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Background: In acromegaly, chronic growth hormone (GH) and insulin-like growth factor-1 (IGF-1) exacerbate comorbidities in multiple organs. Differentiated thyroid carcinoma (DTC) has been reported as being a comorbid condition in acromegaly. Acromegaly is usuallysporadic, but 5% of cases may be genetic. The most frequent inheritable form of acromegaly is related to germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Epidemiological data on the relationship between active acromegaly, its familial forms and DTC are sparse. We present the investigation of a FIPA family (familial isolated pituitary adenoma) with homogeneous acromegaly and 6 sporadic acromegaly patients with DTC., Patients and Methods: A study of 59 acromegaly patients assessed thyroid nodules on ultrasound and fine-needle aspiration biopsy following the ATA 2015 criteria. We diagnosed 7 differentiated thyroid carcinomas. Resected thyroid carcinoma tissues were stained using an anti-AIP antibody. Analysis of germline and tumor-derived DNA for variants in the AIP and MEN1 genes were performed in the FIPA kindred., Results: We describe one FIPA patient and 6 sporadic acromegaly cases with DTC. The FIPA family (AIP mutation negative) consisted of two sisters, one of whom had a DTC with intermediate risk and incomplete structural response to therapy. In our study, DTC in sporadic acromegaly had a low recurrence rate (6/6), and excellent response to therapy (6/6). Immunohistochemistry for AIP showed similar or increased staining intensity in DTC versus normal thyroid tissue., Conclusion: In our cohort of sporadic and familial forms of acromegaly with DTC, AIP did not appear to influence thyroid cancer progression., (Copyright © 2020. Published by Elsevier Masson SAS.)

Pituitary adenomas are usually nonmalignant, but have a heavy burden on patients and health care systems. Increased availability of MRI has led to an increase in incidentally found pituitary lesions and clinically relevant pituitary adenomas. Epidemiologic studies show that pituitary adenomas are increasing in incidence (between 3.9 and 7.4 cases per 100,000 per year) and prevalence (76 to 116 cases per 100,000 population) in the general population (approximately 1 case per 1000 of the general population). Most new cases diagnosed are prolactinomas and nonsecreting pituitary adenomas. Most clinically relevant pituitary adenomas occur in females, but pituitary adenomas are clinically heterogeneous., Competing Interests: Disclosure The work was supported in part by grants from the FIRS funds of the CHU de Liège and by the JABBS Foundation, UK., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Somatostatin analogs (SSAs) are first-line medical therapy for the treatment of acromegaly and neuroendocrine tumors that express somatostatin receptors (SSTR). Somatostatin suppresses secretion of a large number of hormones through the stimulation of the five SSTR. However, unbalanced inhibition of secretion as observed with the highly potent SSAs pasireotide causes hyperglycaemia mainly by inhibiting insulin secretion. In contrast, AP102 a new SSAs has neutral effect on blood glucose while suppressing GH secretion. Our objective was to establish the cellular effects of AP102 on SSTR2 and SSTR5 that may explain the differences observed between AP102 and other SSAs., Methods: We compared the binding and agonist activity of AP102 with somatostatin-14, octreotide and pasireotide in HEK293 cells transfected with human SSTR2 and SSTR5 receptors. SSAs signal transduction effects (cAMP concentrations) were measured in forskolin-treated cells in the presence of SSAs. Proliferation and apoptotic effects were determined and binding assays were performed using 125 I- somatostatin-14., Results: AP102 has comparable affinity and agonist effect to octreotide at SSTR2 (IC50's of 112 pM and 244 pM, respectively; EC50's of 230 pM and 210 pM, respectively) in contrast to pasireotide that exhibits a 12-27 fold higher IC50 (3110 pM) and about 5-fold higher EC50 (1097 pM). At SSTR5, AP102 has much higher affinity and stimulating effect than octreotide (IC50's of 773 pM and 16,737 pM, respectively; EC50's of 8526 pM and 26,800 pM), and an intermediate affinity and agonist effect between octreotide and pasireotide. AP102, octreotide and pasireotide have variable anti-proliferative effects on HEK cells transfected with SSTR2 and SSTR5., Conclusion: AP102 is a new SSA that better reduces signaling at SSTR2 than SSTR5 and prevents cell proliferation at both receptors. The euglycaemic effect of AP102 observed in preclinical studies may be related to this intermediate agonistic potency between pasireotide and octreotide at SSTR2 and SSTR5., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Adipsic diabetes insipidus is a rare complication of intracranial tumors in which impaired antidiuretic hormone secretion is associated with the loss of thirst sensation. Here, we present the case of a patient with bifocal intracranial germinoma, diagnosed due to symptoms mainly caused by adipsic diabetes insipidus. This is, to our knowledge, the first case of adipsic diabetes insipidus revealing an intracranial germinoma reported in the literature. We describe the diagnostic procedures and the three-year follow-up of this patient. Management of intracranial germ-cell tumors is made complex by the wide range of histological features. Although germinomas have a generally better prognosis than most nongerminomatous tumors, they can have severe or even life-threatening presentations. Adipsic diabetes insipidus is one such severe presentation and its rarity can make it difficult to recognize and manage. Awareness of this potential entity is therefore important for clinical practice., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

X-linked acrogigantism (XLAG) is a new, pediatric-onset genetic syndrome, due to Xq26.3 microduplications encompassing the GPR101 gene. XLAG has a remarkably distinct phenotype with disease onset occurring before the age of 5 in all cases described to date, which is significantly younger than in other forms of pituitary gigantism. These patients have mixed GH and prolactin positive adenomas and/or mixed-cell hyperplasia and highly elevated levels of GH/IGF-1 and prolactin. Given their particularly young age of onset, the significant GH hypersecretion can lead to a phenotype of severe gigantism with very advanced age-specific height Z-scores. If not adequately treated in childhood, this condition results in extreme final adult height. XLAG has a clinical course that is highly similar to some of the tallest people with gigantism in history., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

AIP mutations are rare in sporadic acromegaly but they are seen at a higher frequency among certain specific populations of pituitary adenoma patients (pituitary gigantism cases, familial isolated pituitary adenoma (FIPA) kindreds, and patients with macroadenomas who are diagnosed ≤30 years). AIP mutations are most prevalent in patients with pituitary gigantism (29% of this group were found to have mutations in AIP gene). These data support targeted genetic screening for AIP mutations/deletions in these groups of pituitary adenoma patients. Earlier diagnosis of AIP-related acromegaly-gigantism cases enables timely clinical evaluation and treatment, thereby improving outcomes in terms of excessive linear growth and acromegaly comorbidities., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Acromegaly and pituitary gigantism are very rare conditions resulting from excessive secretion of growth hormone (GH), usually by a pituitary adenoma. Pituitary gigantism occurs when GH excess overlaps with the period of rapid linear growth during childhood and adolescence. Until recently, its etiology and clinical characteristics have been poorly understood. Genetic and genomic causes have been identified in recent years that explain about half of cases of pituitary gigantism. We describe these recent discoveries and focus on some important settings in which gigantism can occur, including familial isolated pituitary adenomas (FIPA) and the newly described X-linked acrogigantism (X-LAG) syndrome., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

The most frequent conditions that are associated with inherited/familial pituitary adenomas are familial isolated pituitary adenoma (FIPA) and multiple endocrine neoplasia type 1 (MEN1), which together account for up to 5% of pituitary adenomas. One important genetic cause of FIPA are inactivating mutations or deletions in the aryl hydrocarbon receptor interacting protein (AIP) gene. FIPA is the most frequent clinical presentation of AIP mutations. This article traces the current state of knowledge regarding the clinical features of FIPA and the particular genetic, pathologic, and clinical characteristics of pituitary adenomas due to AIP mutations., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Acromegaly is a chronic rare disease associated with negative pathological effects on multiple systems and organs. We designed a new informatics tool to study data from patients with acromegaly, the Liege Acromegaly Survey (LAS). This relational database permits the inclusion of anonymous historical and prospective data on patients and includes pathophysiology, clinical features, responses to therapy and long term outcomes of acromegaly. We deployed the LAS in a validation study at a single center in order to study the characteristics of patients with acromegaly diagnosed at our center from 1970-2011. A total of 290 patients with acromegaly were included (147 males and 143 females). There was a linear relationship between age at diagnosis and the date of diagnosis, indicating that older patients are being diagnosed with acromegaly more frequently. A majority presented with macroadenomas (77.5%) and the median diameter was 14 mm. Patients with macroadenomas were significantly younger than patients with microadenomas (P=0.01). GH values at diagnosis decreased with the age of the patients (P=0.01) and there was a correlation between GH values and tumor size at diagnosis (P=0.02). No correlation existed between insulin-like growth factor 1 (IGF-1) levels and tumor characteristics. The prevalence of diabetes was 21.4% in this population and 41.0% had hypertension. The presence of hypertension and diabetes were significantly associated with one another (P<0.001). There was a linear relation between initial GH and IGF-1 levels at diagnosis and those obtained during SSA analog treatment and the lowest GH and IGF-1 values following SSA therapy were obtained in older patients (GH: P<0.001; IGF-1: P<0.001). The LAS is a new relational database that is feasible to use in the clinical research setting and permits ready pooling of anonymous patient data from multiple study sites to undertake robust statistical analyses of clinical and therapeutic characteristics., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Clinically-relevant pituitary adenomas occur with a prevalence of one case per 1000-1300 of the general population. Although most are sporadic, there are several inherited conditions that incur an increased risk of developing a pituitary adenoma. Multiple endocrine neoplasia type 1 and Carney complex (due to mutations in MEN1 and PRKAR1A, respectively) are established pituitary adenoma predisposition conditions, while multiple endocrine neoplasia type 4 (due to CDKN1B mutations) is an emerging rare condition. Familial isolated pituitary adenomas (FIPA) is a novel condition not associated with these multiple endocrine neoplasias. Mutations in the aryl hydrocarbon receptor interacting protein gene account for about 15% of FIPA kindreds and are associated with about 10-20% of macroadenomas that occur in children, adolescents and young adults. When treating a pituitary adenoma patient, relevant familial and clinical factors such as associated tumors or syndromic features should be assessed at the outset in order to guide the correct choice of genetic testing in appropriate individuals., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

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.)

According to data derived from autopsy and radiological imaging series, pituitary tumours occur very commonly in the general population; however, most of these tumours are incidental findings with no obvious clinical impact. The historical data on the prevalence of pituitary adenomas in the clinical setting are scant and point to such tumours being relatively rare. Recent studies have shown that the prevalence of clinically relevant pituitary adenomas is 3-5 times higher than previously reported, which adds impetus to research into the aetiology of these tumours. Although the majority of pituitary adenomas are sporadic, approximately 5% of all cases occur in a familial setting and over half of these are due to Multiple Endocrine Neoplasia Type 1 (MEN-1) and Carney's Complex (CNC) disorders. Since the late 1990 s, we have described non-MEN1/CNC familial pituitary tumours that include all tumour phenotypes as a condition termed Familial Isolated Pituitary Adenomas (FIPAs). The clinical characteristics of the FIPAs vary from those sporadic pituitary adenomas, as patients with FIPAs have a younger age at diagnosis and larger tumours. About 15% of the FIPA patients have mutations in the aryl hydrocarbon receptor-interacting protein gene (AIP), which indicates that the FIPA may have a diverse genetic pathophysiology.

Background: Impotence and decreased libido are the cardinal features of prolactinomas in males. We describe the unusual clinical, pathological and biochemical features in a male patient with a giant prolactinoma and normal gonadal function., Case Report: A 57 year-old man presented with visual symptoms related to a 30x25x60mm tumor of the sella and skull base. Biopsy revealed a pituitary adenoma and subsequent hormone profiles demonstrated grossly elevated serum prolactin (131,412ng/ml), LH at the upper limit of normal and normal testosterone. The patient had no symptoms of decreased libido or impotence related to this giant prolactinoma. Immunohistochemistry revealed a tumor that was positive for prolactin, alpha-subunit and LH. Cabergoline greatly reduced prolactin levels but these remained above normal. LH, testosterone and alpha-subunit levels were decreased in parallel. Loss of libido and impotence became apparent when testosterone fell below normal, a situation that resolved with further cabergoline treatment and prolactin inhibition and testosterone therapy., Conclusions: Sexual dysfunction is a hallmark of prolactinomas in males. Tumors that co-secrete prolactin and LH are extremely rare and this is the first such case reported in an adult male. In this case, normal testosterone was maintained by intact LH levels even in the face of the highest prolactin level reported to date.

Many causes of thyroxine malabsorption are described in the literature, but the most common cause of failure of thyroxine therapy is poor patient compliance, or pseudomalabsorption. We describe the case of a female patient who underwent total thyroidectomy for Basedow-Graves disease. Post-operatively, several treatment regimens were employed to achieve euthyroidism, but only injectable thyroxine was found to be effective. To exclude levothyroxine malabsorption, the patient was hospitalized in a hypothyroid state while a single oral test dose of levothyroxine (1000 microg) was administered. Within 4 hours a decrease of TSH level (from 59.7 to 55.6 microUI/ml) and a significant increase in free T4 levels (from 0.8 to 15.5 pg/ml) was observed, eliminating a malabsorption problem. The cause of resistance to thyroid hormone therapy was poor patient compliance, leading to the designation of this as a case of pseudomalabsorption.