Silent gonadotroph pituitary neuroendocrine tumor in a patient with tuberous sclerosis complex: evaluation of a possible molecular link

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem hereditary cutaneous condition, characterized by multiple hamartomas. In rare cases, pituitary neuroendocrine tumors (PitNETs) have been described in patients with TSC, but the causal relationship between these two diseases is still under debate. TSC is mostly caused by mutations of two tumor suppressor genes, encoding for hamartin (TSC1) and tuberin (TSC2), controlling cell growth and proliferation. Here, we present the case of a 62-year-old Caucasian woman with TSC and a silent gonadotroph PitNET with suprasellar extension, treated with transsphenoidal endoscopic neurosurgery with complete resection. Therapeutic approaches based on mTOR signaling (i.e. everolimus) have been successfully used in patients with TSC and tested in non-functioning PitNET cellular models with promising results. Here, we observed a reduction of cell viability after an in vitro treatment of PitNET's derived primary cells with everolimus. TSC analysis retrieved no disease-associated variants with the exception of the heterozygous intronic variant c.4006-71C>T found in TSC2: the computational tools predicted a gain of a new splice site with consequent intron retention, not confirmed by an in vitro analysis of patient's lymphocyte-derived RNA. Further analyses are therefore needed to provide insights on the possible mechanisms involving the hamartin-tuberin complex in the pathogenesis of pituitary adenomas. However, our data further support previous observations of an antiproliferative effect of everolimus on PitNET

A constitutive active MAPK/ERK pathway due to BRAFV600E positively regulates AHR pathway in PTC

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor mediating the toxicity and tumor-promoting properties of dioxin. AHR has been reported to be overexpressed and constitutively active in a variety of solid tumors, but few data are currently available concerning its role in thyroid cancer. In this study we quantitatively explored a series of 51 paired-normal and papillary thyroid carcinoma (PTC) tissues for AHR-related genes. We identified an increased AHR expression/activity in PTC, independently from its nuclear dimerization partner and repressor but strictly related to a constitutive active MAPK/ERK pathway. The AHR up-regulation followed by an increased expression of AHR target genes was confirmed by a meta-analysis of published microarray data, suggesting a ligand-independent active AHR pathway in PTC. In-vitro studies using a PTC-derived cell line (BCPAP) and HEK293 cells showed that BRAF(V600E) may directly modulate AHR localization, induce AHR expression and activity in an exogenous ligand-independent manner. The AHR pathway might represent a potential novel therapeutic target for PTC in the clinical practice

The GIP/GIPR axis is functionally linked to GH-secretion increase in a significant proportion of gsp(-) somatotropinomas

Glucose-dependent insulinotropic polypeptide receptor (GIPR) overexpression has been recently described in a proportion of gsp(-) somatotropinomas and suggested to be associated with the paradoxical increase of GH (GH-PI) during an oral glucose load

A Novel Mutation in the Upstream Open Reading Frame of the CDKN1B Gene Causes a MEN4 Phenotype

PubMed ID: 23555276This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Missense mutations in Desmocollin-2 N-terminus, associated with arrhythmogenic right ventricular cardiomyopathy, affect intracellular localization of desmocollin-2 in vitro

<p>Abstract</p> <p>Background</p> <p>Mutations in genes encoding desmosomal proteins have been reported to cause arrhythmogenic right ventricular cardiomyopathy (ARVC), an autosomal dominant disease characterised by progressive myocardial atrophy with fibro-fatty replacement.</p> <p>We screened 54 ARVC probands for mutations in desmocollin-2 (<it>DSC2</it>), the only desmocollin isoform expressed in cardiac tissue.</p> <p>Methods</p> <p>Mutation screening was performed by denaturing high-performance liquid chromatography and direct sequencing.</p> <p>To evaluate the pathogenic potentials of the <it>DSC2 </it>mutations detected in patients affected with ARVC, full-length wild-type and mutated cDNAs were cloned in eukaryotic expression vectors to obtain a fusion protein with green fluorescence protein (GFP); constructs were transfected in neonatal rat cardiomyocytes and in HL-1 cells.</p> <p>Results</p> <p>We identified two heterozygous mutations (c.304G>A (p.E102K) and c.1034T>C (p.I345T)) in two probands and in four family members. The two mutations p.E102K and p.I345T map to the N-terminal region, relevant to adhesive interactions.</p> <p>In vitro functional studies demonstrated that, unlike wild-type DSC2, the two N-terminal mutants are predominantly localised in the cytoplasm.</p> <p>Conclusion</p> <p>The two missense mutations in the N-terminal domain affect the normal localisation of DSC2, thus suggesting the potential pathogenic effect of the reported mutations. Identification of additional DSC2 mutations associated with ARVC may result in increased diagnostic accuracy with implications for genetic counseling.</p

Carney Complex in clinical practice

Carney complex (CNC) is a rare autosomal dominantly inherited syndrome with near-to-complete penetrance characterized by multiple endocrine and nonendocrine neoplasia. Morbidities are mainly associated with cardiac myxoma and hormonal overactivity. Although genetically heterogeneous, most CNC cases are a consequence of germline inactivating mutations in the gene encoding the cAMP-dependent protein kinase A type I-alpha regulatory subunit (PRKAR1A). Here, we present the case of a patient with Cushing\u2019s syndrome due to primary pigmented nodular adrenocortical disease (PPNAD) and an asymptomatic IGF-1 and GH excess, with a positive family history for adrenal cortisol-secreting adenoma. DNA mutation analysis revealed a heterozygous splice site mutation in PRKAR1A with possible deleterious effects on protein function. After medical treatment with steroidogenesis inhibitors, left monolateral laparoscopic adrenalectomy was performed, achieving a recovery of cortisol-related signs and symptoms. After substitutive glucocorticoid discontinuation, the pituitary-adrenal function was consistent with autonomous cortisol secretion without overt hypercortisolism. Treatment with somatostatin analogues was efficacious in normalizing IGF-1 levels

Paradoxical response to GH predicts glucose metabolism alterations in acromegaly

Objective: A paradoxical increase in GH after oral glucose load (GH-Par) characterizes about one-third of acromegaly patients and is associated with a better response to first-generation somatostatin receptor ligands (fg-SRLs). Pasireotide is typically considered as a second-/third-line treatment. Here, we aimed to investigate the predictive role of GH-Par in Pasireotide response and the development of adverse events. Design: Multi-center Italian retrospective cohort of 78 patients treated for at least 3 months with Pasireotide. Results: IGF-1 median levels were 1.38 times the upper limit of normality (ULN) in patients with large (median 18 mm) and invasive (78%) adenomas after fg-SRL treatment failure. After a 37-month median treatment, Pasireotide effectively reduced IGF-1 ULN levels in 65 patients. Notably, 74% of cases experienced a ≥30% reduction, with normalization achieved in 58%. Among 59 patients with available OGTTs, 13 showed GH-Par (22%). Despite similar pre-Pasireotide IGF-1 levels, GH-Par patients more frequently exhibited >50% reduction in basal IGF-1 ULN after prior treatments compared to GH-NPar (83% vs 42%, p=0.02). The median Pasireotide duration (16.0 vs 24.5 months), dosage (40 vs 50 mg/monthly), and efficacy in reducing IGF-1 ULN (-49.5% vs -57.3%) were similar between the GH-Par and GH-NPar groups. Pasireotide was discontinued in 11 patients due to new-onset or worsening of glucose metabolism alterations, with higher incidence in GH-Par (77%) vs GH-NPar (37%) (p=0.011). Conclusions: The GH-Par does not predict the response to Pasireotide in acromegaly but can predict new-onset Pasireotide-induced glucose metabolism alterations

The Role of Glucocorticoid Receptor in the Pathophysiology of Pituitary Corticotroph Adenomas

Adrenocorticotropic Hormone (ACTH)-secreting pituitary adenomas are rare tumors characterized by autonomous ACTH secretion with a consequent increase in circulating cortisol levels. The resulting clinical picture is called Cushing's disease (CD), a severe condition burdened with high morbidity and mortality. Apart from increased cortisol levels, CD patients exhibit a partial resistance to the negative glucocorticoid (GC) feedback, which is of paramount clinical utility, as the lack of suppression after dexamethasone administration is one of the mainstays for the differential diagnosis of CD. Since the glucocorticoid receptor (GR) is the main regulator of negative feedback of the hypothalamic-pituitary-adrenal axis in normal conditions, its implication in the pathophysiology of ACTH-secreting pituitary tumors is highly plausible. In this paper, we review GR function and structure and the mechanisms of GC resistance in ACTH-secreting pituitary tumors and assess the effects of the available medical therapies targeting GR on tumor growth

Lesioni ipofisarie nel Carney Complex

Il Carney Complex (CNC) \ue8 una rara sindrome ereditaria caratterizzata da pigmentazione cutanea anomala, mixomi cardiaci e cutanei, schwannomi e anomalie endocrine. Nel 70% dei casi il CNC \ue8 trasmesso con modalit\ue0 autosomica dominante a penetranza pressoch\ue9 completa. Nel restante 30% dei casi questa condizione si manifesta in forma sporadica, spesso come risultato di mutazioni de novo. Caratterizzata da eterogeneit\ue0 genetica, il CNC \ue8 dovuto nel 70% dei casi a mutazioni inattivanti del gene PRKAR1A, un elemento del complesso multiproteico della protein chinasi A (PKA), centrale nella trasduzione del segnale cAMP. L\u2019iperattivit\ue0 endocrina pu\uf2 derivare da una serie di neoplasie, tra cui la displasia surrenalica nodulare pigmentata (PPNAD), adenomi ipofisari (AI), il tumore a grandi cellule del Sertoli calcifico e tumori tiroidei