Patients with DeSanto-Shinawi syndrome: Further extension of phenotype from Italy.

Here we describe three patients with neurodevelopmental disorders characterized by mild-to-moderate intellectual disability, mildly dysmorphic features, and hirsutism, all of which carry de novo sequence variants in the WW domain-containing adaptor of the coiled-coil (WAC) gene; two of these-c.167delA, p.(Asn56I1efs*136) and c.1746G>C, p.(Gln582His)-are novel pathogenic variants, and the third-c.1837C>T, p(Arg613*)-has been previously described. Diseases associated with WAC include DeSanto-Shinawi syndrome; to date, de novo heterozygous constitutional pathogenic WAC variants have caused a syndromic form of intellectual disability and mild dysmorphic features in 33 patients, yet potential associations with other clinical manifestations, such as oligomenorrhea and hyperandrogenism, remain unknown, because the phenotypic spectrum of the condition has not yet been delineated. The patient bearing the novel c.167delA WAC gene variant presented a normal psychomotor development, oligomenorrhea, hyperandrogenism, and hirsutism, and hirsutism was also observed in the patient with the c.1746G>C WAC gene variant. Hypertrichosis and hirsutism have been described in nine DeSanto-Shinawi patients, only in 17 of the 33 aforementioned patients thus far reported this aspect, and no hormonal-pattern data are available. In conclusion, we note that the pathogenic c.167delA WAC variant may be associated with a mild phenotype; and in addition to the neurodevelopmental problems nearly all DeSanto-Shinawi patients experience (i.e., intellectual disability and/or developmental delay), we recommend the addition of mild dysmorphic features, hirsutism, and hypertrichosis to this clinical presentation.

Cardiac Computed Tomography Evaluation of Association of Left Ventricle Disfunction and Epicardial Adipose Tissue Density in Patients with Low to Intermediate Cardiovascular Risk.

Background and objectives: Epicardial adipose tissue density (EAD) has been associated with coronary arteries calcium score, a higher load of coronary artery disease (CAD) and plaque vulnerability. This effect can be related to endocrine and paracrine effect of molecules produced by epicardial adipose tissue (EAT), that may influence myocardial contractility. Using coronary computed tomography angiography (CCT) the evaluation of EAD is possible in basal scans. The aim of the study is to investigate possible associations between EAD and cardiac function. Material and Methods: 93 consecutive patients undergoing CCT without and with contrast medium for known or suspected coronary CAD were evaluated. EAD was measured on basal scans, at the level of the coronary ostia, the lateral free wall of the left ventricle, at the level of the cardiac apex, and at the origin of the posterior interventricular artery. Cardiac function was evaluated in post-contrast CT scans in order to calculate ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV), and stroke volume (SV). Results: A statistically significant positive correlation between EAD and ejection fraction (r = 0.29, p-value < 0.01) was found. Additionally, a statistically significant negative correlation between EAD and ESV (r = -0.25, p-value < 0.01) was present. Conclusion: EAD could be considered a new risk factor associated with reduced cardiac function. The evaluation of this parameter with cardiac CT in patients with low to intermediate cardiovascular risk is possible.

Perchlorates in the treatment of hyperthyroidism and thyrotoxicosis: a comprehensive review.

INTRODUCTION: Perchlorates are ionic inhibitors antagonizing iodine transport into thyrocytes, hampering thyroid hormone synthesis. Nevertheless, perchlorates are not considered as first-line treatment in hyperthyroidism and thyrotoxicosis as compared to other pharmacological and non-pharmacological interventions. AIM: Reassessing the therapeutic role of perchlorates in hyperthyroidism and thyrotoxicosis throughout a systematic review of the Literature. METHODS: Guidelines were searched and examined to summarize current recommendations on the use of perchlorates in the management of hyperthyroidism. Randomized and non-randomized clinical trials were also searched and reviewed to summarize the efficacy/effectiveness and safety of perchlorates in hyperthyroidisms and thyrotoxicosis. RESULTS: The management of specific forms of hyperthyroidism was considered, including Graves' disease (GD) in non-pregnant adults, hyperthyroidisms in pregnancy, iodine media contrast-induced hyperthyroidism, amiodarone-induced hyperthyroidisms, and thyroid storm. Most of the reported studies had remarkable limitations in terms of study design (non-controlled trials, lack of blinding), low number of participants, and the lack of clinically relevant endpoints, such as cardiovascular events, cardiovascular mortality, and teratogenicity. Overall, perchlorates could be considered a second-line treatment after thionamides, radioiodine, and total thyroidectomy in both GD and hyperthyroidisms in pregnancy. The therapeutic potential of perchlorates alone or in combination with other agents could be considered a second-line treatment of iodine-related hyperthyroidisms and thyroid storm. CONCLUSION: Despite the low level of evidence, perchlorates could be considered in such specific forms of thyroid disorders, including iodine-induced hyperthyroidism and thyroid storm.

Thyroid dysfunction in Hashimoto's thyroiditis: a pilot study on the putative role of miR-29a and TGFß1.

PURPOSE: Hashimoto's thyroiditis (HT) is one of the most common causes of thyroid dysfunction in iodine sufficient worldwide areas, but its molecular mechanisms are not completely understood. To this regard, this study aimed to assess serum levels of miRNA-29a (miR-29a) and transforming growth factor beta 1 (TGFß1) in HT patients with different patterns of thyroid function. METHODS: A total of 29 HT patients, with a median age of 52 years (21-68) were included. Of these, 13 had normal thyroid function (Eu-HT); 8 had non-treated hypothyroidism (Hypo-HT); 8 had hypothyroidism on replacement therapy with LT4 (subst-HT). All patients had serum miR-29a assayed through qRT-PCR and serum TGFß1 assayed by ELISA. RESULTS: Serum miR-29a levels were significantly down-regulated in patients with Hypo-HT compared to Eu-HT patients (P < 0.01) and subst-HT patients (P < 0.05). A significant negative correlation was detected between serum miR-29a levels and TSH levels (r = -0.60, P < 0.01). Serum TGFß1 levels were significantly higher in Hypo-HT than both Eu-HT (P < 0.01) and subst-HT patients (P < 0.05). A negative correlation was observed between serum miR-29a and TGFß1 (r = -0.75, P < 0.01). CONCLUSIONS: In conclusion, Hypo-HT patients had lower levels of serum miR-29a and higher levels of TGFß1 in comparison with Eu-HT patients. Worthy of note, subst-HT patients showed restored serum miR-29a levels compared with Hypo-HT group, associated with lower serum TGFß1. These novel findings may suggest a possible impact of replacement therapy with levothyroxine on serum miR-29a levels in HT.

Increased prevalence of nodular thyroid disease in patients with Klinefelter syndrome.

PURPOSE: Thyroid dysfunction in patients with Klinefelter syndrome (KS) remains an unresolved issue. Although low free thyroxine (FT4) levels within the normal range and normal thyroid stimulating hormone (TSH) levels have been reported, there is currently no data on nodular thyroid disease in this population. This study aims to evaluate the results of thyroid ultrasound (US) examinations in KS patients compared with healthy controls. METHODS: A cohort of 122 KS and 85 age-matched healthy male controls underwent thyroid US screening and thyroid hormone analysis. According to US risk-stratification systems, nodules ≥1 cm were examined by fine needle aspiration (FNA). RESULTS: Thyroid US detected nodular thyroid disease in 31% of KS compared to 13% of controls. No statistical differences in the maximum diameter of the largest nodules and in moderate and highly suspicious nodules were found between patients and the control group. Six KS patients and two controls with nodules underwent FNA and were confirmed as cytologically benign. In line with published data, FT4 levels were found significantly near the lower limit of the normal range compared to controls, with no differences in TSH values between the two groups. Hashimoto's thyroiditis was diagnosed in 9% of patients with KS. CONCLUSIONS: We observed a significantly higher prevalence of nodular thyroid disease in KS compared to the control group. The increase in nodular thyroid disease is likely linked to low levels of FT4, inappropriate TSH secretion, and/or genetic instability.

Type 2 Diabetes: Also a "Clock Matter"?

BACKGROUND: We investigated whether chronotype is associated with glycemic control, antidiabetic treatment, and risk of developing complications in patients with type 2 diabetes (T2DM). METHODS: The diabetologists filled out an online questionnaire on the Google Form platform to collect the following parameters of subjects with T2DM: body mass index (BMI), fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), diabetes history, antidiabetic treatment, diabetic complications, and chronotype categories. RESULTS: We enrolled 106 subjects with T2DM (M/F: 58/48; age: 63.3 ± 10.4 years; BMI: 28.8 ± 4.9 kg/m2). Thirty-five point eight% of the subjects showed a morning chronotype (MC), 47.2% an intermediate chronotype (IC), and 17% an evening chronotype (EC). EC subjects reported significantly higher HbA1c (p < 0.001) and FPG (p = 0.004) values, and higher prevalence of cardiovascular complications (CVC) (p = 0.028) and of subjects taking basal (p < 0.001) and rapid insulin (p = 0.01) compared to MC subjects. EC subjects reported significantly higher HbA1c (p < 0.001) and FPG (p = 0.015) than IC subjects. An inverse association was found between chronotype score, HbA1c (r = -0.459; p < 0.001), and FPG (r = -0.269; p = 0.05), remaining significant also after adjustment for BMI, age, and disease duration. CONCLUSIONS: EC is associated with higher prevalence of CVC and poorer glycemic control independently of BMI and disease duration in subjects with T2DM.

Patients with adrenal insufficiency have cardiovascular features associated with hypovolemia.

CONTEXT: Patients with adrenal insufficiency (AI) have excess mortality and morbidity, mainly due to cardiovascular (CV) diseases. The mechanisms for this is unclear. OBJECTIVE: To assess CV structure and function in AI patients on conventional replacement therapy and after switching to once-daily, modified-release hydrocortisone (OD-HC) in comparison with healthy matched controls. METHODS: This was a retrospective analysis of 17 adult AI patients (11 with primary AI, 6 with secondary AI) on stable replacement with cortisone acetate [median (minimum, maximum) 33.5 (12.5-50) mg] and, if needed, fludrocortisone [0.1 (0.05-0.2) mg], and 17 healthy matched controls. Ten patients were switched to an equivalent dose of OD-HC. Data from echocardiography, 24 h Holter-ECG and 24 h blood pressure monitoring were collected at baseline and 6 months after the switch to OD-HC. RESULTS: At baseline, AI patients had smaller left ventricular diastolic diameter (47.1 ± 4.2 vs. 51.6 ± 2.3 mm; P = 0.001) and left atrial diameter (34.9 ± 4.7 vs. 38.2 ± 2.6 cm; P = 0.018), and a higher ejection fraction (62.5 ± 6.9% vs. 56.0 ± 4.7%; P = 0.003) than controls. AI patients had lower nocturnal systolic and diastolic blood pressure than controls (108 ± 15 mmHg vs. 117 ± 8 mmHg; P = 0.038 and 65 ± 9 mmHg vs. 73 ± 7 mmHg; P = 0.008, respectively). After the switch to OD-HC, nocturnal diastolic blood pressure normalised. No significant changes were observed in echocardiographic and Holter-ECG parameters following the switch. CONCLUSIONS: AI patients on conventional treatment display cardiovascular abnormalities that could be related to hypovolemia. Switch to OD-HC seems to have beneficial effect on blood pressure profile, but no effect on cardiovascular structure and function.

Management of cardiovascular complications in Klinefelter syndrome patients.

INTRODUCTION: Klinefelter syndrome (KS), also known as 47, XXY, shows increased mortality when compared with mortality rates among the general population. Cardiovascular, hemostatic, metabolic diseases are implicated. Moreover, cardiac congenital anomalies in KS can contribute to the increase in mortality. AREAS COVERED: In this study, we have systematically reviewed the relationships between KS and the cardiovascular system and the management of cardiovascular complication. In summary, patients with KS display increased cardiovascular risk profile, characterized by increased prevalence of metabolic alterations including dyslipidemia, diabetes mellitus (DM), and abnormalities in biomarkers of cardiovascular disease. KS subjects are characterized by subclinical abnormalities in endothelial function and in left ventricular (LV) systolic and diastolic function, which - when associated with chronotropic incompetence - may negatively influence cardiopulmonary performance. Moreover, KS patients appear to be at a higher risk for cardiovascular disease, due to thromboembolic events with high prevalence of recurrent venous ulcers, venous insufficiency, recurrent venous and arterial thromboembolism leading to deep venous thrombosis or pulmonary embolism. EXPERT OPINION: Considering the unequivocal finding of increased mortality of KS patients, we suggest a periodic cardiovascular follow up in specialized centers with multidisciplinary care teams that comprise endocrinologists and cardiologists dedicated to KS syndrome.

Sexual function and sex hormones in breast cancer patients.

PURPOSE: Breast cancer patients (BCP) are at risk of female sexual dysfunction (FSD). Our aim was to clarify the effects of treatment strategies, and steroid hormones levels on FSD. METHODS: We enrolled 136 BCP (46.9 ± 0.8 years), and 122 completed questionnaires. BCP were divided into four groups: 22 women with advanced breast cancer on neoadjuvant therapy (NAT), 48 on adjuvant therapy (AT), 30 taking hormonal therapy (HT) and 22 with metastatic cancer on first line chemotherapy (FLT). Fifty-eight healthy women (43 ± 2.8 years) were enrolled as controls. FSD was evaluated by FSFI, and sexual distress was assessed with FSDS-R. We have collected demographic data, laboratory values, and LH, FSH, total testosterone (T), and estradiol (E2) levels. RESULTS: BCP showed a prevalence of FSD of 69%, total FSFI score was 17. FSDS-R was 8.3. FSD had a prevalence of 72 % in NAT, 65% in AT, 77% in metastatic BCP under FLT, 67% in HT, compared with a prevalence of 20% in controls. BCP showed lower E2 than normal values, as well as T. LH and FSH were significantly elevated than normal values. Total FSFI score was positively correlated with T in 122 BCP, no significant correlation was found between E2 and FSFI. Significant differences were found between NAT and HT in lubrication, pain domains and total FSDS-R score, AT and HT in pain domain, AT and NAT in lubrication domain. CONCLUSIONS: BCP are at high risk of developing FSD both for treatment choice and hormonal status, but they have not sexually related personal distress.

Genetics of medullary thyroid cancer: An overview.

Medullary thyroid carcinoma (MTC) represents 3-5% of thyroid cancers. 75% is sporadic and 25% is the dominant component of the hereditary multiple endocrine neoplasia (MEN) type 2 syndromes. Three different subtypes of MEN2, such as MEN2A, MEN2B, and Familial MTC (FMTC) have been defined, based on presence or absence of hyperparathyroidism, pheocromocytoma and characteristic clinical features. Mutations of the RET proto-oncogene are implicated in the pathogenesis of MTC, but there are many other mutational patterns involved. In MEN2A, Codon 634 in exon 11 (Cys634Arg), corresponding to a cysteine in the extracellular cysteine-rich domain, is the most commonly altered codon. Many other mutations include codons 611, 618, 620. In the genetical testing of RET mutations in MTCs, Next-Generation Sequencing (NGS) is taking an increasingly important role. One of the most important benefit is the comprehensive analysis of molecular alterations in MTC, which allows rapidly to select patients with different risk levels. There is a difference in miRNA expression pathway between sporadic and hereditary MTCs. Among sporadic cases, expression of miR-127 was significantly lower in those who harbor somatic RET mutations than those with wild-type RET. CDKN1B mutations are associated with many clinical pictures of cancers, such as MEN4. V109G polymorphism is associated with sporadic MTCs negative for RET mutations, and might influence the clinical course of the patients affected by MTC. Although surgery (i.e. total thyroidectomy with neck lymph node dissection) is the elective treatment for MTCs, about 80% of patients have distant metastases at diagnosis and in this cases surgery is not enough and an additional treatment is needed. Interesting results come from two large phase III clinical trials with two targeted tyrosine kinase inhibitors (TKIs), vandetanib and cabozantinib. CONCLUSIONS: New genetical testings and therapeutical approaches open new perspectives in MTC management.

Klinefelter syndrome, cardiovascular system, and thromboembolic disease: review of literature and clinical perspectives.

Klinefelter syndrome (KS) is the most frequently occurring sex chromosomal aberration in males, with an incidence of about 1 in 500-700 newborns. Data acquired from large registry-based studies revealed an increase in mortality rates among KS patients when compared with mortality rates among the general population. Among all causes of death, metabolic, cardiovascular, and hemostatic complication seem to play a pivotal role. KS is associated, as are other chromosomal pathologies and genetic diseases, with cardiac congenital anomalies that contribute to the increase in mortality. The aim of the current study was to systematically review the relationships between KS and the cardiovascular system and hemostatic balance. In summary, patients with KS display an increased cardiovascular risk profile, characterized by increased prevalence of metabolic abnormalities including Diabetes mellitus (DM), dyslipidemia, and alterations in biomarkers of cardiovascular disease. KS does not, however, appear to be associated with arterial hypertension. Moreover, KS patients are characterized by subclinical abnormalities in left ventricular (LV) systolic and diastolic function and endothelial function, which, when associated with chronotropic incompetence may led to reduced cardiopulmonary performance. KS patients appear to be at a higher risk for cardiovascular disease, attributing to an increased risk of thromboembolic events with a high prevalence of recurrent venous ulcers, venous insufficiency, recurrent venous and arterial thromboembolism with higher risk of deep venous thrombosis or pulmonary embolism. It appears that cardiovascular involvement in KS is mainly due to chromosomal abnormalities rather than solely on low serum testosterone levels. On the basis of evidence acquisition and authors' own experience, a flowchart addressing the management of cardiovascular function and prognosis of KS patients has been developed for clinical use.

Testicular parenchymal abnormalities in Klinefelter syndrome: a question of cancer? Examination of 40 consecutive patients.

Klinefelter syndrome (KS) is a hypergonadotropic hypogonadism characterized by a 47, XXY karyotype. The risk of testicular cancer in KS is of interest in relation to theories about testicular cancer etiology generally; nevertheless it seems to be low. We evaluated the need for imaging and serum tumor markers for testicular cancer screening in KS. Participants were 40 consecutive KS patients, enrolled from December 2009 to January 2013. Lactate dehydrogenase (LDH), alpha-fetoprotein (AFP), and beta-human chorionic gonadotrophin subunit (ß-HCG) serum levels assays and testicular ultrasound (US) with color Doppler, were carried out at study entry, after 6 months and every year for 3 years. Abdominal magnetic resonance (MR) was performed in KS when testicular US showed micro-calcifications, testicular nodules and cysts. Nearly 62% of the KS had regular testicular echotexture, 37.5% showed an irregular echotexture and 17.5% had micro-calcifications and cysts. Eighty seven percent of KS had a regular vascular pattern, 12.5% varicocele, 12.5% nodules <1 cm, but none had nodules >1 cm. MR ruled out the diagnosis of cancer in all KS with testicular micro calcifications, nodules and cysts. No significant variations in LDH, AFP, and ß-HCG levels and in US pattern have been detected during follow-up. We compared serum tumor markers and US pattern between KS with and without cryptorchidism and no statistical differences were found. We did not find testicular cancer in KS, and testicular US, tumor markers and MR were, in selected cases, useful tools for correctly discriminating benign from malignant lesions.

Cardiovascular abnormalities in Klinefelter syndrome.

BACKGROUND: Several epidemiological studies have demonstrated an increased mortality from cardiovascular causes in patients with Klinefelter Syndrome (KS). Little information is available about the nature of the underlying cardiovascular abnormalities. Aim of the study was to investigate exercise performance, left ventricular architecture and function, vascular reactivity, and carotid intima-media thickness in a group of patients with KS. MATERIALS AND METHODS: Sixty-nine patients with KS and 48 age-matched controls participated in our population-controlled study. Forty-eight Klinefelter subjects were on testosterone treatment at the time of the investigation while 21 were naive and underwent a complete Doppler echocardiographic examination, a cardiopulmonary exercise test as well as a vascular study including measures of carotid intima-media thickness and endothelial function with flow-mediated dilation of the brachial artery. Patients with KS on testosterone therapy (n=48) were also matched against a population of men with treated secondary hypogonadism (n=21). RESULTS: Patients with KS exhibited a wide array of cardiovascular abnormalities including left ventricular diastolic dysfunction, reduced maximal oxygen consumption (p<0.01), increased intima-media thickness (p<0.05) (-34% and +42% vs. controls, respectively) and a high prevalence of chronotropic incompetence (55% of patients, p<0.01). No significant difference was found between treated and untreated KS in variance with men treated for secondary hypogonadism. CONCLUSION: Left ventricular diastolic dysfunction, impaired cardiopulmonary performance, chronotropic incompetence, and increased intima-media thickness suggest that cardiovascular abnormalities are a common finding in KS that is not reversed by testosterone replacement therapy and may represent the pathophysiological underpinnings of the increased risk of dying from heart disease.

Upregulation of endocrine gland-derived vascular endothelial growth factor in papillary thyroid cancers displaying infiltrative patterns, lymph node metastases, and BRAF mutation.

BACKGROUND: Endocrine gland-derived vascular endothelial growth factor (Prok1) and prokineticin 2 (Prok2) are involved in the organ-specific regulation of angiogenesis, which is a crucial step toward cancer progression in most tumors, including those of thyroid gland. The oncogene BRAF V600E mutation is associated with poor clinical outcome of papillary thyroid cancer (PTC) and can independently predict its recurrence. DESIGN: Our hypothesis was that Prok1 and Prok2 expression levels associated with BRAF mutations can be prognostic factors for PTC outcome. Prok1 and Prok2 were examined in PTC, a cell line derived from a human PTC (designated FB-2), euthyroid multinodular goiter (MNG), Graves' disease (GD), and contralateral normal thyroid (NT) tissues from PTC cases. We evaluated BRAF mutation and its relationship with Prok1 expression pattern in PTC. METHODS: We studied Prok1 and Prok2 mRNAs by real-time polymerase chain reaction and BRAF mutation by mutant allele-specific polymerase chain reaction amplification. Formalin-fixed, paraffin-embedded blocks of PTC and NT were used for the immunohistochemical determination of Prok1 using anti-endocrine gland vascular endothelial growth factor primary antibody. RESULTS: Prok1 and Prok2 transcripts were both present in thyroid tissues, and Prok1 was differentially expressed in PTC compared to MNG, GD, and NT. Prok1 mRNA levels were very low in NT and MNG and significantly higher in PTC, FB-2, and GD (p<0.05). Prok1 protein was almost undetectable in NT but was highly expressed in all PTC samples having an infiltrative pattern of growth and lymph node metastases ( p<0.05). Further, the expression of Prok1 in PTC was associated with 60% of the samples being positive for the BRAF mutation ( p<0.05). CONCLUSIONS: We found that Prok1 is significantly increased in PTC, and its expression in PTC is related to BRAF mutation. These results suggest that Prok1 could be a new useful marker for thyroid cancer progression. Prok1 therefore could also be a potential target for novel therapeutic strategies, although the lack of functional data suggests caution against generalization of this assumption

CDKN1B V109G polymorphism a new prognostic factor in sporadic medullary thyroid carcinoma.

CONTEXT: CDKN1B encodes the cyclin-dependent kinase inhibitor p27Kip1 and is mutated in multiple endocrine neoplasia-like syndromes. CDKN1B also harbors single nucleotide polymorphisms; the T/G transversion at nucleotide 326 (the V109G variant) has been reported to be protective in breast, hereditary prostate, and pancreatic tumors. Association of CDNK1B mutations or polymorphisms with sporadic medullary thyroid carcinoma (MTC) has not been investigated yet. OBJECTIVE AND DESIGN: We screened germline DNA from 84 patients affected by sporadic MTC and 90 healthy age- and gender-matched controls for CDKN1B mutations or polymorphisms by PCR amplification and sequencing of the amplicons. We also tested all germline and 50 tumor tissue DNA for RET proto-oncogene mutations. Computed tomography, ultrasound scans, and serum calcitonin were carried out before surgery and during the follow-up and associated with CDKN1B polymorphism and disease remission. RESULTS: The T/G transversion at nucleotide 326 was the only DNA variation detected. The overall frequency of the T/G and G/G alleles in combination was 46.4%. This variant (V109G) was correlated with post-operative calcitonin levels in the normal range and biochemical remission. Conversely, the wild-type (T/T) allele was associated with post-operative calcitonin levels above normal and a higher risk to develop clinical recurrence and distant metastases. Somatic RET mutations were significantly associated with a more aggressive behavior especially in wild-type allele-bearing patients. CONCLUSIONS: Collectively, in sporadic MTC, the CDKN1B V109G polymorphism correlates with a more favorable disease progression than the wild-type allele and might be considered a new promising prognostic marker.