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  Disease summary:

  
  
  
  
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    The term multiple endocrine neoplasia 1 (MEN1) refers to a familial tumor syndrome characterized by the combination of tumors of the parathyroid glands, pancreatic islet cells, and anterior pituitary gland.

    
    
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    Patients may also develop adrenal cortical tumors, carcinoid tumors, facial angiofibromas, collagenomas, and lipomas.

    
    
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    Parathyroid tumors are the first manifestation of MEN1 in more than 85% of patients. In less than 15% of patients, the first manifestation may be an insulinoma or prolactinoma.

    
    
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    The frequency of MEN1 is estimated to be 1 case in 30,000 persons with a female to male ratio of 1:1.

    
    
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    The age of onset of endocrine tumors is usually in the teenaged years; however, the diagnosis is frequently delayed until the fourth decade of life.

  
  

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  Hereditary basis:

  
  
  
  
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    The gene for MEN1 has been localized to chromosome band 11q13 and codes for a 610-amino acid protein, referred to as menin.

    
    
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    Loss of heterozygosity (LOH) has been found in the region associated with MEN1, suggesting that the gene has tumor suppression function consistent with Knudson’s two hit hypothesis. More than 90% of tumors from MEN1 patients have LOH.

    
    
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    MEN1 germline mutations are identified in about 80% to 90% of probands with familial MEN1 syndrome and about 65% of individuals with sporadic MEN1 syndrome (ie, a single occurrence of MEN1 syndrome in a family)

    
    
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    5-10% of patients with MEN1 may not harbor mutations in the coding region of the MEN1 gene; these individuals may have whole gene deletions or mutations in the promoter or untranslated regions.

    
    
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    More than 10% of the MEN1 mutations arise de novo.

  
  

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  Differential diagnosis:

  
  
  
  
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    MEN4 syndrome: Germline mutations in CDKN1B/p27 gene, encoding the p27kip protein, have been reported in (a) a small family presented with characteristics of MEN1: somatotropinoma, parathyroid tumors, and renal angiomyolipoma, (b) in a Dutch patient diagnosed with three lesions compatible with a diagnosis of MEN1: small-cell neuroendocrine cervical carcinoma, adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma and hyperparathyroidism.

    
    
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    Sporadic primary hyperparathyroidism (PHPT)

    
    
    
    
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      It presents as a single parathyroid adenoma, mostly in the sixth decade of life.

      
      
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      Symptoms are due to hypercalcemia, in contrast to individuals with MEN1 syndrome, who are often asymptomatic and identified during evaluation for manifestations of MEN1 syndrome.

    
    

  
  
  
  
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    Familial isolated hyperparathyroidism due to mutations other than MEN1

    
    
    
    
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      CASR, the gene encoding the calcium-sensing receptor, responsible for familial benign hypercalcemia (FBH), also called familial hypocalciuric hypercalcemia (FHH or FBHH) and neonatal severe primary hyperparathyroidism (NSHPT).

      
      
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      HRPT2, the gene encoding parafibromin, which is responsible for the hyperparathyroidism-jaw tumor (HPT-JT) syndrome

    
    

  
  
  
  
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    MEN2 syndrome, caused by mutations in RET characterized by medullary thyroid carcinoma, pheochromocytoma, and PHPT.

    
    
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    Familial isolated pituitary adenoma (FIPA)

    
    
    
    
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      Germline mutations in the AIP gene, encoding aryl hydrocarbon receptor-interacting protein, have been identified in 15% to 20% of FIPA cases.

      
      
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      The causative gene or genes in the majority (70%-80%) of FIPA families is currently unknown.

    
    

  
  
  
  
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    Zollinger-Ellison Syndrome (ZES)

    
    
    
    
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      Gastric acid hypersecretion and severe peptic ulceration due to tumor (gastrinoma) of the duodenum or pancreas producing the hormone gastrin

      
      
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      Symptoms generally occur one decade later than in MEN1

      
      
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      25% of all ZES can be attributed to MEN1

    
    

  
  
  
  
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    Insulinoma

    
    
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    Carcinoid tumors

    
    
    
    
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      Carcinoid tumors not associated with MEN1 syndrome usually occur in derivatives of the midgut and hindgut, are argentaffin positive, and secrete serotonin (5-hydroxytryptamine).

    
    

  
  

Diagnostic Criteria

Clinical diagnostic criteria for MEN1 syndrome include the presence of two of the following endocrine tumors, which may become evident either by overproduction of polypeptide hormones or by growth of the tumor itself (Table 58-1).