A Novel MAX Gene Mutation Variant in a Patient With Multiple and “Composite” Neuroendocrine–Neuroblastic Tumors

Abstract

Pheochromocytomas (PCCs), paragangliomas (PGLs), ganglioneuroblastomas (GNBs), and ganglioneuromas (GNs) are neuroendocrine neoplasms (NENs) that were thought to share a common embryologic origin from neural crest cells. However, they rarely occur concurrently and recurrently. We describe the case of a 40-years-old woman with "composite PCC-GN" and multiple NENs and neuroblastic tumors. Case presentation: The patient was first referred to our department at the age of 15 years for paroxysmal hypertension, headache, sweating, and watery diarrhea. Her personal history included the diagnosis of a pelvic GNB with lumbar-aortic lymph node metastases at 11 months. Her family history was positive for cerebral glioblastoma multiforme (father). An abdominal ultrasound showed a right adrenal mass that histologically was a "composite adrenal PCC-GN." The symptoms disappeared after surgery. At the age of 20 years, the symptoms returned: computed tomography (CT) and 131I-metaiodobenzylguanidine (MIBG) scintigraphy showed an inter-aortocaval mass, found histologically to be an inter-aortocaval PGL. Her symptoms reappeared again at 28 years: CT and magnetic resonance imaging revealed four left adrenal gland nodules, found histologically to be multifocal PCCs with some atypia. Genetic screening for VHL,

Composite pheochromocytoma/paraganglioma-ganglioneuroma: analysis of SDH and ATRX status, and identification of frequent HRAS and BRAF mutations

“…Here, all of our composite PCC/PGL-GN cases show no loss of expression of SDHB or ATRX, which suggests the lack of SDH and ATRX mutations. A review of the English literature also reveals the rarity of SDH mutation in composite PCC/PGL-GN, which might indicate its uniqueness compared with its pure counterparts ( 8 , 30 , 32 , 33 ).…”

“…Several limitations are of concern: first, due to the limited amount of normal paired tissue and the extreme rarity of this entity, the number of cases for next-generation sequencing is small and could only represent part of the pathogenesis of composite PCC/PGL-GN. For instance, a recent case reports a MAX mutation in multiple and composite neuroendocrine-neuroblastic neoplasms ( 33 ). Besides, CP with other neurogenic components is not diagnosed in our study and needs more investigation.…”

Familial Acromegaly and Bilateral Asynchronous Pheochromocytomas in a Female Patient With a MAX Mutation: A Case Report

“…A wide range of other tumors has been described in patients with MAX mutations: breast cancer, renal oncocytoma, squamous cell carcinoma of the tongue, renal carcinoma (5), ganglioneuroblastoma, ganglioneuroma, chondrosarcoma, lung adenocarcinoma, parathyroid adenomas (9,13). In patients with a combination of PA and PCC and MAX mutations (Table 1), a follicular variant of papillary thyroid cancer was described in case 2 (7), and in the son of case 1 (7) with the same confirmed mutation-deletion of exon 3-a neuroendocrine tumor of the pancreas was detected in the absence of other manifestations (14), as well as a rib chondrosarcoma and multiple parathyroid tumors in a case described by Seabrook et al (9); thus it can be assumed that for MAX mutation carriers, life-long surveillance in order to detect early various tumors may be necessary.…”

Case Report: Pheochromocytoma and Synchronous Neuroblastoma in a Family With Hereditary Pheochromocytoma Associated With a MAX Deleterious Variant

“…The association of PPGL and neuroblastic tumours is uncommon and fewer cases had a genetic link. The majority of these reported cases are composite pheochromocytomaganglioneuroma and comprised an association with MEN2 (20)(21)(22)(23)(24), VHL (25), NF1 (26)(27)(28) and, most recently (29), one case of a new MAX gene heterozygous variant, c.299G>C (p.Arg100Pro, NM_002382). Our case is, to the best of our knowledge, the first with a simultaneous PPGL and neuroblastoma presenting as two distinct entities in association with a MAX pathogenic variant.…”