Second MAFA Variant Causing a Phosphorylation Defect in the Transactivation Domain and Familial Insulinomatosis

Fottner, Christian; Sollfrank, Stefanie; Ghiasi, Mursal; Adenaeuer, Anke; Musholt, Thomas J.; Schad, Arno; Miederer, Matthias; Schadmand-Fischer, S.; Weber, Matthias M.; Lackner, Karl J.; Rossmann, Heidi

doi:10.3390/cancers14071798

Cited by 8 publications

(17 citation statements)

References 46 publications

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“…Approximately 22 cases of sporadic insulinomatosis and 3 kindreds with familial insulinomatosis have been described to date (Tragl & Mayr 1977, Anlauf et al 2009, Iacovazzo et al 2018, Snaith et al 2020, Anoshkin et al 2021, Mintziras et al 2021, Fottner et al 2022, Tartaglia et al 2022. Among the patients with sporadic insulinomatosis, 17/22 are females (77.3%).…”

Section: Clinical Features Of Insulinomatosismentioning

confidence: 99%

Insulinomatosis: new aspects

Christ

Iacovazzo

Korbonits

et al. 2023

Endocrine-Related Cancer

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Endogenous hyperinsulinemic hypoglycemia (EHH) is a rare condition with an incidence of approximately 4-6 per million person-years and comprises a group of disorders causing hyperinsulinemic hypoglycemia without exogenous administration of insulin or its secretagogues. In adults, most cases (approximately 90%) are secondary to a single insulinoma. Other causes include insulinoma in the context of multiple endocrine neoplasia type 1 (approximately 5% of cases) and non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS), which is estimated to account for 0.5-5% of all cases. Recently, an entity called insulinomatosis has been described as a novel cause of EHH in adults. The characteristic feature of insulinomatosis is the synchronous or metachronous occurrence of multiple pancreatic neuroendocrine micro-tumors expressing exclusively insulin. While most cases arise sporadically, there is recent evidence that autosomal dominant inheritance of mutations in the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA) gene can cause a familial form of insulinomatosis. In these families EHH is paradoxically associated with the occurrence of diabetes mellitus within the same family. This review summarizes the current clinical, biochemical, imaging and genetic knowledge of this disease.

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Section: Clinical Features Of Insulinomatosismentioning

confidence: 99%

Insulinomatosis: new aspects

Christ

Iacovazzo

Korbonits

et al. 2023

Endocrine-Related Cancer

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“…First described in 2009 by Anlauf et al [143], adult-onset familial insulinomatosisis is a rare disorder characterized by recurrent, severe hypoglycemia caused by multiple insulin-secreting pancreatic tumors. It occurs more frequently in females, and the mean age at the diagnosis is 39.5 years [144][145][146]. Up to date, a few cases have been reported in the literature, so that the prevalence/incidence of the disorder in the general population cannot be estimated.…”

Section: Familial Insulinomatosismentioning

confidence: 99%

“…The cause of the disorder is represented by loss-of-function mutations in the β V-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA) gene, encoding for a transcription factor, the MAFA protein, that is a key coordinator of β-cell insulin secretion [145,146,148] (Table 1).…”

Section: Familial Insulinomatosismentioning

confidence: 99%

Neuroendocrine neoplasms in the context of inherited tumor syndromes: a reappraisal focused on targeted therapies

Ruggeri

Benevento²,

Cicco³

et al. 2022

J Endocrinol Invest

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Purpose Neuroendocrine neoplasms can occur as part of inherited disorders, usually in the form of well-differentiated, slow-growing tumors (NET). The main predisposing syndromes include: multiple endocrine neoplasias type 1 (MEN1), associated with a large spectrum of gastroenteropancreatic and thoracic NETs, and type 4 (MEN4), associated with a wide tumour spectrum similar to that of MEN1; von Hippel-Lindau syndrome (VHL), tuberous sclerosis (TSC), and neurofibromatosis 1 (NF-1), associated with pancreatic NETs. In the present review, we propose a reappraisal of the genetic basis and clinical features of gastroenteropancreatic and thoracic NETs in the setting of inherited syndromes with a special focus on molecularly targeted therapies for these lesions. Methods Literature search was systematically performed through online databases, including MEDLINE (via PubMed), and Scopus using multiple keywords' combinations up to June 2022. Results Somatostatin analogues (SSAs) remain the mainstay of systemic treatment for NETs, and radiolabelled SSAs can be used for peptide-receptor radionuclide therapy for somatostatin receptor (SSTR)-positive NETs. Apart of these SSTR-targeted therapies, other targeted agents have been approved for NETs: the mTOR inhibitor everolimus for lung, gastroenteropatic and unknown origin NET, and sunitinib, an antiangiogenic tyrosine kinase inhibitor, for pancreatic NET. Novel targeted therapies with other antiangiogenic agents and immunotherapies have been also under evaluation. Conclusions Major advances in the understanding of genetic and epigenetic mechanisms of NET development in the context of inherited endocrine disorders have led to the recognition of molecular targetable alterations, providing a rationale for the implementation of treatments and development of novel targeted therapies.

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“…10,19 Finally, somatic mutation analysis was not performed on the surgical specimen, and recent research has implicated variants of a triad of genes, CEBPA, FOXL2, and IRS2 as well as the MAFA protein in the pathogenesis of recurrent insulinomatosis. 15,[20][21][22] Hence, it is imperative to explore these genetic factors in future cases of recurrent insulinomatosis, particularly in those lacking a known familial syndrome.…”

Section: Discussionmentioning

confidence: 99%

The Medical and Surgical Management of Recurrent Multicenter Insulinomatosis Without Known Genetic Predisposition

Jaquillard,

Pusateri,

Krishna

2024

ACG Case Rep J

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Insulinomas are rare neuroendocrine tumors characterized by episodic hypoglycemia. Typically, insulinomas are benign, solitary, intrapancreatic, and measure less than 2 cm in diameter. When insulinomas are multicenter or recurrent, they are often associated with genetic conditions such as multiple endocrine neoplasia type 1, neurofibromatosis type 1, or von Hippel-Lindau disease. Most insulinomas can be resolved with surgery. Multicenter and recurrent insulinomas, known as insulinomatosis, may require additional medical and surgical management. We report a distinctive case involving recurrent multicenter insulinomatosis devoid of any identified genetic familial predisposition. The patient's complex medical history spans nearly 2 decades, marked by unsuccessful attempts at resolution through surgical enucleation and noninvasive medical management, culminating in the decision for total pancreatectomy.

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Second MAFA Variant Causing a Phosphorylation Defect in the Transactivation Domain and Familial Insulinomatosis

Cited by 8 publications

References 46 publications

Insulinomatosis: new aspects

Insulinomatosis: new aspects

Neuroendocrine neoplasms in the context of inherited tumor syndromes: a reappraisal focused on targeted therapies

The Medical and Surgical Management of Recurrent Multicenter Insulinomatosis Without Known Genetic Predisposition

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