Does Genotype-Specific Phenotype in Patients with Multiple Endocrine Neoplasia Type 2 Occur as Current Guidelines Predict?

The clinical manifestation of multiple endocrine neoplasia type 2 (MEN2) in terms of developing medullary thyroid cancer (MTC), pheochromocytoma (PCC), and/or primary hyperparathyroidism (PHPT) is related to the respective pathogenic variant of the RET proto-oncogene. The aim of this study is to retrospectively analyze the individual, genotype-dependent clinical manifestations of a large cohort of MEN2 patients. By comparing their clinical profile with currently existing evidence-based knowledge, an optimal therapy and prevention strategy in terms of prophylactic thyroidectomy and clinical follow-up could be ensured. This is a retrospective single-center study of 158 MEN2 patients who were diagnosed and/or surgically treated at a tertiary referral care center between 1990 and 2022. All participants were categorized according to their pathogenic variant of the RET proto-oncogene. Subsequently, the clinical manifestation of the disease and its time of occurrence was documented. Our analysis showed results in line with existing studies, except for a considerably lower-than-predicted occurrence of PCC in patients with V804M/L mutations. This study supports the current recommendation regarding the pathogenic variant-dependent management of this rare cancer-associated syndrome.

Bilateral inferior petrosal sinus sampling with human CRH stimulation in ACTH-dependent Cushing's syndrome: results from a retrospective multicenter study.

OBJECTIVE: Bilateral inferior petrosal sinus sampling (BIPSS) is regarded as gold standard to differentiate between Cushing´s disease (CD) and ectopic Cushing's syndrome (ECS). However, published data e.g. on the diagnostic value of additional prolactin analysis is controversial. Thus, we evaluated the diagnostic performance of BIPSS with and without prolactin in a multicenter study. DESIGN AND METHODS: Retrospective study in 5 European reference centers. Patients with overt adrenocorticotropin (ACTH)-dependent Cushing's syndrome at the time of BIPSS with human corticotropin-releasing hormone stimulation were eligible. Cut-offs for the inferior petrosal sinus (IPS) to peripheral (P) ACTH ratio and the normalized ACTH:prolactin IPS:P ratio were calculated via receiver operator characteristics analyses (reference: CD). RESULTS: 156 patients with BIPSS were identified. Of these, 120 patients (92 (77%) females; 106 (88%) CD, 14 (12%) ECS) had either histopathologically confirmed tumors or biochemical remission and/or adrenal insufficiency after surgery; only this subgroup was analyzed by ROC analysis. The optimal cut-offs for the ACTH IPS:P ratio were ≥1.9 at baseline (sensitivity 82.1% (95%CI 73.2-88.6), specificity 85.7% (95%CI 56.2-97.5), AUC 0.86) and ≥2.1 at 5 minutes post-CRH (sensitivity 91.3% (95%CI 83.6-95.7), specificity 92.9%(95%CI 64.1-99.6), AUC 0.96). A subgroup underwent additional prolactin analysis. An optimal cut-off of ≥1.4 was calculated for the normalized ACTH:prolactin IPS:P ratio (sensitivity 96.0% (95%CI 77.7-99.9), specificity 100% (95%CI 56.1-100), AUC 0.99). CONCLUSION: Our study confirms the high accuracy of BIPSS in the differential diagnosis of ACTH-dependent Cushing's syndrome and suggests that the simultaneous measurement of prolactin might further improve the diagnostic performance of this test.

The Interaction of Insulin and Pituitary Hormone Syndromes.

Pituitary hormone axes modulate glucose metabolism and exert direct or indirect effects on insulin secretion and function. Cortisol and growth hormone are potent insulin-antagonistic hormones. Therefore impaired glucose tolerance, elevated fasting glucose concentrations and diabetes mellitus are frequent in Cushing's disease and acromegaly. Also prolactinomas, growth hormone (GH) deficiency, hypogonadism and hypothyroidism might be associated with impaired glucose homeostasis but usually to a lesser extent. Therefore glucose metabolism needs to be closely monitored and treated in patients with pituitary adenomas. Correction of the pituitary dysfunction is frequently followed by improvement of glucose homeostasis.

Acute and Life-threatening Complications in Cushing Syndrome: Prevalence, Predictors, and Mortality.

CONTEXT: Cushing syndrome (CS) results in significant morbidity and mortality. OBJECTIVE: To study acute and life-threatening complications in patients with active CS. METHODS: We performed a retrospective cohort study using inpatient and outpatient records of patients with CS in a tertiary center. A total of 242 patients with CS were included, including 213 with benign CS (pituitary n = 101, adrenal n = 99, ectopic n = 13), and 29 with malignant disease. We collected acute complications necessitating hospitalization, from appearance of first symptoms of hypercortisolism until 1 year after biochemical remission. Mortality data were obtained from the national registry. Baseline factors relating to and predicting acute complications were tested using uni- and multivariate analysis. RESULTS: The prevalence of acute complications was 62% in patients with benign pituitary CS, 40% in patients with benign adrenal CS, and 100% in patients with ectopic CS. Complications observed in patients with benign CS included infections (25%), thromboembolic events (17%), hypokalemia (13%), hypertensive crises (9%), cardiac arrhythmias (5%), and acute coronary events (3%). Among these patients, 23% had already been hospitalized for acute complications before CS was suspected, and half of complications occurred after the first surgery. Glycated hemoglobin (HbA1c) and 24-hour urinary free cortisol positively correlated with the number of acute complications per patient. Patients with malignant disease had significantly higher rates of acute complications. Mortality during the observation period was 2.8% and 59% in benign and malignant CS, respectively. CONCLUSIONS: This analysis highlights the whole spectrum of acute and life-threatening complications in CS, and their high prevalence even before disease diagnosis and after successful surgery.

Prkar1a haploinsufficiency ameliorates the growth hormone excess phenotype in Aip-deficient mice.

Mutations of the regulatory subunit (PRKAR1A) of the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), leading to activation of the PKA pathway, are the genetic cause of Carney complex which is frequently accompanied by somatotroph tumors. Aryl hydrocarbon receptor-interacting protein (AIP) mutations lead to somatotroph tumorigenesis in mice and humans. The mechanisms of AIP-dependent pituitary tumorigenesis are still under investigation and evidence points to a connection between the AIP and PKA pathways. In this study, we explore the combined effects of Aip and Prkar1a deficiency on mouse phenotype and, specifically, pituitary histopathology. Aip+/- mice were compared with double heterozygous Aip+/-, Prkar1a+/- mice. The phenotype (including histopathology and serological studies) was recorded at 3, 6, 9 and 12 months of age. Detailed pituitary histological and immunohistochemical studies were performed at 12 months. Twelve-month old Aip+/- mice demonstrated phenotypic and biochemical evidence of GH excess including significantly elevated insulin-like growth factor 1 levels, larger weight and body length, higher hemoglobin and cholesterol levels and a higher frequency of growth plate thickening in comparison to Aip+/, Prkar1a+/- mice. Pituitary histopathology did not uncover any pituitary adenomas or somatotroph hyperplasia in either group. These results demonstrate a slow progression from elevated GH release to the formation of overt somatotropinomas in Aip+/- mice; the acromegalic phenotype of these mice is surprisingly ameliorated in Aip+/-, Prkar1a+/- mice. This highlights the complexities of interaction between the AIP and PKA pathway. Specifically targeting GH secretion rather than somatotroph proliferation may be an advantage in the medical treatment of AIP-dependent human acromegaly.

Chaperones, somatotroph tumors and the cyclic AMP (cAMP)-dependent protein kinase (PKA) pathway.

The cAMP-PKA pathway plays an essential role in the pituitary gland, governing cell differentiation and survival, and maintenance of endocrine function. Somatotroph growth hormone transcription and release as well as cell proliferation are regulated by the cAMP-PKA pathway; cAMP-PKA pathway abnormalities are frequently detected in sporadic as well as in hereditary somatotroph tumors and more rarely in other pituitary tumors. Inactivating variants of the aryl hydrocarbon receptor-interacting protein (AIP)-coding gene are the genetic cause of a subset of familial isolated pituitary adenomas (FIPA). Multiple functional links between the co-chaperone AIP and the cAMP-PKA pathway have been described. This review explores the role of chaperones including AIP in normal pituitary function as well as in somatotroph tumors, and their interaction with the cAMP-PKA pathway.

Influence of Genotype and Hyperandrogenism on Sexual Function in Women With Congenital Adrenal Hyperplasia.

BACKGROUND: Depending on CYP21A2 genotype, congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency leads to biochemical alterations (including hyperandrogenism, hypocortisolism, and hypoaldosteronism) and a wide spectrum of phenotypic disease manifestation. The latter include life-threatening salt-wasting crises, prenatal virilization of genitalia in women (classic CAH [C-CAH]) as well as milder forms of the disease exclusively presenting with hirsutism, acne or reduced fertility (nonclassic CAH [NC-CAH]), and could influence sexual function and identity. AIM: The present study evaluated sexual function, gender identification, and partner preference in women with C-CAH and NC-CAH. METHODS: In a cross-sectional cohort analysis, 35 female patients with CAH were divided into 2 groups: C-CAH (salt-wasting/simple virilizing; n = 17) and NC-CAH (n = 18) according to genotype and phenotype. Sexual function and sexual distress were assessed using established questionnaires, including the Female Sexual Function Index. Phenotype (defined by signs of hyperandrogenism) was assessed clinically (Ferriman-Gallwey score) and with the ovulatory function index. CYP21A2 genotype was determined by Sanger sequencing and multiplex ligation-dependent probe amplification. Sexual function was also separately analyzed in the context of clinical signs of androgenization in women with (n = 13) and without acne (n = 22). OUTCOMES: The study outcomes were sexual function and sexual distress in relation to genotype, clinical signs of androgenization, and biochemical parameters. RESULTS: Women with NC-CAH had significantly lower orgasm scores, a trend toward lower sexual function with higher sexual distress, as well as biochemical evidence of hyperandrogenism (higher dehydroepiandrosterone sulfate and lower SHBG) and a trend toward more clinical signs of hyperandrogenism (hirsutism). Indicators of in utero and childhood androgen excess as well as the presence of acne in all patients were related to lower sexual function and higher sexual distress. Clinical signs of hyperandrogenism correlated well with cardiovascular and metabolic risk factors. CLINICAL TRANSLATION: Women with NC-CAH and women with clinical signs of hyperandrogenism demonstrated higher distress compared to women with C-CAH and women without clinical signs of hyperandrogenism, respectively, regarding different aspects of sexual function. CONCLUSIONS: These data underline the importance of early diagnosis and therapy initiation, especially in patients with NC-CAH. Schernthaner-Reiter MH, Baumgartner-Parzer S, Egarter HC, et al. Influence of Genotype and Hyperandrogenism on Sexual Function in Women With Congenital Adrenal Hyperplasia. J Sex Med 2019;16:1529-1540.

Correction to: Factors predicting long-term comorbidities in patients with Cushing's syndrome in remission.

The original version of this article unfortunately published with traditional Springer copyright instead of open access under Springer compact agreement.

Factors predicting long-term comorbidities in patients with Cushing's syndrome in remission.

PURPOSE: In Cushing's syndrome, comorbidities often persist after remission of glucocorticoid excess. Here, we aim to identify factors predicting long-term comorbidities in patients with Cushing's syndrome in remission. METHODS: In a retrospective cross-sectional study, 118 patients with Cushing's syndrome in remission (52 pituitary, 58 adrenal, 8 ectopic) were followed for a median of 7.9 years (range 2-38) after the last surgery. Associations between baseline anthropometric, metabolic, hormonal parameters at diagnosis, and comorbidities (obesity, diabetes, hyperlipidemia, hypertension, osteoporosis, depression) at last follow-up, were tested by uni- and multivariate regression analysis. RESULTS: In patients with manifest comorbidities at diagnosis, remission of Cushing's syndrome resolved diabetes in 56% of cases, hypertension in 36% of cases, hyperlipidaemia in 23%, and depression in 52% of cases. In a multivariate regression analysis, age, fasting glucose, BMI, and the number of comorbidities at diagnosis were positive predictors of the number of long-term comorbidities, while baseline 24-h urinary free cortisol (UFC) negatively correlated with the persistence of long-term comorbidities. The negative relationship between baseline UFC and long-term comorbidities was also found when pituitary and adrenal Cushing's cases were analyzed separately. Baseline UFC was negatively related to the time of exposure to excess glucocorticoids. CONCLUSIONS: Long-term comorbidities after remission of Cushing's syndrome depend not only on the presence of classic cardiovascular risk factors (age, hyperglycemia, BMI), but also on the extent of glucocorticoid excess. Lower baseline UFC is associated with a higher number of long-term comorbidities, possibly due to the longer exposure to excess glucocorticoids in milder Cushing's syndrome.

Interaction of AIP with protein kinase A (cAMP-dependent protein kinase).

Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene cause mostly somatotropinomas and/or prolactinomas in a subset of familial isolated pituitary adenomas (FIPA). AIP has been shown to interact with phosphodiesterases (PDEs) and G proteins, suggesting a link to the cyclic AMP (cAMP)-dependent protein kinase (PKA) pathway. Upregulation of PKA is seen in sporadic somatotropinomas that carry GNAS mutations, and those in Carney complex that are due to PRKAR1A mutations. To elucidate the mechanism of AIP-dependent pituitary tumorigenesis, we studied potential functional and physical interactions of AIP with PKA's main subunits PRKAR1A (R1α) and PRKACA (Cα). We found that AIP physically interacts with both R1α and Cα; this interaction is enhanced when all three components are present, but maintained during Cα-R1α dissociation by PKA activation, indicating that AIP binds Cα/R1α both in complex and separately. The interaction between AIP and R1α/Cα is reduced when the frequent AIP pathogenic mutation p.R304* is present. AIP protein levels are regulated both by translation and the ubiquitin/proteasome pathway and Cα stabilizes both AIP and R1α protein levels. AIP reduction by siRNA leads to an increase of PKA activity, which is disproportionately enhanced during PDE4-inhibition. We show that AIP interacts with the PKA pathway on multiple levels, including a physical interaction with both the main regulatory (R1α) and catalytic (Cα) PKA subunits and a functional interaction with PDE4-dependent PKA activation. These findings provide novel insights on the mechanisms of AIP-dependent pituitary tumorigenesis.

Diabetes in the older patient: heterogeneity requires individualisation of therapeutic strategies.

Owing to the worldwide increase in life expectancy, the high incidence of diabetes in older individuals and the improved survival of people with diabetes, about one-third of all individuals with diabetes are now older than 65 years. Evidence is accumulating that type 2 diabetes is associated with cognitive impairment, dementia and frailty. Older people with diabetes have significantly more comorbidities, such as myocardial infarction, stroke, peripheral arterial disease and renal impairment, compared with those without diabetes. However, as a consequence of the increased use of multifactorial risk factor intervention, a considerable number of older individuals can now survive for many years without any vascular complications. Given the heterogeneity of older individuals with type 2 diabetes, an individualised approach is warranted, which must take into account the health status, presence or absence of complications, and life expectancy. In doing so, undertreatment of otherwise healthy older individuals and overtreatment of those who are frail may be avoided. Specifically, overtreatment of hyperglycaemia in older patients is potentially harmful; in particular, insulin and sulfonylureas should be avoided or, if necessary, used with caution. Instead, glucose-dependent drugs that do not induce hypoglycaemia are preferable since older patients with diabetes and impaired kidney function are especially vulnerable to this adverse event.

Genetics of Diabetes Insipidus.

Diabetes insipidus is a disease characterized by polyuria and polydipsia due to inadequate release of arginine vasopressin from the posterior pituitary gland (neurohypophyseal diabetes insipidus) or due to arginine vasopressin insensitivity by the renal distal tubule, leading to a deficiency in tubular water reabsorption (nephrogenic diabetes insipidus). This article reviews the genetics of diabetes insipidus in the context of its diagnosis, clinical presentation, and therapy.

Growth differentiation factor 15 increases following oral glucose ingestion: effect of meal composition and obesity.

OBJECTIVE: Growth differentiation factor 15 (GDF15) is a cardiovascular biomarker belonging to the transforming growth factor-ß superfamily. Increased GDF15 concentrations are associated with insulin resistance, diabetes and obesity. We investigated the physiological effects of meal composition and obesity on the regulation of systemic GDF15 levels. DESIGN: Lean (n = 8) and obese (n = 8) individuals received a carbohydrate- or fat-rich meal, a 75 g oral glucose load (OGTT) or short-term fasting. OGTTs were performed in severely obese patients (n = 6) pre- and post-bariatric surgery. METHODS: Circulating serum GDF15 concentrations were studied in lean and obese individuals in response to different meals, OGTT or short-term fasting, and in severely obese patients pre- and post-bariatric surgery. Regulation of GDF15 mRNA levels and protein release were evaluated in the human hepatic cell line HepG2. RESULTS: GDF15 concentrations steadily decrease during short-term fasting in lean and obese individuals. Carbohydrate- and fat-rich meals do not influence GDF15, whereas an OGTT leads to a late increase in GDF15 levels. The positive effect of OGTT on GDF15 levels is also preserved in severely obese patients, pre- and post-bariatric surgery. We further studied the regulation of GDF15 mRNA levels and protein release in HepG2, finding that glucose and insulin independently stimulate both GDF15 transcription and secretion. CONCLUSION: In summary, high glucose and insulin peaks upregulate GDF15 transcription and release. The nutrient-induced increase in GDF15 levels depends on rapid glucose and insulin excursions following fast-digesting carbohydrates, but not on the amount of calories taken in.

Growth hormone and risk for cardiac tumors in Carney complex.

Carney complex (CNC) is a multiple neoplasia syndrome that is caused mostly by PRKAR1A mutations. Cardiac myxomas are the leading cause of mortality in CNC patients who, in addition, often develop growth hormone (GH) excess. We studied patients with CNC, who were observed for over a period of 20 years (1995-2015) for the development of both GH excess and cardiac myxomas. GH secretion was evaluated by standard testing; dedicated cardiovascular imaging was used to detect cardiac abnormalities. Four excised cardiac myxomas were tested for the expression of insulin-like growth factor-1 (IGF-1). A total of 99 CNC patients (97 with a PRKAR1A mutation) were included in the study with a mean age of 25.8 ± 16.6 years at presentation. Over an observed mean follow-up of 25.8 years, 60% of patients with GH excess (n = 46) developed a cardiac myxoma compared with only 36% of those without GH excess (n = 54) (P = 0.016). Overall, patients with GH excess were also more likely to have a tumor vs those with normal GH secretion (OR: 2.78, 95% CI: 1.23-6.29; P = 0.014). IGF-1 mRNA and protein were higher in CNC myxomas than in normal heart tissue. We conclude that the development of cardiac myxomas in CNC may be associated with increased GH secretion, in a manner analogous to the association between fibrous dysplasia and GH excess in McCune-Albright syndrome, a condition similar to CNC. We speculate that treatment of GH excess in patients with CNC may reduce the likelihood of cardiac myxoma formation and/or recurrence of this tumor.

Characterization of GPR101 transcript structure and expression patterns.

We recently showed that Xq26.3 microduplications cause X-linked acrogigantism (X-LAG). X-LAG patients mainly present with growth hormone and prolactin-secreting adenomas and share a minimal duplicated region containing at least four genes. GPR101 was the only gene highly expressed in their pituitary lesions, but little is known about its expression patterns. In this work, GPR101 transcripts were characterized in human tissues by 5'-Rapid Amplification of cDNA Ends (RACE) and RNAseq, while the putative promoter was bioinformatically predicted. We investigated GPR101 mRNA and protein expression by RT-quantitative PCR (qPCR), whole-mount in situ hybridization, and immunostaining, in human, rhesus monkey, rat and zebrafish. We identified four GPR101 isoforms characterized by different 5'-untranslated regions (UTRs) and a common 6.1kb long 3'UTR. GPR101 expression was very low or absent in almost all adult human tissues examined, except for specific brain regions. Strong GPR101 staining was observed in human fetal pituitary and during adolescence, whereas very weak/absent expression was detected during childhood and adult life. In contrast to humans, adult monkey and rat pituitaries expressed GPR101, but in different cell types. Gpr101 is expressed in the brain and pituitary during rat and zebrafish development; in rat pituitary, Gpr101 is expressed only after birth and shows sexual dimorphism. This study shows that different GPR101 transcripts exist and that the brain is the major site of GPR101 expression across different species, although divergent species- and temporal-specific expression patterns are evident. These findings suggest an important role for GPR101 in brain and pituitary development and likely reflect the very different growth, development and maturation patterns among species.

EMPA-REG and Other Cardiovascular Outcome Trials of Glucose-lowering Agents: Implications for Future Treatment Strategies in Type 2 Diabetes Mellitus.

During the last decade, the armamentarium for glucose-lowering drugs has increased enormously by the development of DPP-4 inhibitors, GLP-1 receptor agonists and SGLT2 inhibitors, allowing individualization of antidiabetic therapy for patients with type 2 diabetes (T2DM). Some combinations can now be used without an increased risk for severe hypoglycemia and weight gain. Following a request of the US Food and Drug Administration, many large cardiovascular (CV) outcome studies have been performed in patients with longstanding disease and established CV disease. In the majority of CV outcome studies, CV risk factors were well controlled and a high number of patients were already treated with ACE inhibitors/angiotensin receptor blockers, statins and antiplatelet drugs. Most studies with insulin glargine and newer glucose-lowering drugs (saxagliptin, alogliptin, sitagliptin, lixisenatide) demonstrated safety of newer glucose-lowering agents but did not show superiority in the CV outcomes compared with placebo. By contrast, in the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) study, CV death, all-cause mortality, and hospitalization for heart failure were significantly decreased when empagliflozin was added instead of placebo to therapy for patients with high CV risk and T2DM already well treated with statins, glucose-lowering drugs, and blood pressure-lowering drugs as well as antiplatelet agents. In addition, renal endpoints including endstage renal disease were also significantly reduced when empagliflozin was added instead of placebo. Interestingly, the reduction of these clinically relevant end points was observed after a few months, making antiatherogenic effects an unlikely cause. The fact that the incidence of myocardial infarction (MI) and stroke were not reduced is in line with the hypothesis that hemodynamic factors in particular have contributed to the impressive improvement of the prognosis. To reduce the CV burden of patients with T2DM, drugs influencing factors involved in atherogenesis (eg, insulin resistance, chronic inflammation, increase of HDL, prothrombotic state) are more promising. The recent IRIS (Insulin Resistance Intervention after Stroke) study documented a significant reduction in stroke and MI when pioglitazone instead of placebo was given to nondiabetic patients presenting with both stroke/transient ischemic attack and insulin resistance, confirming results from the PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) study in patients with T2DM. Based on these new data, we suggest that the addition of both empagliflozin and pioglitazone to metformin might be the relative best option to reduce the high CV morbidity and mortality of patients with T2DM and already established CV complications. The very recent announcement that the CV outcome study with liraglutide (LEADER) also demonstrated a significant reduction of the composite endpoint (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) gives new hope for further beneficial treatment options for T2DM patients with established CVD.

A novel AVPR2 splice site mutation leads to partial X-linked nephrogenic diabetes insipidus in two brothers.

UNLABELLED: X-linked nephrogenic diabetes insipidus (NDI, OMIM#304800) is caused by mutations in the arginine vasopressin (AVP, OMIM*192340) receptor type 2 (AVPR2, OMIM*300538) gene. A 20-month-old boy and his 8-year-old brother presented with polyuria, polydipsia, and failure to thrive. Both boys demonstrated partial DDAVP (1-desamino-8-D AVP or desmopressin) responses; thus, NDI diagnosis was delayed. While routine sequencing of AVPR2 showed a potential splice site variant, it was not until exome sequencing confirmed the AVPR2 splice site variant and did not reveal any more likely candidates that the patients' diagnosis was made and proper treatment was instituted. Both patients were hemizygous for two AVPR2 variants predicted in silico to affect AVPR2 messenger RNA (mRNA) splicing. A minigene assay revealed that the novel AVPR2 c.276A>G mutation creates a novel splice acceptor site leading to 5' truncation of AVPR2 exon 2 in HEK293 human kidney cells. Both patients have been treated with high-dose DDAVP with a remarkable improvement of their symptoms and accelerated linear growth and weight gain. CONCLUSION: We present here a unique case of partial X-linked NDI due to an AVPR2 splice site mutation; patients with diabetes insipidus of unknown etiology may harbor splice site mutations that are initially underestimated in their pathogenicity on sequence analysis. WHAT IS KNOWN: • X-linked nephrogenic diabetes insipidus is caused by AVPR2 mutations, and disease severity can vary depending on the functional effect of the mutation. What is New: • We demonstrate here that a splice site mutation in AVPR2 leads to partial X-linked NDI in two brothers. • Treatment with high-dose DDAVP led to improvement of polyuria and polydipsia, weight gain, and growth.

MEN1, MEN4, and Carney Complex: Pathology and Molecular Genetics.

Pituitary adenomas are a common feature of a subset of endocrine neoplasia syndromes, which have otherwise highly variable disease manifestations. We provide here a review of the clinical features and human molecular genetics of multiple endocrine neoplasia (MEN) type 1 and 4 (MEN1 and MEN4, respectively) and Carney complex (CNC). MEN1, MEN4, and CNC are hereditary autosomal dominant syndromes that can present with pituitary adenomas. MEN1 is caused by inactivating mutations in the MEN1 gene, whose product menin is involved in multiple intracellular pathways contributing to transcriptional control and cell proliferation. MEN1 clinical features include primary hyperparathyroidism, pancreatic neuroendocrine tumours and prolactinomas as well as other pituitary adenomas. A subset of patients with pituitary adenomas and other MEN1 features have mutations in the CDKN1B gene; their disease has been called MEN4. Inactivating mutations in the type 1α regulatory subunit of protein kinase A (PKA; the PRKAR1A gene), that lead to dysregulation and activation of the PKA pathway, are the main genetic cause of CNC, which is clinically characterised by primary pigmented nodular adrenocortical disease, spotty skin pigmentation (lentigines), cardiac and other myxomas and acromegaly due to somatotropinomas or somatotrope hyperplasia.

Combination therapy of SGLT2 inhibitors with incretin-based therapies for the treatment of type 2 diabetes mellitus: Effects and mechanisms of action.

Type 2 diabetes mellitus (T2DM) is a growing health problem worldwide; its pathogenesis is multifactorial and its progressive nature often necessitates a combination therapy with multiple antihyperglycemic agents. Sodium glucose cotransporter 2 (SGLT2) inhibitors and the incretin-based therapies - dipeptidyl peptidase 4(DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists - were introduced for the treatment of T2DM within the last decade. Evidence of the beneficial effects of these antihyperglycemic agents on micro- and macrovascular complications have started to emerge, which will become important in individualizing different combinations of antihyperglycemic agents to different patient populations. We review here the mechanisms of action, glycemic and cardiovascular effects of SGLT2 inhibitors and incretin-based therapies and their combination in the treatment of T2DM.