Figure 2. A) Schematic representation of the MEN1 gene mutation c.1224_1225insGTCC. White and green boxes are translated exons. Dark boxes are untranslated regions which include NLS1, NLSa, NLS2 domains. B) Schematic representation of the mutant menin with the p.Cys409Valfs*41 variation. White box represents the amino acids of the menin protein that are transcribed. Dark boxes represent amino acids that are disrupted. Diagonal lines represent the stop signal at position 450 which results in truncation of the protein including the NLS1, NLSa, and NLS2 domains. Ins: insertion. NLS: Nuclear localization signal. Modified from: (Marini et al., 2009)
Discussion
The estimated prevalence of MEN 1 is between 1-10 per 100,000 (Jensen & Norton, 2017). MEN 1 syndrome was first described in 1903 by Erdheim in a report of an autopsy of a patient with acromegaly and enlarged parathyroid glands (Marini et al., 2009). In 1988, the MEN1 locus was mapped to chromosome 11q13, and by 1997 MEN1 mutations were confirmed to cause MEN1 (Chandrasekharappa et al., 1997; Jensen, Berna, Bingham, & Norton, 2008; Lemos & Thakker, 2008; Marini et al., 2009). To our knowledge this is the first confirmed case of a Costa Rican patient with a novel pathogenic MEN1 mutation.
MEN1 is located on chromosome 11q13 and consists of 10 exons which contain a coding region of 1.83 kb organized into nine exons that encode a 610-amino acid protein called menin (Falchetti, 2017; Jensen et al., 2008; Jensen & Norton, 2017; Lemos & Thakker, 2008; Marini et al., 2009; Norton, Krampitz, & Jensen, 2015; Thakker, 2014; Thakker et al., 2012). Menin is an ubiquitous protein that has at least three nuclear localization signals (NLS1, NLSa, and NLS2) at its C terminus, at amino acids 479-497, 546-572, and 588-608, respectively (Falchetti, 2017; Falchetti et al., 2009; Jensen et al., 2008; Lemos & Thakker, 2008; Marini et al., 2009; Thakker, 2014). These regions, rich in positively charged residues, have been reported to directly bind to double-stranded DNA which is thought to be necessary to target menin into the nucleus (Falchetti et al., 2009; Lemos & Thakker, 2008; Thakker, 2014). Menin interacts with several proteins involved in DNA transcriptional regulation, genome stability, cell division, cell proliferation, and epigenetic regulation (Jensen et al., 2008; Lemos & Thakker, 2008; Norton et al., 2015; Thakker, 2014).
Inheritance of a germline MEN1 mutation (familial cases) or aMEN1 mutation developed in an early embryonic stage (sporadic cases) predisposes an individual to develop tumors (Marini et al., 2009). MEN1 is a tumor suppressor gene that follows the Knudson´s two hit hypothesis (Falchetti et al., 2009; Marini et al., 2009; Thakker et al., 2012).
MEN1 mutations can be identified in 70-95% of MEN1 patients (Lemos & Thakker, 2008; Marini et al., 2009). Of these mutations, 41% are frameshift insertions or deletions, 23% are nonsense mutations, 20% are missense mutations, 6% are in-frame insertions or deletions, 9% are splice site mutations and 1% large deletions3. Most frameshift and nonsense mutations are predicted to result either in a truncated protein or in loss of the translated protein because of nonsense-mediated mRNA decay (Lemos & Thakker, 2008). Our MEN1 mutation causes a premature translational stop signal downstream to the 450 codon level and disrupts the last 202 amino acids which results in truncation of the functionally conserved NLS domains of menin 1 gene.
Skin and subcutaneous tumors may arise in 90% of MEN1 patients (Jensen & Norton, 2017). Approximately 88% of MEN1 patients present angiofibromas, 72% collagenomas, and 34% lipomas (Norton et al., 2015). The presence of cutaneous tumors may be helpful in the clinical presymptomatic diagnosis of MEN1 patients, as often they appear before any clinical manifestations of MEN1-associated hormone-secreting tumors (Marini et al., 2009). Our patient on clinical examination had two palpable lipomas.
PHPT affects 95% of patients and presents as the first endocrine MEN1 manifestation in 90-100% of cases(Marini et al., 2009; Norton et al., 2015; Thakker, 2014). PHPT presents typically between 20 and 25 years of age with 100% of penetrance by the age of 50 (Falchetti et al., 2009; Marini et al., 2009; Norton et al., 2015; Thakker, 2014). This is consistent with our case given that he presented PHPT as his first manifestation.
Insulinomas arise in about 10-30% of MEN1 patients and are the second most frequent functioning pancreatic islet tumor after gastrinomas (Marini et al., 2009; Norton et al., 2015; Thakker et al., 2012). Insulinomas usually occur in the third decade of life (Jensen et al., 2008; Marini et al., 2009; Norton et al., 2015; Thakker et al., 2012). The most reliable test for the diagnosis is a supervised 72h fast, during which an increased concentration of plasma insulin in association with hypoglycemia is demonstrated, along with an elevated C-peptide and proinsulin concentrations (Marini et al., 2009; Norton et al., 2015; Thakker et al., 2012). In our case, the diagnosis was made with a fasting test positive at 3 hours when the patient was 37 years old.
Insulinomas usually present as multiple lesions which are generally small (<2cm), benign, and distributed uniformly throughout the whole pancreas (Marini et al., 2009; Norton et al., 2015). The multiplicity makes it difficult to define which tumor is secreting the excessive insulin, nonetheless the majority of MEN1 patients typically have a dominant insulinoma predominantly found in the body or tail of the pancreas (Norton et al., 2015). In our case, the patient’s recurrence of hypoglycemic episodes after surgery and the multiplicity of the nodules in histological studies suggests the presence of residual lesions in the remaining pancreas.
Insulinomas in MEN1 patients are almost invariably treated surgically (Jensen et al., 2008; Marini et al., 2009; Norton et al., 2015; Thakker et al., 2012). Diazoxide combined with frequent feedings is can also be used to control the hypoglycemia (Jensen et al., 2008; Norton et al., 2015). However, like in our case, approximately 40-50% of the patients do not respond adequately to this treatment
(Jensen et al., 2008). Long-acting somatostatin analogues such as octreotide or lanreotide are an alternative treatment (Jensen et al., 2008). Nevertheless, they are effective in only 40-50% of patients(Jensen et al., 2008).
Anterior pituitary tumors occur in 15-90% of MEN1 patients (Marini et al., 2009; Thakker et al., 2012). Approximately 60% secrete prolactin, fewer than 25% secrete GH, 5% secrete ACTH, and the remainder appear to be non-functioning(Marini et al., 2009). Our patient presented serum hypophysiary hormones within the normal range.
Individuals in which there is a high suspicion of clinical MEN1 or those with familial MEN1, should be offered genetic counseling and MEN1mutation testing as early genetic diagnosis of MEN1 is likely to reduce the morbidity and mortality related to the syndrome (Falchetti, 2017; Falchetti et al., 2009; Marini et al., 2009; Thakker et al., 2012). The identification of a germline MEN1 mutation should prompt entry into a periodic clinical, biochemical, and radiological screening program (Thakker et al., 2012).
To our knowledge this is the first report of a molecularly confirmed case of MEN1 in our country and is the first report of the c.1224_1225insGTCC mutation related to a clinically affected patient.
Author contribution
All authors had equal contribution in conceptualization, writing, reviewing, and editing the document.
Acknowledgements
The Authors would like to thank the patient and family for all the support collecting information and their interest in getting the patient’s case published.
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