucagonomas 478 Glucagonomas De \201 nition Glucagonomas are neuroendocrine tumors that usually arise from the alpha ce lls of the pancreas and produce the glucagonoma syndrome through the secretion of glucagon and other peptides derived from the preproglucagon gene. The large majority of glucagonomas are malignant, but they are also very indolent tumors, and the diagnosis may be overlooked for many years. Up to 90% of patients will have lymph node or liver metastases at the time of presentation. They are classically associated with the rash of necrolytic migratory erythema. Incidence The annual incidence is estimated at 1 per 20 million population. Clinical presentation See Table 82.1. The characteristic rash \200\224necrolytic migratory erythema \200\224occurs in >70% of cas es and usually manifests initially as a well-demarcated area of erythema in the groin befor e migrating to the limbs, buttocks, and perineum. Mucous membrane involvement is common, with stomatitis, glossitis, vaginitis, and urethritis being frequent features. Glucagon antagonizes the effects of insulin, particularly on hepatic glu- cose metabolism, and glucose intolerance is a frequent association (>90%). Sustained gluconeogenesis also ca uses amino acid de \201 ciencies and results in protein catabolism, which can be associate d with unrelenting weight loss in >60% of patients. Glucagon has a direct suppressive effect on the bone marrow, resulting in a normochromic normocytic anemia in almost all patients. Up to 20% of glucagonoma patients will have associated MEN1. 82-Draznin-Chap82.indd 478 3/31/2011 8:48:55 PM TUMOR LOCALIZATION 479 Table 82.1 Clinical features of the glucagonoma syndrome Site Clinical features Skin Necrolytic migratory erythema Mucous membranes Angular stomatitis Atrophic glossitis Vulvovaginitis Urethritis Nails Onycholysis Scalp Alopecia Metabolism Glucose intolerance Protein catabolism and weight loss Hematological Anemia Venous thromboses Psychiatric Depression Psychosis Biochemical investigations The diagnosis is con \201 rmed on \201 nding raised plasma gl ucagon levels. A gut hormone pro \201 le may also show elevated neuroendocrine mark- ers such as pancreatic polypeptide. Impaired glucose intolerance and hypoaminoacidemia may be present. Tumor localization At the time of diagnosis >60% of glucagonomas will have metastasized to the liver and most primary tumors will be >3 cm in diameter. These tumors rarely present problems of radiological localization. Transabdominal US and CT scanning are usually adequate. Small tumors may require more sophisticated imaging techniques ( b see Tumor localization, p. 473). Octreotide scanning probably offers the best means of evaluating the extent of met astatic disease. 82-Draznin-Chap82.indd 479 3/31/2011 8:48:55 PM CHAPTER 82 Glucagonomas 480 Treatment Surgery is the only curative therapeutic option, but the potential for a complete cure may be as low as 5%. In malignant disease, a surgical cure may still be achieved in those rare cases where the m etastases are con \201 ned to the liver and the patient is deemed suitable for a liver tra nsplant. Somatostatin analogs are the treatment of choice with excellent response rates in treating the necrolytic migratory erythema. They are less effective at reversing the weight loss and have an inconsistent effect on glycemic control such that diabetes mellitus may need to be managed with insulin therapy. If octreotide fails, the rash may be improved using IV amino acids and fatty acids. Palliative chemotherapy using streptozotocin and 5-FU has been shown to produce a 50% reduc tion in glucagon levels in 75% of patients, but the bene \201 t is frequently only tempora ry. Hepatic artery embolization may result in a dramatic relief of symptoms with remissions of several months recorded. As for the other pancreatic islet cell tumors, there are preliminary data to suggest that r adiolabeled somatostatin analogs may be therapeutic in the glucagonoma syndrome. 82-Draznin-Chap82.indd 480 3/31/2011 8:48:55 PM CLINICAL PRESENTATION 481 VIPomas De \201 nition In 1958, Verner and Morrison 1 \201 rst described a syndrome consisting o f refractory watery diarrhea and hypokalemia associated with a neuroendo- crine tumor of th e pancreas. The syndrome of watery diarrhea, hypokalemia, and acidosis (WDHA) is due to secretion of vasoactive intestinal polypeptide (VIP). Tumors that secrete VIP are known as VIPomas . VIPomas account for <10% of islet cell tumor s and mainly occur as solitary tumors. More than 60% are malignant and metastasize to the l ymph nodes, liver, kidneys, and bone. Clinical presentation The most prominent symptom in most patients is profuse watery diarrhe a that is secretory in nature and therefore rich in electrolytes (Box 83.1). Other causes o f secretory diarrhea should be considered in the differen- tial diagnosis (see Box 83.2 ). VIPomas are rare in MEN1 patients, occurring in <1% of cases. Box 83.1 Clinical features of the VIPoma syndrome \200 Watery diarrhea \200 Hypokalemia \200 Achlorhydria \200 Metabolic acidosis \200 Hypercalcemia \200 Hyperglycemia \200 Hypomagnesemia \200 Facial \202 ushing Box 83.2 Differential diagnosis of secretory diarrhea \200 Infection, e.g., Escherichia c oli or cholera toxins \200 Laxative abuse \200 Villous adenoma \200 Other gut neuroen docrine tumors, e.g., carcinoid tumors or gastrinomas \200 Carcinoma of the lung \200 M edullary carcinoma of the thyroid \200 Systemic mastocytosis \200 Immunoglobulin A de \201 ciency 1 Verner JV, Morrison AB (1958). Islet cell tumor and a syndrome of refractory watery diarr hea and hypokalemia. Am J Med 25(3):374 \200\223380. 83-Draznin-Chap83.indd 481 3/31/2011 8:49:49 PM CHAPTER 83 VIPomas 482 Biochemical investigations Elevated levels of plasma VIP are found in all patients with the VIPoma syndrome, although false positives may occur in dehydrated patients due to diarrhea from other causes. A gut hormone pro \201 le may identify other raised tumor markers such as pancreatic polyp eptide and aid detection of some other causes of watery diarrhea, e.g., gastrinomas. Urinary catecholamine excretion should be assessed, especially in chil- dren, in whom it is common to \201 nd the tumors residing in the adrenal medulla. Tumor localization The majority of tumors secreting VIP originate in the pancreas, whereas others arise from the sympathetic chain. Primary VIPomas have very rarely been reported to arise from a vari- ety of other sites, su ch as the lung, esophagus, small bowel, colon, and kidney. Most patients present with large tumors that can be easily identi \201 ed by transabdomina l US or CT, although small tumors may require additional methods of tumor localization as p reviously discussed ( b p. 473). Treatment Severe cases require IV \202 uid replacement and careful correction of elec- tr olye disturbances. Surgery to remove the tumor is the treatment of \201 rst choice if tech- nically possible and may be curative in around 40% of patients. Surgical debulking may also be of palliativ e bene \201 t. Somatostatin analogs produce effective symptomatic relief from the diarrhea in most patient s. Long-term use does not result in tumor regression. Glucocorticoids in high dosage have also been shown to provide good relief of symptoms. A t rial of lithium may be warranted in resistant cases and this therapy may be combined with o ctreotide. Chemotherapy using streptozotocin in combination with 5-FU has resulted in response rates of >30%. Hepatic artery embolization can offer temporary respite from severe diarrhea. 83-Draznin-Chap83.indd 482 3/31/2011 8:49:49 PM CLINICAL FEATURES 483 Somatostatinomas De \201 nition Somatostatinomas are very rare neuroendocrine tumors occurring both in the pancreas and in the duodenum. More than 60% are large tumors located in the head or body of the pancreas. The clinical syndrome may be diagnosed late in the course of the disease when metastatic sp read to local lymph nodes and the liver has already occurred. Clinical features See Box 84.1. Glucose intolerance or frank diabetes mellitus may have been observed for many years prior to the diagnosis and retrospectively often represents the \201 rst clinical sign. It is p robably due to the inhibitory effect of somato- statin on insulin secretion. A high incidence of gallstones has been described similar to that seen as a side effect with long-term somatostatin analog therapy. Diarrhea, steatorrhea, and weight loss appear to be consistent clinical features and may be associated with inhibition of the exocrine pancreas by somatostatin. Small duodenal somatostatinomas may occur in association with NF1 (43%). Although these rar ely cause the inhibitory clinical syndrome, they present with obstructive biliary disease t hrough local spread of the tumor. Somatostatinomas are infrequently associated with MEN1 (7 %). Box 84.1 Clinical features of the somatostatin syndrome \200 Glucose intolerance/diabetes mellitus (95%) \200 Gallstones (68%) \200 Diarrhea and steatorrhea \200 Weight loss (25%) \200 Anemia (14%) \200 Hypochlorhydria 84-Draznin-Chap84.indd 483 3/31/2011 8:51:19 PM CHAPTER 84 Somatostatinomas 484 Biochemical investigations Plasma somatostatin levels will be raised and may also be associ ated with raised levels of other neuroendocrine tumor markers, including ACTH and calcitoni n. Multisecretory activity is more common with pancreatic (33%) than with duodenal (16%) somatostatinomas. Tumor localization Transabdominal US and CT scanning may demonstrate the tumor, since metas tatic disease is often apparent at presentation. Additional methods of tumor localization as previously described may also be required ( b see p. 473) Treatment Surgery should be considered \201 rst-line treatment. Although a cure is rare, even debulking surgery may result in signi \201 cant palliation. Hepatic embolization can be considered and chemotherapy with strep- tozotocin and 5-FU may be used to control malignant disease. 84-Draznin-Chap84.indd 484 3/31/2011 8:51:19 PM Part 9 Inherited endocrine syndromes and multiple endocrine neoplasia (MEN) Boris Draznin 85 McCune \200\223Albright syndrome 86 Neuro \201 bromatosis 87 Von Hippel \200\223Lindau disease 88 Carney complex 89 Cowden syndrome 90 POEMS syndrome 91 MEN type 1 92 MEN type 2 93 Inherited primary hyperparathyroidism 94 Inherited renal calculi 486 489 492 496 497 498 499 503 507 509 85-Draznin-Chap85.indd 485 3/31/2011 4:20:49 PM CHAPTER 85 McCune \200\223Albright syndrome 486 McCune \200\223Albright syndrome De \201 nition The syndrome is characterized by the following: \200 Polyostotic \201 b rous dysplasia \200 Caf -au-lait pigmented skin lesions \200 Autonomous function of mu ltiple endocrine glands A clinical diagnosis requires two of these pathologies. Genetics This syndrome is a genetic but not an inherited condition due to a postzy- gotic s omatic mutation in the gene ( GNAS1 ) that encodes the A-chain of the stimulating G protein of adenyl cyclase (GSA mutation). This results in activation of adenyl cyclase. The somatic mutation results in mosaicism. Consequently, the propor- tion and distribution of affected cells in a tissue will be determined by the precise stage in development at whi ch the mutation occurred. Mutational analysis of the GNAS1 gene from affected tissues or blood may be available. 85-Draznin-Chap85.indd 486 3/31/2011 4:20:49 PM CLINICAL FEATURES 487 Clinical features Polyostotic \201 brous dysplasia Solitary or multiple expansile bony lesions that can cau se fracture deform- ities and nerve entrapment typically develop before the age of 10 years . The femoral and the pelvic bones are most frequently affected. Radiographs of these bones a re useful for screening. Osteosarcomas are a rare complication. For treatment, b see Box 85.1. Box 85.1 Treatment of polyostotic \201 brous dysplasia \200 Surgery may be complicated by bleeding, and radiotherapy has a limited effect. There is recent evidence to support the use of bisphosphonates, particularly pamidronate, f or both symptomatic pain relief and the radiological healing of bone. Caf -au-lait pigmentation The lesions are characterized by an irregular border (in neuro \201 bromatosis the border is smooth), do not cross the midline, and tend to be ipsilateral to the bone lesions. Endocrinopathies See Table 85.1. Involvement of other organs Hepatobiliary complications such as neonatal jaundice, elevated transami- nases, and cholestasis are relatively common. Cardiomegaly, tachyarrythmias, and sudden cardiac death may occur. Gastrointestinal polyps, splenic hyperplasia, and pancreatitis are reported complications. Recognized CNS associati ons include microcephaly, failure to thrive, and developmental delay. 85-Draznin-Chap85.indd 487 3/31/2011 4:20:49 PM CHAPTER 85 McCune \200\223Albright syndrome 488 Table 85.1 Endocrinopathies in McCune-Albright syndrome Condition Presentaion Treatment Precocious puberty Frequent initial presentation Typically aged 1 \200\2239 years Low gonadotrophins Adults fe rtile Less frequent in boys Cyproterone acetate Thyroid nodules Present in almost 100% of patients 50% become toxic due to autonomous nodule function Antithyroid drugs, radioiodine, surgery GH-secreting pituitary tumors and prolactinomas Present with features of acromegaly or hyperprolactinemia Somatostatin analogs, dopamine agonists, surgery Cushing \200\231s syndrome Adrenal hyperplasia or adenoma d Phosphate d 1,25 vitamin D i ALP Normal calcium, 25 OH vit amin D, and PTH Adrenalectomy Hypophosphatemic rickets Calcitriol, phosphate supplements Prognosis Most patients live well beyond reproductive age. Bone deformities may reduce life expectancy. Sudden cardiac death is uncommon. Further reading Lumbroso S, Paris F, Sultan C (2002). McCune \200\223Albright syndrome: mol ecular genetics. J Paediatr Endocrinol Metab 15(3):875 \200\223882. Spiegel AM, Weinstein LS (2004). Inherited diseases involving G proteins and G protein \200 \223coupled receptors. Annu Rev Med 55:27 \200\22339. 85-Draznin-Chap85.indd 488 3/31/2011 4:20:50 PM DEFINITION 489 Neuro \201 bromatosis De \201 nition Neuro \201 bromatosis type 1 (NF1) is also known as von Recklinghausen dis - ease and refers to the occurrence of multiple neuro \201 bromas, caf -au-lait spots, an d Lisch nodules affecting the iris. Endocrinopathies are sometimes associated with NF1. The prevalence of NF1 is estimated to be 1 in 3500 of the population. NF type 2 (NF2) is characterized by the presence of bilateral acoustic neuromas typically r esulting in deafness. Other features of NF2 include posterior subcapsular cataracts, retina l gliomas, pigmented retinopathy, and gaze palsies. NF2 has no common associated endocrinopathies. NF2 is rare with an estimated frequency of 1 in 40,000 live births. 86-Draznin-Chap86.indd 489 3/31/2011 4:21:10 PM CHAPTER 86 Neuro \201 bromatosis 490 NF1 Genetics NF1 is a highly penetrant, autosomal dominant condition. The NF1 gene is located on chromosome 17 and encodes a GTPase- activating protein (neuro \201 bromin). Neuro \201 bromin promotes cleavage of GTP to GDP. Epidemiology The incidence of NF1 is 1 per 3000 of the population. NF1 is nearly 100% penet rant but shows variable clinical expression. Approximately 50% of cases are sporadic. Clinical features Diagnosis is generally apparent by the age of 1 year. The caf -au-lait s pots become visible shortly after birth (95%), and 70% have axillary or grain freckling. The multiple cutaneous and subcutaneous neuro \201 bromas appear around puberty (95%). Lis ch nodules affecting the iris start to appear typi- cally after the age of 5 years (95%). The endocrine features are detailed in Box 86.1. Learning disabilities occur in 60% of pati ents with NF1. Box 86.1 Endocrine features of NF1 Puberty and pregnancy \200 Both are associated with a change in size of neuro \201 broma s. Hypothalamus and pituitary \200 Optic gliomas impinge on adjacent tissues and may affe ct hypothalamic and/or pituitary function. Pheochromocytoma 0.1 \200\2235.0% \200 Serious complication of NF1 \200 Uncommon before age 20 years \200 Most commonly adrenal (20% bilateral) but extra adrenal lesions are reported Gut neuroendocrine tumors \200 Found in around 1% of NF1 patients \200\224carcinoid Gliomas may be found in around 15% of patients, most commonly affecting the optic pathways. Neuro \201 brosarcomas complicate around 6% of cases. Skeletal dysplasias (e.g. sphenoid wing dysplasia, scoliosis, tibial pseu- doarthrosis, pectus excavatum) may be found in up to 5% of cases. Vascuar dysplasia may occur, the most common region affected being the renal vasculature, r esulting in renovascular hypertension in up to 3% of cases. 86-Draznin-Chap86.indd 490 3/31/2011 4:21:10 PM NF1 491 Macrocephaly (16%), seizures (5%), and short stature (6%) are all reported features of NF1. Associated pheochromocytomas are seen in <5% of NF1 patients. Further reading Arun D, Gutmann DH (2004). Recent advances in neuro \201 bromatosis type 1 . Curr Opin Neurol 17(2):101 \200\223105. Rose VM (2004). Neurocutaneous syndromes. Mol Med 101(2):112 \200\223116. 86-Draznin-Chap86.indd 491 3/31/2011 4:21:11 PM CHAPTER 87 Von Hippel \200\223Lindau disease 492 Von Hippel \200\223Lindau disease De \201 nition Characterized by \200 CNS hemangioblastomas \200 Retinal angiomas \200 Renal cysts an d carcinomas \200 Pheochromocytomas \200 Pancreatic neuroendocrine tumors (less common) and pancreatic cysts \200 Occasional endolymphatic sac tumors b See Box 87.1. Box 87.1 Less common manifestations of von Hippel \200\223Lindau disease Pancreas Cysts Adenomas Epididymis Cystadenoma CNS Syringomyelia Meningioma Liver Adenoma Hemangioblastoma Cysts Lung Angioma Cysts Spleen Angioma Clinical diagnosis established by \200 Two or more hemangioblastomas \200 A hemangiobla stoma and a visual manifestation \200 One hemangioblastoma or visual manifestation and a family history of hemangioblastoma The condition occurs in approximately 1 in 36,000 live births. The average age of presentat ion is 27 years, and the condition is nearly 100% penetrant by the age of 65 years. VHL may be subdivided into type 1 and type 2 disease. 87-Draznin-Chap87.indd 492 3/31/2011 4:21:50 PM GENETICS 493 Type 1 VHL is the commonest form of the disease and is characterized by a tendency to devel op tumors in the eyes, brain, spinal cord, kidney, and pancreas Affected family members with VHL type 2 are also susceptible to developing pheochromocytomas. This may be further subdivided into VHL type 2A (develop phec ochromocytomas and renal cell carcinomas). Genetics VHL is a highly penetrant, autosomal dominant condition. The VHL gene is on chromo some 3 and is a tumor suppressor gene. Genetic testing in affected families is recommended from the age of 5 years. 87-Draznin-Chap87.indd 493 3/31/2011 4:21:50 PM CHAPTER 87 Von Hippel \200\223Lindau disease 494 Clinical features Retinal angiomas are the initial manifestation of VHL in 40% of patients. They are uncommon before the age of 10 years but continue to develop throughout life. They tend to be peripheral in the retina, appearing as red, oval lesions. Bleeding and retinal detachment may occur, and treatment is with laser therapy. Seventy- \201 ve percent of hemangioblastomas occur in the cerebellum. They are the initia l presenting feature in 40% of VHL patients. Treatment is with surgery or radiotherapy. Renal carcinoma is the most common cause of death in VHL patients. By the age of 60 years, 70% of VHL patients will be affected, with a mean age of presentation of 44 years. The lesi ons tend to be multifocal. The management of choice is surgical resection. Pheochromocytomas occur in up to 20% of VHL families and are bilat- eral in 40% of cases. T he frequency of this condition varies widely among families, as certain mutations are parti cularly associated with a high risk of pheochromocytoma. Regular biochemical screening is e ssential in these high-risk families. Treatment is with A- and B-blockade followed by surgi cal resection. Most pancreatic tumors associated with VHL are nonfunctioning, but they may secrete VIP, in sulin, glucagons, or calcitonin. They occur in 10 \200\22320% of VHL patients and should be treated expectantly unless sympto- matic, enlarging, or >2 \200\2233 cm. Table 87.1 lists the recommended ages to start tests for VHL. Table 87.1 Testing for VHL Test Recommended age to start (years) Palpation (renal and epididymal lesions) 5 Urinalysis 5 24-hour urinary catecholamines 5 Fundoscopy and \202 uorescein angiography 5 Cerebral MRI 10 Abdominal MRI for renal, adrenal, and pancreatic lesions 5 87-Draznin-Chap87.indd 494 3/31/2011 4:21:50 PM PROGNOSIS 495 Prognosis Until recently, the median survival for a VHL patient was 40 \200\22350 years of age with the majority of deaths attributable to renal cell carcinoma. Currently, the prognosis for individual patients depends on the location and complications of the tumors but overall is improving as a result of the institution of screening programs and consequent earlier therapeutic interventions. For surveillance in VHL, b see Table 87.2. Table 87.2 Surveillance in VHL Affected At risk Annual Clinical examination Urinalysis 24-hour urinary catecholamines Fundoscopy Clinical examination Urinalysis 24h urinary catecholamines Fundoscopy (aged 5 \200\22360 ye ars) Triennial Cerebral MRI (to age 50, then every 5 years) Abdominal MRI Cerebral MRI (aged 5 \200\22340 years, then every 5 years to age 60) Abdominal MRI (aged 25 \200\22365 years) Further reading Kaelin WG Jr (2003). The von Hippel \200\223Lindau gene, kidney cancer and oxygen sensing. Am Soc Nephrol 14(11):2703 \200\2232711. Lonser RR, et al. (2003). Von Hippel-Lindau disease. Lancet 361:2059 \200\2232067. Richard S, Graff J, Lindau J, et al. (2005). Von Hippel \200\223Lindau disease. Lancet 363: 1231 \200\2231234. 87-Draznin-Chap87.indd 495 3/31/2011 4:21:50 PM CHAPTER 88 Carney complex 496 Carney complex De \201 nition A clinical diagnosis is made by \201 nding two of the clinical features l isted in Clinical presentation (below) or one of these features plus either an affected \201 rst-degree relative or an inactivating mutation in the relevant gene ( PRKARI A). Genetics \200 Autosomal dominant \200 An inactivating mutation of the PRKARI A gene on the long arm of chromosome 17q2 can be identi \201 ed in approximately 50% of families. Clinical presentation \200 Spotty skin pigmentation \200 Cardiac, skin, or mucosal myxo mas \200 Endocrine tumors ( b see Box 88.1 ). \200 Psammomatous melanotic schwannoma Box 88.1 Endocrine tumors associated with Carney complex \200 The most common endocrine m anifestation is primary pigmented nodular adrenocortical disease (PPNAD) causing Cushing \200\231s syndrome. Large-cell calcifying Sertoli cell tumor (LCCSCT) \200 GH/PRL-secreting pituitary adenoma (also somatotrope/ mammotrope hyperplasia) Thyroid adenoma \200 Ovarian cysts Further reading Sandrini F, Stratakis C (2003). Clinical and molecular genetics of Carney c omplex. Mol Genet Metab 78(2):83 \200\22392. Stergiopolous SG, Abu-Asab MS, Tsokos M, et al. (2004). Pituitary pathology in Carney compl ex patients. Pituitary 7:73 \200\22382. Stratakis CA, Kirschner LS, Carney JA (2001). Clinical and molecular features of the Carney complex. J Clin Endocrinol Metab 86(9):4041 \200\2234046. 88-Draznin-Chap88.indd 496 3/31/2011 4:22:10 PM CLINICAL PRESENTATION 497 Cowden syndrome Incidence This syndrome is estimated to affect 1 in 200,000 individuals. Genetics \200 Autosomal dominant condition \200 Inactivating mutations in the PTEN tumo r suppressor gene can be identi \201 ed in approximately 80% of affected probands. Clinical presentation Also b see Box 89.1. The condition is characterized by multiple hamartomas involving organ systems derived from all three germ cell layers. Patients are also at risk for breast, thyroid, and endometrial carcinomas. Thyroid pathology occurs in > 2/3 of patients, and the lesions may be multifocal. Box 89.1 Endocrine features of Cowden syndrome \200 Nonmedullary thyroid carcinomas, espe cially follicular thyroid carcinoma Multinodular goiter \200 Thyroid adenomas \200 Parathyroid adenomas are extremely rare. Further reading Pilarski R, Eng C (2004). Will the real Cowden syndrome please stand up (ag ain)? Expanding mutational and clinical spectra of the PTEN hamartoma tumor syndrome. J Med Genet 41(5):323 \200\223326. 89-Draznin-Chap89.indd 497 3/31/2011 4:22:30 PM CHAPTER 90 POEMS syndrome 498 POEMS syndrome De \201 nition P rogressive polyneuropathy, o rganomegaly, e ndocrinopathy, m onoclonal ga mmopathy, and s kin changes (POEMS) is a rare disorder of unclear pathogenesis that is prob ably mediated by i production of light chains from abnormal plasma cells. Clinical presentation \200 Progressive polyneuropathy \200 Organomegaly, especially hep atosplenomegaly and lymphadenopathy \200 Common endocrinopathies (84%) (multiple in 65%) include hypogonadotrophic hypogonadism (70% \200\2242/3 central, 1/3 primary), hypothyroidism (60%) , hypoadrenalism (60%), and diabetes mellitus (50%) hyperprolactinemia (20%). Monoclonal gammopathy \200 Skin changes Treatment Treatments include chemotherapy, irradiation, and surgery. Further reading Dispenzieri A, Gertz MA (2004). Treatment of POEMS syndrome. Curr Treat Opt ions Oncol 5(3):249 \200\223257. 90-Draznin-Chap90.indd 498 3/31/2011 4:22:49 PM CLINICAL FEATURES 499 MEN type 1 De \201 nition Characterized by \200 Parathyroid tumors/hyperplasia \200 Anterior pituitary adenomas \200 Pancreatic neuroendocrine tumors A clinical diagnosis of MEN1 is reached in the prese nce of two out of three of these tumors or one of these tumors in the context of a family h istory of MEN1. The prevalence of MEN1 has been estimated at 1 in 10,000 of the population. Genetics MEN1 is an autosomal dominant condition with an estimated penetrance of 98% by the age of 40 years. The MEN1 gene is located on the long arm of chromosome 11 (11q13) and is a tumor suppressor gene, although the function of the encoded protein, MENIN, is unknown. The mutations causing MEN1 are inactivating mutations. Many muta- tions in the MEN1 gene ha ve been described in affected families. There is no clear genotype \200\223phenotype correl ation. Mutational analysis is available in the US, although it is important to note that up to 10% of MEN1 patients will not have mutations identi \201 able within the coding region of the MEN1 gene. Clinical features Primary hyperparathyroidism is the most common presenting feature in MEN1 and occurs in up to 95% of patients with MEN1. Pituitary adenomas are found in approximately 30% of MEN1 patients ( b see Table 91.1). The incidence of pancreatic endocrine tumors varies between 30% and 80% in different series ( b see Table 91.2). Other lesions are also associated with MEN1 (b see Table 91.3). 91-Draznin-Chap91.indd 499 3/31/2011 8:55:29 PM CHAPTER 91 MEN type 1 500 Table 91.1 Pituitary tumors in MEN1 Tumor Frequency Prolactinoma 60% Acromegaly 25% Nonfunctioning tumor 1% Cushing \200\231s disease <1% Table 91.2 Pancreatic tumors in MEN1 Tumor Frequency Gastrinoma 60% Insulinoma 30% Glucagonoma 2% VIPoma <1% PPoma <1% Nonfunctioning tumor 1% Table 91.3 Other lesions in MEN1 Tumor Frequency Adrenal cortical tumors 5% Carcinoid tumors 4% Lipomas 1% Pheochromocytoma 0.5% Malignant melanoma 0.5% Testicular teratoma 0.5% Multiple (>3) angio \201 bromas 75% 91-Draznin-Chap91.indd 500 3/31/2011 8:55:29 PM MUTATIONAL ANALYSIS 501 Management Primary hyperparathyroidism The hypercalcemia is frequently mild with an early age of onset and is the \201 rst manifestation of the disease in 90% of patients. Multiple gland disease (adenomas or hyperplasia) is common, in con- trast with sporadic pri mary hyperparathyroidism, where usually a single adenoma is found. No effective medical treatments are currently available and surgical management is the gold standard. In view of the potential for multigland disease, total parathyroidectomy with li felong oral calcitriol replacement should always be considered. The timing of surgery in asymptomatic patients with borderline hyper- calcemia is still controversial. Pituitary adenomas These are managed with surgery, medical therapies, or radiotherapy as pe r sporadic pituitary tumors ( b see p. 87). Pancreatic tumors An experienced surgeon is essential to resection of these tumors. For patients with aggressive disease, the pancreas and duodenum together with surrounding l ymph nodes may be removed, whereas simple enucleation may be suf \201 cient for some lesio ns. Gastrinomas are the major cause of morbidity and mortality in MEN1 patients and these may r espond to medical therapy with proton pump inhibitors. Mutational analysis The criteria for performing mutational analysis are controversial. One approach is to recommend assessing the following categories of patient: \200 Patients wit h 2 MEN1 tumors \200 First- and second-degree relatives of patients with MEN1 \200 Cons ider screening in patients with primary hyperparathyroidism <40 years of age, particularly in the presence of multigland disease. Consider screening in patients with isolated pancreatic neuroendocrine tumors, especially gastrinomas or insulinomas. 91-Draznin-Chap91.indd 501 3/31/2011 8:55:29 PM CHAPTER 91 MEN type 1 502 Screening Screening is relevant for affected patients, asymptomatic mutation car- riers, an d \201 rst- and second-degree relatives in families with a clinical diagnosis of MEN1 but where a mutation has not been identi \201 ed. Manifestations of MEN1 are very rare before the teenage years but have been described in pa tients as young as 5 years. Careful parental counseling can encourage some childhood monito ring, which should include a careful history for symptoms (e.g., hypoglycaemia) and height and weight assess- ment in addition to calcium and prolactin measurements. Screening involves a careful clinical history and examination as well as biochemical assessment and imaging modalities ( b see Table 91.4). Age-related penetrance is as follows: age 10 \200\2237%, age 20 \200\22352%, age 30 \200 \22387%, age 40 \200\22398%, age 60 \200\223100%. Table 91.4 Screening adults in MEN1 Tumor Frequency Calcium, phosphate, and PTH Annual Basal anterior pituitary function (particularly prolactin and IGF-1) Annual Fasting gut hormones Annual Fasting glucose Annual 24-hour urinary 5HIAA and chromogranin A Annual MRI abdomen Annual \200\223every 3 years MRI pituitary Baseline Box 91.1 Prognosis Malignant pancreatic tumors, especially gastrinomas, are the major cause of mortality in ME N1, but outcomes have been improving with the introduc- tion of appropriate screening progr ams for affected and at-risk individuals. Further reading Asgharian B, Turner ML, Gibril F, et al. (2004). Cutaneous tumors in patien ts with multiple endo- crine neoplasm type 1 (MEN1) and gastrinomas: prospective study of f requency and development of criteria with high sensitivity and speci \201 city for MEN1. J Clin Endocrinol Metab 89:5328 \200\2235336. Brandi ML Gagel AF, Angeli A, et al. (2001). Guidelines for diagnosis and therapy of MEN ty pe 1 and 2. J Clin Endocrinol Metab , 86(12):5658 \200\2235671. 91-Draznin-Chap91.indd 502 3/31/2011 8:55:29 PM GENETICS 503 MEN type 2 De \201 nition MEN2 may be divided into three forms (see Table 92.1): \200 MEN2a compris es familial medullary thyroid carcinoma (FMTC) in combination with pheochromocytoma and par athyroid tumors. \200 MEN2b is de \201 ned as the occurrence of familial MTC in associat ion with pheochromocytoma, mucosal neuromas, and a marfanoid habitus. FMTC may also occur in isolation. MEN2a accounts for >75% of all MEN2 cases. Table 92.1 Classi \201 cation and presentation of MEN2 Pathology MEN2a MEN2b 7100% 50% FMTC 7100% Not present MTC 95% Pheochromocytoma 50% Parathyroid neoplasia 20 \200\22330% Not present Not present Marfanoid habitus Not present 75% Not present Mucosal neuromas Not present 10 \200\22320% 740% Not present Intestinal ganglioneuromatosis Not present Not present Genetics MEN2 is an autosomal dominant condition. The C-RET protooncogene, mutations in whi ch cause MEN2, is located on the long arm of chromo- some 10 (10q11.2). This gene encodes RET, which is a transmembrane receptor with an extracellular cysteine-ric h domain and an intracellular tyrosine kinase domain. The mutations causing MEN2 are activating mutations. Different germline mutations cause dif ferent clinical syndromes, so in contrast to MEN1, MEN2 shows a strong genotype \200\223phe notype correlation. The C-RET proto-oncogene is also involved, via inactivating mutations, in the etiology of Hirschsprung \200\231s disease. 92-Draznin-Chap92.indd 503 3/31/2011 4:23:32 PM CHAPTER 92 MEN type 2 504 Clinical features \200\224MEN2a Medulllary thyroid cancer (MTC) MTC is often the initial manifestation and is generally mul tifocal. Pheochromocytoma and parathyroid disease typically develop later. Diagnosis of MTC requires histological analysis that reveals C-cell hyperplasia and stromal amyloid. Circulating calcitonin levels are generally elevated (see Box 92.1 ), but hypocal cemia is not seen. With metastatic disease, diarrhea is common (30%). Rarely, these tumors secrete ACTH, resulting in Cushing \200\231s syndrome due to ectopic ACTH secretion. Box 92.1 Pentagastrin test \200 Indication borderline basal calcitonin and screening of f amilies with medullary carcinoma (calcitonin slightly raised with thyroiditis) Patient fasting \200 0.5 mcg/kg pentagastrin IV over 5 seconds and \202 ush cannula \200 Calcitonin measured at 0, 2, and 10 minutes \200 Elevated basal levels of calcitoni n, which do not rise with pentagastrin stimulation, are seen in children, pregnancy, with some tumors (e.g., carcinoi ds), pernicious anemia, thyroiditis, and chronic renal failure. Side effects of the test include nausea, \202 ushing, and substernal tightness, which typically resolves in <5 minutes. Stimulated calcitonin Stimulated calcitonin Stimulated calcitonin 30 \200\223100 ng/L 100 \200\223200 ng/L 200 ng/L Follow-up screening recommended Probable C-cell hyperplasia or early medullary thyroid carcinoma Medullary thyroid carcinoma very likely Pheochromocytoma \200 Tend to present later than MTC \200 50% will be bilateral but mal ignancy is rare (<10%). \200 These lesions must be excluded prior to surgery for any othe r indication. Primary hyperparathyroidism \200 Generally results from hyperplasia of the glands \200 Hypercalcemia is typically mild. 92-Draznin-Chap92.indd 504 3/31/2011 4:23:32 PM MANAGEMENT 505 Clinical features \200\224MEN2b Mucosal neuromas can be found on the distal tongue, conjunc tiva, and throughout the gastrointestinal tract. A marfanoid habitus is typically evident. MTC tends to present earlier than in MEN2a and fr equently follows a more aggressive course. Management MTC The de \201 nitive treatment is adequate surgery by total thyroidectomy and careful ly mph node dissection. Postoperative levothyroxine is adminis- tered to all patients. Tumor spread is usually local but distant metastases do occur. Regular postoperative calcit onin assessment ( \201 rst 3 months, then every 6 \200\22312 months) is used to monitor for disease recurrence. MRI, octreotide scanning, and venous catheterization may all be helpful in staging disease recurrence. Treatment of recurrent disease responds poorly to radiotherapy or chemotherapy and consequently is generally surgical if appropriate. Somatostatin analogs may help symptom control, e.g., diarrhea, but do not appear to have an antitumor effect. Few data are available to date, but therapy with radiolabeled MIBG or somatostatin analogs appears to offer signi \201 cant symptomatic improve- ment, although tumor stabilization a nd/or regression was observed only rarely.