Table 4.

Genetic Syndromes Associated with Pituitary Tumors

Gene(s)DisorderMOIPituitary Tumor FeaturesOther Features
MEN1 Multiple endocrine neoplasia type 1 (MEN1)ADPituitary tumors occur in 30%-40% of affected persons, most often prolactinomas.Parathyroid adenoma w/hypercalcemia; well-differentiated neuroendocrine neoplasms of pancreas, gastrointestinal tract & other locations; adrenocortical tumors; non-endocrine tumors
CDKN1B Multiple endocrine neoplasia type 4 (MEN4)ADPituitary tumors occur in 45%. 1Rare disorder; clinical findings similar to those of MEN1
PRKAR1A
PRKACB 2		 Carney complex AD≤75% of affected persons have somatotroph hyperplasia / GH-producing adenoma.Skin pigmentary abnormalities; cardiac, skin, breast, & female genital tract myxomas; schwannomas; primary pigmented nodular adrenocortical disease; large cell calcifying Sertoli cell tumors; thyroid nodules; acromegaly
GNAS Fibrous dysplasia / McCune-Albright syndrome NA (postzygotic somatic activating pathogenic variant)~15%-20% have GNAS pathogenic variants in anterior pituitary that can lead to autonomous GH production; ~80% of persons w/autonomous GH production also have hyperprolactinemia.Polyostotic fibrous dysplasia; hyperpigmented skin macules; multiple endocrine disorders (e.g., multinodular goiter, multinodular adrenal hyperplasia, & precocious puberty)
MAX
SDHA
SDHB
SDHC
SDHD
RET 3		 Hereditary paraganglioma-pheochromocytoma syndromes ADRarely assoc w/PitNETs; 4 metastatic PitNET described, vacuolated histology pictureParagangliomas; pheochromocytomas; gastrointestinal stromal tumors; clear cell renal cell carcinoma
DICER1 DICER1 tumor predisposition ADACTH-secreting pituitary blastoma (rare)↑ risk for pleuropulmonary blastoma, which typically presents in infants & children age <6 yrs
MLH1
MSH2
MSH6
PMS2 5		 Lynch syndrome ADLow penetrance of pituitary disease; ACTH-secreting macroadenomasColorectal, endometrial, ovarian, & other carcinomas
USP8 Pituitary adenoma 4 (OMIM 219090)Most often due to somatic pathogenic variants; one germline de novo pathogenic variant reported 6Small corticotropinoma w/high ACTH secretion, predominantly occurring in young femalesDevelopmental delay; dysmorphic features; ichthyosiform hyperkeratosis; chronic lung disease; chronic kidney disease; hyperglycemia; dilated cardiomyopathy; hyperinsulinism; partial GH deficiency reported in assoc w/germline pathogenic variant

ACTH = adrenocorticotropic hormone; AD = autosomal dominant; GH = growth hormone; MOI = mode of inheritance

1.
2.

One individual with Carney complex (<1% of families with Carney complex) had a germline rearrangement resulting in four copies of PRKACB [Forlino et al 2014]. PRKACB encodes the catalytic subunit Cβ of the cyclic AMP-dependent protein kinase A (PKA). Levels of Cβ and PKA activity were increased in the individual's lymphoblasts and fibroblasts; the authors propose that this is a Carney complex-causing gain-of-function variant.

3.

Hereditary paraganglioma-pheochromocytoma syndromes are also caused by pathogenic variants in SDHAF2 and TMEM127. These genes are not listed in Table 4 because there are no reports of PitNETs associated with SDHAF2 or TMEM127 germline pathogenic variants.

4.
5.

Lynch syndrome is also caused by deletions in EPCAM. This gene is not listed in Table 4 because there are no reports of PitNETs associated with EPCAM germline pathogenic variants.

6.

From: AIP Familial Isolated Pituitary Adenomas

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