Prolactinoma in Two Brothers - Unidentified Genetic Cause Versus Co-Incidence?

Background: Most prolactinomas occur sporadically. Familial prolactinomas are uncommon. Clinical Case(s): A 35 YO male with no significant past medical history presented to endocrine clinic with c/o fatigue, decreased libido, and erectile dysfunction. Labs showed low total testosterone of 177 ng/dl (normal range 250-1100 ng/dl), low free testosterone of 19.9 pg/ml (normal range 46-224), low LH 1.1 (normal range 1.5-9.3 mIU/ml) with elevated prolactin of 47 ng/ml (normal range 2-18). MRI pituitary showed a 4.2x4x6 mm pituitary microadenoma. Physical exam was unremarkable except for obese body habitus. No known family history of MEN syndromes or parathyroid /calcium disorders. Dopamine agonist therapy resulted in significant improvement in testosterone levels, fatigue, and libido. One year after patient’s diagnosis his 32 YO younger brother was evaluated for c/o fatigue, inability to lose weight, left breast enlargement, galactorrhea, and decreased libido. Work up showed markedly elevated prolactin levels of 2405 ng/ml (normal range 4-15), decreased total testosterone of 70 ng/dl (normal range 249-836), low free testosterone of 4.8 pg/ml (normal range 8.7 to 25.1), FSH <0.1 mIU/ml (normal range 1.4-15.4), LH < 0.1 mIU/ml (normal range 1.7-8.6). MRI Pituitary showed a 25x28x20 mm pituitary macroadenoma invading the right cavernous sinus, encasing the right internal carotid artery, and abutting the optic chiasma. Our patient had genetic testing done for sequencing and deletion/duplication analysis of MEN1 and AIP (Aryl hydrocarbon receptor interacting protein) genes—two well identified causes of familial pituitary adenomas—and tested negative for both. His brother was treated with dopamine agonists with marked improvement in Prolactin to undetectable levels within a few weeks. His energy levels, headaches, and sexual function improved and galactorrhea resolved. However, testosterone levels remained below normal range even after 11 months, despite normal prolactin levels. Discussion: Prolactinomas are the most common functional pituitary adenomas, majority of them sporadic. Familial pituitary adenomas in non-syndromic form are rare. Familial isolated pituitary adenoma (FIPA) and Multiple endocrine neoplasia type 1(MEN 1) are two main causes of familial pituitary adenomas. In FIPA, pituitary adenomas occur as a result of mutations or deletions in aryl hydrocarbon receptor interacting protein gene (AIP). Identifying these mutations is important as pituitary adenomas in FIPA tend to be more aggressive, present at a younger age and are resistant to treatment. Our patient tested negative for both MEN 1 and AIP gene mutations. Whether our patient has an unidentified genetic cause or whether it was a coincidence that two brothers have prolactinomas is unclear.

Metabolic changes in patients with familial pituitary adenomas associated with mutations in the AIP gene

Currently, many AIP mutations responsible for the development of pituitary adenomas have been described. Penetence of pituitary adenomas in AIP-positive FIPA families is incomplete and varies widely. Data on the characteristics of metabolic changes in patients with familial pituitary adenomas associated with mutations in the AIP gene continues to be inadequate. Evaluation of the results of molecular genetic studies, as well as a thorough analysis of metabolic changes in these clinical cases, will help to develop and improve diagnostic and treatment algorithms, identify patient groups that require special attention of endocrinologists, timely screening, aggressive treatment, and careful dynamic observation.

The enzyme succinate dehydrogenase (SDH) and its role in hereditary pituitary adenomas

Despite active research involving familial pituitary adenomas and characterization of five hereditary syndromes, the genetic defects in more than 80 - 95% of patients remain not found. Besides, there is more than 25 cases of coexistence of pheochromocytomas and pituitary adenomas described in literature that up to date is not integrated in any syndrome; genetic defects of such coexistence also aren't defined. However it is supposed that in pituitary tumorigenesis, germline mutations of SDH can take part that is obviously important aspect of further investigation. Germline mutations of SDH were found in patients with different phenotypes of pituitary adenomas. Studying of mutations in genes SDHD, SDHB, SDHC, SDHA and their prevalence in patients with familial pituitary adenomas or with phenotypes of multiple endocrine neoplasia without mutations in MEN1, CDKN1B, PRKAR1A, AIP genes can provide clarity in a role of mutations in SDH in endocrine and in particular pituitary tumorigenesis.