MAX Gene Mutation: A New Marker for Multiple Endocrine Neoplasia Syndrome

The novel germline MAX (MYC-associated factor X) gene mutation is a known cause of hereditary paraganglioma-pheochromocytoma syndrome. Here we describe a novel case suggesting a link between Multiple Endocrine Neoplasia and MAX mutation.

Case Description:

At age 11, a healthy 6’6” male presented with headache, vision changes, and sinus pressure. Testing confirmed the diagnosis of gigantism and imaging showed a pituitary macroadenoma. Following initial transsphenoidal resection, he achieved biochemical remission. Four years later, he returned with acral enlargement and excessive sweating. Repeat transsphenoidal resection followed by gamma knife radiation achieved biochemical remission. A year later, he noted recurrent headaches, excessive sweating, and palpations. Plasma normetanephrines showed over 5-fold elevation and abdominal MRI showed a 1.9cm left adrenal mass with 50 Housenfield Units. Pathology found pheochromocytoma. After surgical resection, biochemical remission was confirmed. Five years later, he presented again with the same symptoms. Workup noted 4-fold elevation in plasma normetanephrine and nuclear scan showed uptake in the right adrenal bed with pathology confirming right adrenal pheochromocytoma. After bilateral adrenalectomy, hydrocortisone, and florinef, symptomatic relief was achieved.

Five years later, plasma normetanephrine was noted to be elevated along with incidental findings of left adrenal bed nodules on abdominal CT done for trauma evaluation. Nuclear scan did not show uptake in the incidental nodules. He underwent surgical resection of the left adrenal for suspected recurrence of pheochromocytoma, which was confirmed on pathology. A clonidine suppression test prior to surgery showed no suppression of plasma metanephrines, consistent with pheochromocytoma. On follow-up, plasma normetaphrine was 1.4 ng/dL (normal < 0.9 ng/dL), however the patient was on sertraline for anxiety at the time. Gallium dotatate scan showed 1.4cm uptake medial to the left kidney. A 0.3mg clonidine suppression test showed 42% suppression in plasma normetanephrine from baseline. A 14 gene panel 12 months later found the patient was heterozygous for MAX Exon 4 c.228del variant.

Discussion:

There have been a handful of cases in previous literature of pheochromocytomas (often bilateral) and pituitary tumors, sometimes with hyperparathyroidism as well, affiliated with germline MAX mutations. This patient had both MAX mutation and 3P’s of MEN: pituitary macroadenoma, bilateral pheochromocytoma, and carotid paraganglioma, suggesting a possible link between Multiple Endocrine Neoplasia and MAX mutation.