Patients with McCune-Albright syndrome have a broad spectrum of abnormalities in the gastrointestinal tract and pancreas

Abstract

McCune-Albright Syndrome (MAS) is a rare sporadic syndrome caused by post-zygotic mutations in the GNAS oncogene, leading to constitutional mosaicism for these alterations. Somatic activating GNAS mutations also commonly occur in several gastrointestinal and pancreatic neoplasms, but the spectrum of abnormalities in these organs in patients with MAS has yet to be systematically described. We report comprehensive characterization of the upper gastrointestinal tract in seven patients with MAS and identify several different types of polyps, including gastric heterotopia/metaplasia (7/7), gastric hyperplastic polyps (5/7), fundic gland polyps (2/7), and a hamartomatous polyp (1/7). In addition, one patient had an unusual adenomatous lesion at the gastroesophageal junction with high-grade dysplasia. In the pancreas, all patients had endoscopic ultrasound findings suggestive of intraductal papillary mucinous neoplasm (IPMN), but only 2 patients met the criteria for surgical intervention. Both of these patients had IPMNs at resection, one with low-grade dysplasia and one with high-grade dysplasia. GNAS mutations were identified in the majority of lesions analyzed, including both IPMNs and the adenomatous lesion from the gastroesophageal junction. These studies suggest that there is a broad spectrum of abnormalities in the gastrointestinal tract and pancreas in patients with MAS, and that patients with MAS should be evaluated for gastrointestinal pathology, some of which may warrant clinical intervention due to advanced dysplasia.

Neonatal McCune‐Albright Syndrome: A Unique Syndromic Profile With an Unfavorable Outcome

“…In contrast, hypertrophic and hyperplastic islets were described in an adult MAS patient in the absence of hormonal hypersecretion . The GNAS gene is known to be expressed in the pancreas and GNAS mutations have been demonstrated in pancreatic samples obtained at autopsy from MAS patients and in pancreatic neoplasia occuring either within MAS or as an isolated disease . We cannot establish definitely the pathogenetic mechanisms involved in the development of diffuse nesidioblastosis in our case.…”

“…(15) The GNAS gene is known to be expressed in the pancreas (59) and GNAS mutations have been demonstrated in pancreatic samples obtained at autopsy from MAS patients (3) and in pancreatic neoplasia occuring either within MAS or as an isolated disease. (11)(12)(13)(14) We cannot establish definitely the pathogenetic mechanisms involved in the development of diffuse nesidioblastosis in our case. However, different mechanisms, not necessarily mutually exclusive, can be involved, including: (1) an exaggerated b-cell response to the CS-related hyperglycemia; (2) the effect of high levels of glucorticoids that may impair normal islet cell development (60,61) ; and/or (3) a direct contribution of the mutation, which, however, we could not demonstrate because of the unavailability of pancreatic tissue in this particular case.…”

“…Somatic, missense gain‐of‐function mutations of the GNAS gene, encoding the α‐subunit of the stimulatory G protein, Gαs, are known to cause a varied spectrum of clinical expressions, including the McCune‐Albright syndrome (MAS), isolated monostotic or polyostotic fibrous dysplasia (FD) of bone, isolated endocrine tumors, the syndromic association of muscular myxomas with FD, and isolated myxomas . Recently, the same mutations have also been reported in a spectrum of low‐grade and benign hepato‐biliary, pancreatic, and gastrointestinal neoplasias occuring either with or without other clinical features of MAS . In all the different clinical contexts, the GNAS mutation leads to activation and inappropriate activity of cells and tissues normally stimulated through receptors that are coupled to the Gα‐cAMP‐protein‐kinase A dependent pathway …”

“…(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) Recently, the same mutations have also been reported in a spectrum of low-grade and benign hepato-biliary, pancreatic, and gastrointestinal neoplasias occuring either with or without other clinical features of MAS. (11)(12)(13)(14) In all the different clinical contexts, the GNAS mutation leads to activation and inappropriate activity of cells and tissues normally stimulated through receptors that are coupled to the Ga-cAMP-protein-kinase A dependent pathway. (1,2) In MAS, affected tissues and cell types include derivatives of the different germ layers.…”

McCune Albright Syndrome: Gastrointestinal Polyps and Platelet Dysfunction over 12 Years

“…GI hamartomatous polyps, carrying a typical GNAS mutation histologically identical to polyps found in Peutz-Jeghers syndrome (PJS), were first described in 2011 after the observation of oral freckling in a group of patients with MAS [4]. Following this, assessment of the GI tract in MAS cohorts has frequently shown benign upper GI polyps, mostly due to gastric heterotopia/metaplasia [5]. Currently, the natural history and specific risk of malignancy in GI polyps have not been defined in this population.…”