Table 3a.

Hereditary Cancer Syndromes in the Differential Diagnosis of Multiple Endocrine Neoplasia Type 4

GeneDisorderMOIOverlapping Feature(s)Distinguishing Features
AIP AIP-related pituitary adenoma predisposition (PAP) & multiple types of pituitary adenoma (PITA1) (See AIP Familial Isolated Pituitary Adenomas.)ADPituitary adenomas
  • Earlier onset pituitary tumors in AIP-assoc PAP than in MEN4
  • MEN4-assoc tumors are predominantly ACTH-secreting adenomas.
  • AIP-assoc tumors are predominantly GH-secreting adenomas.
GPR101 Pituitary adenoma 2, GH-secreting (PITA2) (OMIM 300943)XLGH-secreting pituitary adenoma
  • Not assoc w/other endocrinopathies typical of MEN4
  • Not assoc w/GEP-NETs
CDH23 Pituitary adenoma 5, multiple types (PITA5) (OMIM 617540)ADGH-secreting & nonfunctional pituitary adenomas in familial pituitary adenoma types; GH-secreting, nonfunctional, PRL-secreting, ACTH-secreting, TSH-secreting, & plurihormonal (GH & TSH) tumors in sporadic pituitary adenoma types
  • Not assoc w/other endocrinopathies typical of MEN4
  • Not assoc w/GEP-NETs
CDC73 2
Familial isolated primary hyperparathyroidism (FIHP) 3 (OMIM 145980, 145000, 617343)ADParathyroid adenoma or hyperplasia
  • Not assoc w/other endocrinopathies typical of MEN4
  • Not assoc w/pituitary tumors or GEP-NETs
MEN1 Multiple endocrine neoplasia type 1 (MEN1)ADAll featuresSee Clinical Description for comparison of MEN1 & MEN4.
RET Multiple endocrine neoplasia type 2A (MEN2A)ADPHPT (in ~20%-30% of persons w/MEN2A); hypercalciuria & renal calculi (in some)
  • MEN2A is assoc w/medullary thyroid carcinoma & pheochromocytoma.
  • MEN2A-assoc PHPT is less penetrant than MEN4-assoc PHPT.

ACTH = adrenocorticotropic hormone; AD = autosomal dominant; GEP-NET = gastroenteropancreatic neuroendocrine tumor; GH = growth hormone; MEN4 = multiple endocrine neoplasia type 4; MOI = mode of inheritance; PHPT = primary hyperparathyroidism; PRL = prolactin; TSH = thyroid-stimulating hormone; XL = X-linked


Between 14% and 18% of families with FIHP have identifiable CASR pathogenic variants [Simonds et al 2002, Warner et al 2004]. CASR pathogenic variants have also been identified in individuals with familial hypocalciuric hypercalcemia (OMIM 601198) and neonatal severe primary hyperparathyroidism (OMIM 239200).


Pathogenic variants in CDC73 are associated with hyperparathyroidism-jaw tumor syndrome (see CDC73-Related Disorders). Of note, Warner et al [2004] did not identify any CDC73 pathogenic variants in 22 individuals with FIHP.


FIHP is characterized by parathyroid adenoma or hyperplasia without other associated endocrinopathies in two or more individuals in one family.

From: Multiple Endocrine Neoplasia Type 4

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