Bilateral granulosa cell tumors: a novel malignant manifestation of multiple endocrine neoplasia 1 syndrome found in a patient with a rare menin in-frame deletion.
BACKGROUND
Multiple endocrine neoplasia 1 (MEN1) is a cancer syndrome resulting from mutations of the MEN1 gene. The syndrome is characterized by neoplasia of the parathyroid and pituitary glands, and malignant tumors of the endocrine pancreas. Other manifestations include benign lipomas, angiofibromas, and carcinoid tumors commonly originating in the colon, thymus, and lung. This is the first report of MEN1 syndrome manifesting as bilateral granulosa cell ovarian tumors, and which is associated with a rare intronic mutation of the MEN1 gene.


METHODS
A 41-year-old woman presented with abdominal pain, increasing abdominal girth, and dysmenorrhea. Ultrasound demonstrated enlarged ovaries and uterine fibroids. After an exploratory laparotomy, she subsequently underwent bilateral salpingo-oophorectomy with hysterectomy where the pathology revealed bilateral cystic granulosa cell tumors of the ovaries. Additional workup including computed tomography imaging discovered a thymic mass, which the pathology showed was malignant, along with a pancreatic mass suspicious for a neuroendocrine tumor. Hyperparathyroidism was also discovered and was found to be secondary to a parathyroid adenoma. Genetic testing revealed an exceedingly rare mutation in the MEN1 gene (c.654 + 1 G>A).


CONCLUSIONS
Mutations of the menin gene leading to MEN1 syndrome are classically nonsense or missense mutations producing a dysfunctional protein product. Recently, researchers described a novel mutation of MEN1 (c.654 + 1 G>A) in a male proband meeting the criteria for clinical MEN1 syndrome. Functional analysis performed on the stable mutant protein showed selective disruption of the transforming growth factor beta signaling pathway, yet it maintained its wild-type ability to inhibit nuclear factor kappa B and to suppress JunD transcriptional activity.


CONCLUSIONS
To our knowledge, this is the first report of MEN1 syndrome associated with bilateral granulosa cell malignancy. We postulate that this presentation may be due to the novel menin gene mutation recently described.
Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
Michael J
MJ
Hall
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
Julie
J
Innocent
Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
Christina
C
Rybak
Department of Internal Medicine, Fox Chase Cancer Center, Philadelphia, PA, USA.
Colleen
C
Veloski
Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
Walter J
WJ
Scott
Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA.
Hong
H
Wu
Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
John A
JA
Ridge
Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
John P
JP
Hoffman
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
Hossein
H
Borghaei
Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
Aruna
A
Turaka
Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
Mary B
MB
Daly
hyperparathyroidism; menin gene; ovarian tumors