Search

The aim of this study was to investigate the potential association of rs11206510 in PCSK9 gene with coronary artery disease (CAD) and myocardial infarction (MI) in Bulgarians.

Objective: We described biochemical outcome in regards to different treatment modalities in patients with acromegaly in Bulgaria. Patients and methods: It was a retrospective analysis using data from the Bulgarian Acromegaly Database. Patients with eligible data on at least one treatment modality were included in the study. Disease control was assessed by both GH and IGF-1 values or by GH/IGF-1 alone in cases with one marker. Last follow-up was median 7.0 (range 0.5-51) years after diagnosis. Results: We identified 534 patients with interpretable data, 65.4 % of whom were females. Overall surgical cure rate was 28.8 %. Adjuvant bromocriptine and cabergoline treatment was analyzed in 133 and 70 patients with disease control achieved in 18.8 % and 31.4 % respectively. Patients without prior radiotherapy had 16.3 % and 18.2 % control rates respectively. Predictors of response to dopamine agonist (DA) therapy were disease activity, radiotherapy and medication dose. Adjuvant somatostatin analog (SSA) treatment led to biochemical control in 38.6 % of 70 patients. Combination of SSA and cabergoline led to remission in 25 % of 20 patients. Growth hormone receptor antagonist (GHRA) alone or in combination resulted in remission in 61.5 % of 13 patients. Approximately one third of the patients were cured median 10 years after irradiation. Overall disease control was observed in 51.4 % of our patients increasing to 70.3 % in the last 5 years of the study period. Conclusion: DAs are efficient in less than 20 % of non-irradiated patients. They are a good costeffective alternative. [ABSTRACT FROM AUTHOR]

Background: Endothelial dysfunction is a common feature of hypertension and is associated with reduced nitric oxide bioavailability. The endogenous inhibitor of nitric oxide syntase, asymmetric dimethylarginine (ADMA), and soluble adhesion molecules such as vascular cell adhesion molecule 1 (sVCAM-1) have been established as markers of endothelial dysfunction in a number of pathologic conditions including essential hypertension. There is little information, however, about these markers in endocrine hypertension. Objective: To investigate the levels of circulating ADMA and sVCAM-1 in patients with pheochromocytoma. Patients and methods: Serum ADMA and sVCAM-1 concentrations were assayed by ELISA technique in 18 patients with pheochromocytoma, 18 patients with essential hypertension (EH) and 18 healthy subjects serving as a control group. Results: ADMA and sVCAM-1 levels were significantly elevated in pheochromocytoma patients compared to normotensive healthy controls (0.479 ± 0.072 vs. 0.433 ± 0.054 μmol/l, p = 0.037 and 690 ± 181 vs. 577 ± 108 ng/ml, p = 0.03, respectively). Patients with EH also had higher ADMA concentrations than the control group, but the difference was not significant (0.476 ± 0.075 vs. 0.433 ± 0.054 μmol/l, p = 0.06). No associations were found between the levels of ADMA, sVCAM-1 and some potential risk factors for endothelial dysfunction. Conclusion: Endothelial function is impaired in patients with pheochromocytoma as indicated by the elevated circulating levels of ADMA and sVCAM-1. The lack of association of these markers with cateholamines, glucose and lipid abnormalities together with their comparable levels in EH patients suggests that endothelial dysfunction is most likely related to hypertension itself [ABSTRACT FROM AUTHOR]

Context. Cardiomyopathy is the most frequent cardiovascular complication in acromegaly. Objective. We aimed to compare some echocardiographic markers in acromegaly patients with controls and find a correlation with disease duration, disease activity, levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). Design. We conducted a cross-sectional case-control study for the period of 2008-2012. Subjects and methods. Acromegaly patients altogether 146 (56 men and 90 women), were divided into four groups according to disease activity and the presence of arterial hypertension (AH). The control group included 83 subjects, matching the patient groups by age, gender and presence of AH. GH was measured by an immunofluorometric method, while IGF-1 by IRMA method. All patients and controls were subjected to one- and two-dimensional transthoracic echocardiography, color and pulse Doppler. Results. We found a thickening of the left ventricular walls and an increase in the left ventricular mass. However, these changes were not statistically significant in all groups and no correlation with disease duration could be demonstrated. As markers of diastolic dysfunction, increased deceleration time and isovolumetric relaxation were registered, which were dependent mainly on age in a binary logistic regression analysis, but not GH or IGF-1. Using absolute values, ejection and shortening fractions were increased in some groups. Using cut-off values, a higher percentage of systolic dysfunction was demonstrated in patients compared to their corresponding controls. Engagement of the right heart ventricle was also found – increased deceleration time and decreased e/a tric ratio. Conclusions. In conclusion, functional impairments of both ventricles were present, with a predominance of left ventricular diastolic dysfunction. [ABSTRACT FROM AUTHOR]

The purpose was to assess the level of medication adherence (MA) and related factors among individuals with acromegaly. The secondary goal was to assess the quality of life of patients and whether and how it correlates with the level of adherence. A prospective one-year study was conducted among patients with acromegaly diagnosed, treated, and monitored in the reference center for rare endocrine diseases in Bulgaria in 2021. Clinical data, patients reported outcomes, and health economics data were collected to define the predictors of non-adherence to medicines. Medication adherence level was assessed through a free Morisky-Green 4-item questionnaire. A total of 179 patients with acromegaly were observed. Approximately 62% were female, 50% were between 41 and 60 years, and the mean age at diagnosis was 40.4 years. The response rate to the questionnaires was 53% ( n = 95; mean age 53.5 years, 73% female and 26% male). Patients with high levels of MA reported higher median values for the 36-Item Short Form Health Survey (SF-36) in comparison with those with low levels: 65.5 vs. 48.5 ( p = 0.017). Similar results for EQ-5D-3L (3-level EuroQol 5D version) values and the level of MA were found: 0.656 vs. 0.796 ( p = 0.0123). A low level of adherence was revealed in 34.7% of the patients, with no difference among different age groups. A significant positive determinant for adherence was years lived with acromegaly (OR = 5.625, 95% CI 1.7401-18.1832, p = 0.0039), as shorter duration was related to higher odds for high level of adherence. The current study demonstrates the importance of MA assessment for patients with acromegaly in Bulgaria. The medication adherence to the prescribed therapy among the observed group of patients with acromegaly varied as the percentage of adherent patients was around 65%. Still, there are low-adherent patients, and the responsible factors should be further investigated.

Acromegaly is a rare condition typically caused by benign pituitary adenomas, resulting in excessive production of growth hormone. Clinical manifestations of acromegaly are diverse, varying from the overgrowth of body tissue to cardiovascular, metabolic, and osteoarticular disorders. Symptoms may emerge slowly, overlapping with other diseases and often involve many different healthcare specialists. In the last decade, efforts to provide an accurate and timely diagnosis of acromegaly have improved disease management and clinical experience. Despite this progress, marked differences in the diagnosis, treatment, and management of acromegaly exist from country-to-country. To address these inconsistencies in the region comprising Central and Eastern Europe, Israel, and Kazakhstan, a panel of acromegaly experts from 13 of these countries was convened. Acromegaly experts from each country provided available information on the approaches from their country, including regional treatment centers and multidisciplinary teams, treatment access, reimbursement and availability, and physician education, disease awareness, and patient advocacy. Across several areas of acromegaly management, divergent approaches were identified and discussed, including the provision of multidisciplinary care, approved and available treatments, and disease awareness programs. These were recognized as areas of potential improvement in the management of acromegaly, in addition to participation in national and regional acromegaly registries. Further experience exchange will facilitate the identification of specific strategies that can be adapted in each country, and widespread participation in acromegaly registries will enable their evaluation. It is anticipated that this approach will support the optimization of acromegaly patient care across this region., Competing Interests: The authors declare competing interests as follows: MB reports personal fees and non-financial support from Novartis; grants, personal fees and non-financial support from Ipsen; personal fees, non-financial support and other from Pfizer; and personal fees from Recordati outside the submitted work. MD reports personal fees from Pfizer and personal fees from Novartis outside the submitted work. MG reports personal fees from Pfizer and personal fees from Novartis outside the submitted work. VH reports personal fees and non-financial support from Pfizer and Ipsen outside the submitted work. II reports lectures’ fees from Pfizer and Ipsen outside the submitted work. DK reports personal fees from Pfizer outside the submitted work. TK reports personal fees from Pfizer and personal fees from Novartis outside the submitted work. MK reports personal fees from Pfizer outside the submitted work. CP reports personal fees from Pfizer, Novartis and Ipsen outside the submitted work. SV reports personal fees from Pfizer outside the submitted work. RG reports employment with Pfizer. SP reports employment with Pfizer. DS reports employment with Pfizer. IS reports personal fees and other from Pfizer; personal fees and other from Medison Pharma; and grants, personal fees and other from Novartis outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This project received funding from Pfizer. The funder had the following involvement with the study: supported the face-to-face advisory board meeting and funded medical writing and editorial assistance., (Copyright © 2022 Bolanowski, Adnan, Doknic, Guk, Hána, Ilovayskaya, Kastelan, Kocjan, Kužma, Nurbekova, Poiana, Szücs, Vandeva, Gomez, Paidac, Simoneau and Shimon.)

Background: Adherence to therapy is one of the most important elements during the therapeutic process ensuring the predefined therapeutic outcomes. The aim is to analyze the need and importance of treatment adherence guideline for acromegaly patients and the possibilities for its development and implementation in Bulgaria. Methods: A set of methods was applied: (1) a literature review in the electronic database for identification of articles and guidelines related to adherence and acromegaly; (2) analysis of Bulgarian legislative documents; (3) a pilot study for assessment of the level of treatment adherence among hospitalized Bulgarian acromegaly patients in 2018; (4) a plan for development and implementation of specific guideline was created entitled BULMEDACRO - BULgarian guideline for MEdication aDherence assessment and improvement in ACROmegaly. Results: No specific guidelines for evaluation, monitoring, reporting and/or improving adherence in acromegaly patients has been found in the literature. Requirements for regular assessment of the level of adherence, application of appropriate methods for improvement and monitoring are not sufficiently formulated and mandatory. The pilot study confirmed that therapy adherence among Bulgarian patients with acromegaly is relatively high as almost 90% of patients report that they strictly comply with their prescribed treatment regimen. It is necessary, however, a specific guideline focused on the methods for assessment and improvement of adherence, in order to ensure monitoring and follow-up of acromegaly patients. Conclusions: Patients with acromegaly should be the focus of specially designed national programs, initiatives and/or guidelines for regular evaluation and improvement of the adherence level. Despite the difficulties and the lack of an adequate legal basis, successive steps initiated by different stakeholder are needed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kamusheva, Parvanova, Rusenova, Vandeva and Elenkova.)

Objective: Acromegaly is characterized by high neoplastic morbidity as a side effect of growth hormone (GH) hypersecretion. Increased incidence of goiter, thyroid carcinoma, and thyroid dysfunction is also reported. The aim of the present study was to find the prevalence of thyroid dysfunction and goiter in patients with acromegaly and determine its relationship to disease activity, disease duration, and the presence of secondary hypothyroidism., Subjects and Methods: In a cross-sectional study of the period 2008-2012 were included 146 patients with acromegaly (56 men, 90 women) of mean age 50.3 ± 12.4 years. Acromegaly disease activity and thyroid function were evaluated in all patients. Thyroid ultrasonography was performed to calculate thyroid volume and detect the presence of nodular goiter., Results: Ninety-one patients were determined to have an active disease, and 55, a controlled disease. The mean thyroid volume in patients without previous thyroid surgery was 37.6 ± 38.8 mL. According to disease activity, thyroid volume was significantly higher in patients with active disease (38.5 ± 45.4 mL vs. 27.2 ± 18.4 mL, p = 0.036). A weak positive correlation was found between thyroid volume and insulin-like growth factor 1 (IGF-1) in the whole group and in females (R = 0.218; p = 0.013, and R = 0.238; p = 0.037, respectively). There was no significant correlation of thyroid volume with disease duration and GH level in the whole group and in both sexes. The patients with secondary hypothyroidism had twofold smaller thyroid volume, relative to the rest of the group. The prevalence of thyroid dysfunction was 39%, with a female to male percentage ratio of 1.73. Goiter was diagnosed in 87% of patients, including diffuse goiter (17.1%) and nodular (69.9%), with no significant difference between patients with active and controlled disease or the presence of secondary hypothyroidism., Conclusions: Thyroid volume in patients with acromegaly depends on disease activity and the presence of secondary hypothyroidism as a complication. The increased prevalence of nodular goiter determines the need of regular ultrasound thyroid evaluation in the follow-up of patients with acromegaly. Arch Endocrinol Metab. 2020;64(3):269-75.

Background: Acromegaly and its comorbidities affect the patients' quality of life, each healthcare system and the society. This study aimed to evaluate clinical characteristics and treatment patterns and the economic burden of acromegaly. Materials and methods: All patients with acromegaly treated with expensive medicines and regularly followed up at the main expert clinical center for acromegaly in the country were included in this nationwide, retrospective, observational, population-based study. Patient characteristics, treatment patterns, healthcare resource use, and costs were assessed for 1-year period (01.01.2018-31.12.2018). Results were processed through statistical analysis using MedCalc software version 16.4.1. Results: A total of 191 acromegaly patients were observed. Approximately 67% were female, 45.5% were between 41 and 60 years and the mean age at diagnosis was 40.73 years. Surgical treatment was preferred as a first-line therapy among almost 89% of all diagnosed patients. The level of comorbidities was very high as more than 95% suffered from at least one concomitant disease. The most frequent comorbidities were other endocrine and metabolic diseases (96.7%), followed by cardiovascular diseases (70.7%). The most common first-line pharmacotherapy was long-acting somatostatin analogs (SSA) (38%) followed by dual combination SSA + pegvisomant (21%). The total economic burden of acromegaly was estimated to be 2,674,499.90 € in 2018 as the direct costs (medication costs, hospitalization costs covered by the patients and the National Health Insurance Fund) outnumbered indirect costs (loss of productivity due to hospitalization): 2,630,568.58 € vs. 43,931.32 €. The average annual per-patient direct and indirect costs were 14,002.62 €. Conclusions: The current study demonstrates a significant clinical and socio-economic burden of acromegaly in the country. Proper diagnosing and regular follow up of acromegaly patients in a specialized pituitary center ensure appropriate innovative pharmacotherapy with achievement of disease control., (Copyright © 2020 Kamusheva, Vandeva, Mitov, Rusenova, Elenkova, Zacharieva, Mitkova, Tachkov, Dimitrova, Doneva, Tcharaktchiev and Petrova.)

Pituitary adenomas are frequently occurring neoplasms that produce clinically significant disease in 1:1000 of the general population. The pathogenesis of pituitary tumors is a matter of interest as it could help to improve diagnosis and treatment. Until recently, however, disruptions in relatively few genes were known to predispose to pituitary tumor formation. In the last decade, several more genes and pathways have been described. Germline pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene were found in familial or sporadic pituitary adenomas, usually with an aggressive clinical course. Cyclin-dependent kinase inhibitor 1B (CDKN1B) pathogenic variants lead to multiple endocrine neoplasia type 4 (MEN4) syndrome, in which pituitary adenomas can occur. Xq26.3 duplications involving the gene GPR101 cause X-linked acrogigantism. The pheochomocytoma and/or paraganglioma with pituitary adenoma association (3PAs) syndrome suggests that pathogenic variants in the genes of the succinate dehydrogenase complex or MYC-associated factor X (MAX) might be involved in pituitary tumorigenesis. New recurrent somatic alterations were also discovered in pituitary adenomas, such as, ubiquitin-specific protease 8 (USP8) and USP48 pathogenic variants in corticotropinomas. The aim of the present review is to provide an overview of the genetic pathophysiology of pituitary adenomas and their clinical relevance.

Background: The potent immunomodulatory action of prolactin has been demonstrated in many experimental in vitro studies. In accordance with these data, our retrospective analyses revealed higher prevalence of autoimmune thyroid diseases in prolactinoma patients compared to general population., Purpose: A cross-sectional case-control study was carried out in a single tertiary referral centre. The main aim was to assess the frequency of newly diagnosed autoimmune thyroid diseases in female patients with prolactinomas., Methods: The study population consisted of 260 females (154 patients and 106 sex-matched, ethnicity-matched, and age-matched healthy controls) enroled in a prospective manner. Physical exam, thyroid ultrasound, and laboratory testing (measurement of antibodies to thyroglobulin, thyroid peroxidase, TSH-receptor, serum TSH and FT4 levels) were performed in all study participants., Results: Autoimmune thyroid diseases were diagnosed in 29.9% of the patients and 10.4% of the healthy subjects (p  = 0.0002). Subclinical hypothyroidism was found in 9.7% of the patients versus 2.8% of the controls (p  = 0.044). Autoimmune hyperthyroidism was observed in 1.3% of all patients., Conclusions: The prevalence of newly diagnosed autoimmune thyroid diseases, and especially the subclinical hypothyroidism, was significantly higher in our female prolactinoma patients in comparison to age-matched healthy women. Based on our results, we suggest routine screening for autoimmune thyroid diseases (thyroid function, immunology and ultrasound examination) in all female patients with prolactinoma at the time of diagnosis. We also recommend a close follow-up of thyroid function in these women in case of pregnancy and after delivery.

Background: Recent studies have revealed a higher rate of cardiovascular complications in primary aldosteronism (PA) compared to patients with essential hypertension (EH). Asymmetric dimethylarginine (ADMA) is a marker of endothelial dysfunction that could contribute to increased cardiovascular risk in patients with PA., Objectives: The aim of this study was to compare the levels of ADMA among patients with PA, controls with EH and healthy participants. Methods: Serum ADMA levels were determined, using commercially available competitive enzyme-linked immunosorbent assay., Methods: Serum ADMA levels were determined, using commercially available competitive enzyme-linked immunosorbent assay., Results: Patients with PA had significantly higher concentrations of ADMA than healthy controls (0.488 ± 0.085 vs. 0.433 ± 0.053 μmol/L, P = 0.027). No difference was found in ADMA levels between cases with PA and EH (0.488 ± 0.085 vs. 0.476 ± 0.075 μmol/L, р = 0.636). The difference between patients with EH and normotensive controls did not reach statistical significance (P = 0.06)., Conclusions: The lack of difference between ADMA levels in patients with PA and EH suggests that endothelial dysfunction is more likely related to hypertension per se than to the specific etiology of elevated blood pressure.

We conducted a case-control study to determine the contribution of polymorphisms in CYP2C8 (CYP2C8*3) and CYP2J2 (CYP2J2*7) to increased risk of coronary artery disease and essential hypertension in Bulgarians. The current analysis included 192 unrelated hypertensive patients, 261 patients with angiographically documented CAD (153 with myocardial infarction and 108 without myocardial infarction), and 496 population controls. The CYP2C8*3 and CYP2J2*7 polymorphisms were genotyped by TaqMan SNP Genotyping Assay. PLINK version 1.07 was used for the statistical analysis. No overall association was observed for the studied polymorphisms with coronary artery disease and essential hypertension. The frequency of -50T mutant allele of CYP2J2*7 was significantly higher in male with coronary artery disease without history of myocardial infarction (OR 2.16 95% CI 1.04-4.48 p = 0.035) compared to population control group, but this association did not survive after Bonferroni correction (p adj = 0.07). A significant association of CYP2C8*3 allele with increased risk of essential hypertension has found in men (OR 2.12 95% CI 1.18-3.81 p = 0.015) and this relationship remained significant after adjustment for multiple comparisons (p adj = 0.03). This is the first study showing significant gene-sex interaction for CYP2C8*3 with twofold increase in the relative risk of essential hypertension and a similar tendency for CYP2J2*7 associated with coronary artery disease without myocardial infarction in Bulgarian males. The association is not seen in females and in the whole group of patients. This result could be partly explained by the effect of estrogens on the vascular tone of coronary arteries and CYP2C8 gene expression.

Various factors influence quality of life (QoL) in acromegaly. Whether disease control and treatment approach are related to QoL is still a matter of debate. The aim of the present study was to evaluate QoL in patients with acromegaly using the disease-specific Acromegaly Quality of Life Questionnaire in respect to disease activity, treatment modalities, and other factors. We studied 212 patients with acromegaly in a cross-sectional manner over a 6-year period in a single tertiary center. As a second step, seventy of the patients who were with active disease at baseline were followed up prospectively and 45 of them were in remission at re-evaluation. In regard to the cross-sectional group, active acromegaly independently predicted worse appearance scores. Prior radiotherapy and older age were independent negative predictors of all scales. Female gender negatively predicted all scales except the appearance domain. Longer duration of remission predicted worse personal relations scores in biochemically controlled patients. The use of somatostatin analog (SSA) was associated with worse personal relations scores, while higher IGF-1 index predicted worse appearance scores in patients with active acromegaly. In the prospective group, achievement of remission independently predicted improvement of the total scale. Lower corresponding baseline scores predicted improvement of the total, physical, and appearance scales, while the absence of hypopituitarism independently predicted improvement of the appearance scale. The use of SSA was associated with improvement of the total and appearance scores. In conclusion, QoL is a multifactorial issue that needs an individualized approach for detection and management.

Background: Mortality in acromegaly strictly depends on optimal control of GH and IGF1 levels. Modern medical therapy with somatostatin analogs (SSAs) and GH receptor antagonists (GHRAs) is not available in many countries due to funding restrictions. This retrospective, comparative, cohort study investigated the impact of different treatment modalities on disease control (GH and IGF1) and mortality in acromegaly patients., Methods: Two cohorts of patients with acromegaly from Bulgaria (n=407) and Campania, Italy (n=220), were compared, and mortality rates were evaluated during a 10-year period (1999-2008)., Results: The major difference in treatment approach between cohorts was the higher utilization of SSAs and GHRAs in Italy, leading to a decreased requirement for radiotherapy. Significantly more Italian than Bulgarian patients had achieved disease control (50.1 vs 39.1%, P=0.005) at the last follow-up. Compared with the general population, the Bulgarian cohort had a decreased life expectancy with a standardized mortality ratio (SMR) of 2.0 (95% CI 1.54-2.47) that was restored to normal in patients with disease control - SMR 1.25 (95% CI 0.68-1.81). Irradiated patients had a higher cerebrovascular mortality - SMR 7.15 (95% CI 2.92-11.37). Internal analysis revealed an independent role of age at diagnosis and last GH value on all-cause mortality and radiotherapy on cerebrovascular mortality. Normal survival rates were observed in the Italian cohort: SMR 0.66 (95% CI 0.27-1.36)., Conclusions: Suboptimal biochemical control was associated with a higher mortality in the Bulgarian cohort. Modern treatment options that induce a strict biochemical control and reduce the necessity of radiotherapy might influence the life expectancy. Other factors, possibly management of comorbidities, could contribute to survival rates., (© 2014 European Society of Endocrinology.)

We describe a patient with a rare combination of acromegaly and primary aldosteronism. A 37 year-old female patient was diagnosed with acromegaly on the basis of typical clinical, hormonal and image characteristics. She presented also with one of the most common co-morbidities - arterial hypertension. The patient has been regularly followed-up and after three surgical interventions, irradiation and adjuvant treatment with a dopamine agonist, acromegaly was finally controlled in 2008 (20 years after diagnosis). Arterial hypertension however, remained a therapeutic problem even after prescription of four antihypertensive drugs. She had normal biochemical parameters, except for low potassium levels 3.2 (3.5-5.6) mmol/l. This raised the suspicion of primary hyperaldosteronism, confirmed by a high aldosterone to plasma rennin activity ratio, high aldosterone level after a Captopril challenge test and visualization of a 35 mm left adrenal nodule on a CT scan. After an operation, the patient recovered from hypokalemia and antihypertensive therapy was reduced to a small dose of a Ca blocker. Co-morbid arterial hypertension is common in acromegaly, though it is rare for this to be caused by Conn's adenoma. The association of Conn's adenoma with acromegaly has been interpreted in two lines: as a component of multiple endocrine neoplasia type (MEN1) syndrome or as a direct mitogenic effect of hyperactivated GH-IGF1 axis.

Objective: Genetic disorders of calcium metabolism arise in a familial or sporadic setting. The calcium-sensing receptor (CASR) plays a key role in maintaining calcium homeostasis and study of the CASR gene can be clinically useful in determining etiology and appropriate therapeutic approaches. We report two cases of novel CASR gene mutations that illustrate the varying clinical presentations and discuss these in terms of the current understanding of CASR function., Patients and Methods: A 16-year-old patient had mild hypercalcemia associated with low-normal urinary calcium excretion and normal-to-high parathyroid hormone (PTH) levels. Because of negative family history, familial hypocalciuric hypercalcemia was originally excluded. The second patient was a 54-year-old man with symptomatic hypocalcemia, hyperphosphatemia, low PTH, and mild hypercalciuria. Familial investigation revealed the same phenotype in the patient's sister. The coding region of the CASR gene was sequenced in both probands and their available first-degree relatives., Results: The first patient had a novel heterozygous inactivating CASR mutation in exon 4, which predicted a p.A423K change; genetic analysis was negative in the parents. The second patient had a novel heterozygous activating CASR mutation in exon 6, which predicted a p.E556K change; the affected sister of the proband was also positive., Conclusions: We reported two novel heterozygous mutations of the CASR gene, an inactivating mutation in exon 4 and the first activating mutation reported to date in exon 6. These cases illustrate the importance of genetic testing of CASR gene to aid correct diagnosis and to assist in clinical management.

Pituitary adenomas are benign intracranial neoplasms that present a major clinical concern because of hormonal overproduction or compression symptoms of adjacent structures. Most arise in a sporadic setting with a small percentage developing as a part of familial syndromes such as multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC), and the recently described familial isolated pituitary adenomas (FIPA) and MEN-4. While the genetic alterations responsible for the formation of sporadic adenomas remain largely unknown, considerable advances have been made in defining culprit genes in these familial syndromes. Mutations in MEN1 and PRKAR1A genes are found in the majority of MEN1 and CNC patients, respectively. About 15% of FIPA kindreds present with mutations of the aryl hydrocarbon receptor-interacting protein (AIP) gene. Mutations in the CDKN1B gene, encoding p27(Kip)¹ were identified in MEN4 cases. Familial tumours appear to differ from their sporadic counterparts not only in genetic basis but also in clinical characteristics. Evidence suggests that, especially in MEN1 and FIPA, they are more aggressive and affect patients at younger age, therefore justifying the importance of early diagnosis. In this review, we summarize the genetic and clinical characteristics of these familial pituitary adenomas., (Copyright © 2010. Published by Elsevier Masson SAS.)

Pituitary adenomas are one of the most frequent intracranial tumors with a prevalence of clinically-apparent tumors close to 1:1000 of the general population. They are clinically significant because of hormone overproduction and/or tumor mass effects in addition to the need for neurosurgery, medical therapies and radiotherapy. The majority of pituitary adenomas have a sporadic origin with recognized genetic mutations seldom being found; somatotropinomas are an exception, presenting frequent somatic GNAS mutations. In this and other phenotypes, tumorigenesis could possibly be explained by altered function of genes implicated in cell cycle regulation, growth factors or their receptors, cell-signaling pathways, specific hormonal factors or other molecules with still unclear mechanisms of action. Genetic changes, such as allelic loss or gene amplification, and epigenetic changes, usually by promoter methylation, have been implicated in abnormal gene expression, but alternative mechanisms may be present. Familial cases of pituitary adenomas represent 5% of all pituitary tumors. MEN1 mutations cause multiple endocrine neoplasia type 1 (MEN1), while the Carney complex (CNC) is characterized by mutations in the protein kinase A regulatory subunit-1alpha (PRKAR1A) gene or changes in a locus at 2p16. Recently, a MEN1-like condition, MEN4, was found to be related to mutations in the CDKN1B gene. The clinical entity of familial isolated pituitary adenomas (FIPA) is characterized by genetic defects in the aryl hydrocarbon receptor interacting protein (AIP) gene in about 15% of all kindreds and 50% of homogenous somatotropinoma families. Identification of familial cases of pituitary adenomas is important as these tumors may be more aggressive than their sporadic counterparts., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Cushing's syndrome (CS) is characterized by pathologically elevated free glucocorticoid levels. Endogenous hypercortisolism is usually due to ACTH-secreting pituitary corticotropic adenomas and less often due to ectopic ACTH-secreting neuroendocrine neoplasms or ACTH-independent adrenal cortisol hypersecretion. CS is a serious chronic disease leading to a several-fold increase in cardiovascular morbidity and mortality. Multiple genetic alterations have been described in the setting of sporadic corticotropinoma formation. Changes in the expression profiles have been demonstrated in growth factors and their receptors, cell-cycle regulators and in various genes related to hormonal gene transcription, synthesis and secretion. Sporadic adrenal adenomas and carcinomas may demonstrate dysfunction in genes such as TP53 among others. Cushing's disease can be an inherited condition also. Multiple endocrine neoplasia type 1 (MEN1) and familial isolated pituitary adenomas (FIPA) together account for 5% of pituitary adenomas. Cushing's disease occurs infrequently in an inherited setting in both of these conditions. To date only 2 cases of Cushing's disease have been described in association with mutations in AIP. One case of Cushing's disease has been reported as part of MEN4, a rare MEN1-like syndrome due to mutation in the CDKN1B gene. Carney complex (CNC) due to PRKAR1A mutations in most cases is associated with CS, mainly as a cause of bilateral adrenal hyperplasia. The cAMP signaling pathway is affected in this setting. In recent times the involvement of genes such as PDE11A, PDE8B and others have expanded the spectrum of the genetic pathophysiology of CS., (Copyright © 2010 S. Karger AG, Basel.)

Pituitary adenomas are one of the most frequent intracranial tumors. Usually, they are benign but are of great clinical significance because of tumor compression syndrome and hormone overproduction. The interest in this pathology is increasing, particularly after some recent reports on their prevalence that proved to be 3-5 times more than previously estimated. Pituitary tumors arise in a sporadic setting and rarely as part of hereditary genetic syndromes. Such rare hereditary conditions like MEN1, Carney complex and McCune-Albright syndrome give significant insight into pituitary tumorigenesis. Newer genes associated pituitary tumor development include CDKN1B (MEN4) and AIP, the latter of which is involved in the pathophysiology of 15% of FIPA kindreds. The number of genes involved in pituitary tumorigenesis is progressively increasing and the possible mechanisms of action include signal transduction pathways, cell cycle regulators, growth factors, chromosome instability and others. Nevertheless, in the majority of sporadic adenomas, the primary genetic defect remains unknown. Furthermore, there is not a well established relationship between the genotype and its influence on the protein expression, ligand-receptor interaction, tumor growth or hormone hyperproduction. Further studies should evaluate the clinical significance of genetic alterations and their implications for existing and new therapeutic options., (Copyright 2010 S. Karger AG, Basel.)

Paraneoplastic endocrine syndromes define a group of secondary signs and symptoms associated to a neoplasia, independently from the location of the primary tumor or its metastases. Paraneoplastic or ectopic endocrine syndromes usually result from aberrant hormone precursors or hormone-like substances by tumours. Knowledge of paraneoplastic endocrine complications is important both for the early diagnosis of neoplasia and the prognosis of the patient. In this review we discuss almost all reported paraneoplastic endocrine syndromes. We analyze their prevalence, etiology, laboratory diagnosis and treatment.