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.

Risk factors for endocrine complications in transfusion-dependent thalassemia patients on chelation therapy with deferasirox: a risk assessment study from a multi-center nation-wide cohort.

Transfusion-dependent patients typically develop iron-induced cardiomyopathy, liver disease, and endocrine complications. We aimed to estimate the incidence of endocrine disorders in transfusiondependent thalassemia (TDT) patients during long-term iron-chelation therapy with deferasirox (DFX). We developed a multi-center follow-up study of 426 TDT patients treated with once-daily DFX for a median duration of 8 years, up to 18.5 years. At baseline, 118, 121, and 187 patients had 0, 1, or ≥2 endocrine diseases respectively. 104 additional endocrine diseases were developed during the follow-up. The overall risk of developing a new endocrine complication within 5 years was 9.7% (95% Confidence Interval [CI]: 6.3-13.1). Multiple Cox regression analysis identified three key predictors: age showed a positive log-linear effect (adjusted hazard ratio [HR] for 50% increase 1.2, 95% CI: 1.1-1.3, P=0.005), the serum concentration of thyrotropin showed a positive linear effect (adjusted HR for 1 mIU/L increase 1.3, 95% CI: 1.1-1.4, P<0.001) regardless the kind of disease incident, while the number of previous endocrine diseases showed a negative linear effect: the higher the number of diseases at baseline the lower the chance of developing further diseasess (adjusted HR for unit increase 0.5, 95% CI: 0.4-0.7, P<0.001). Age and thyrotropin had similar effect sizes across the categories of baseline diseases. The administration of levothyroxine as a covariate did not change the estimates. Although in DFX-treated TDT patients the risk of developing an endocrine complication is generally lower than the previously reported risk, there is considerable risk variation and the burden of these complications remains high. We developed a simple risk score chart enabling clinicians to estimate their patients' risk. Future research will look at increasing the amount of variation explained from our model and testing further clinical and laboratory predictors, including the assessment of direct endocrine magnetic resonance imaging.

Erectile Dysfunction and Decreased Libido in Klinefelter Syndrome: A Prevalence Meta-Analysis and Meta-Regression Study.

BACKGROUND: Only few studies have assessed sexual dysfunction in men with Klinefelter syndrome (KS). AIM: To define pooled prevalence estimates and correlates of erectile dysfunction (ED) and decreased libido (DL) in KS. METHODS: A thorough search of Medline, Embase and Web of Science was performed to identify suitable studies. Quality of the articles was scored using the Assessment Tool for Prevalence Studies. Data were combined using random effect models and the between-studies heterogeneity was assessed by the Cochrane's Q and I2. The sources of heterogeneity were investigated by meta-regression and sub-group analyses. Funnel plot, Begg's rank correlation and trim-and-fill test were used to assess publication bias. MAIN OUTCOME MEASURE: The pooled prevalence of ED and DL in KS as well as 95% confidence intervals (CIs) were estimated from the proportion of cases of sexual dysfunction and the sample size. Variables that could affect the estimates were identified by linear meta-regression models. RESULTS: Sixteen studies included collectively gave information about ED and DL in 482 and 368 KS men, respectively, resulting in a pooled prevalence of 28% (95% CI: 19%-36%) for ED and 51% (95% CI: 36%-66%) for DL, with a large heterogeneity. The trim-and-fill adjustment for publication bias produced a negligible effect on the pooled estimates. At the meta-regression analyses, a higher prevalence of ED was significantly associated with an older age but not with lower testosterone levels. In series with a mean age >35 years, the ED prevalence estimate increased up to 38% (95% CI: 31%-44%) with no heterogeneity (I2=0.0%, P=0.6). On the contrary, the prevalence of DL increased significantly as testosterone levels decreased, without a significant relationship with age. CLINICAL IMPLICATIONS: While DL would largely reflect an androgen deficiency, in older men with KS, erectile function should be assessed irrespective of testosterone levels. STRENGTH & LIMITATIONS: This is the first meta-analysis defining pooled prevalence estimates and correlates of ED and DL in KS. Nevertheless, caution is required when interpreting results, due to the high risk of bias in many studies, as well as the dearth of data about psychosocial and/or psychosexological variables and age at the diagnosis. CONCLUSIONS: ED and DL represent common clinical complaints in KS. While the prevalence of ED would increase with age, DL gets more common as serum testosterone decreases. Further studies are warranted to elucidate the pathogenetic mechanism(s) underlying the age-dependent increase in the prevalence of ED, apparently unrelated to the androgenic status. A Barbonetti, S D'Andrea, W Vena, et al. Erectile Dysfunction and Decreased Libido in Klinefelter Syndrome: A Prevalence Meta-Analysis and Meta-Regression Study. J Sex Med 2021;18:1054-1064.

Single center experience with laparoscopic adrenalectomy on a large clinical series.

BACKGROUND: Laparoscopic adrenalectomy is considered the gold standard technique for the treatment of benign small and medium size adrenal masses (<6 cm), due to low morbidity rate, short hospitalization and patient rapid recovery. The aim of our study is to analyse the feasibility and efficiency of this surgical approach in a broad spectrum of adrenal gland pathologies. METHODS: Pre-operative, intra-operative and post-operative data from 126 patients undergone laparoscopic adrenalectomy between January 2003 and December 2015 were retrospectively collected and reviewed. Diagnosis was obtained on the basis of clinical examination, laboratory values and imaging techniques. Doxazosin was preoperatively administered in case of pheochromocytoma while spironolactone and potassium were employed to treat Conn's disease. Laparoscopic adrenalectomies were all performed by the same surgeon (CG). First 30 procedures were considered as learning curve adrenalectomies. RESULTS: One hundred twenty-six patients were included in the study. Functioning tumors were diagnosed in 84 patients, 27 patients were affected by pheochromocytomas, 29 by Conn's disease, 28 by Cushing disease. Surgery mean operative time was 137.33 min (range 100-180) during the learning curve adrenalectomies and 96.5 min (range 75-110) in subsequent procedures. Mean blood loss was respectively 160.2 ml (range 60-280) and 90.5 ml (range 50-200) in the first 30 procedures and the subsequent ones. Only one conversion to open surgery occurred. No post-operative major complications were observed, while minor complications occurred in 8 patients (0,79%). In 83 out of 84 functioning neoplasms, laparoscopic adrenalectomy was effective in normalization of endocrine profile. CONCLUSIONS: Laparoscopic adrenalectomy is a safe and feasible procedure, even for functioning masses and pheochromocytomas. A multidisciplinary team including endocrinologists, endocrine surgeons and anaesthesiologists, is recommended in the management of adrenal pathology, and adrenal surgery should be performed in referral high volume centers. A thirty-procedures learning curve is recommended to improve surgical outcomes.

Role of prophylactic central compartment lymph node dissection in clinically N0 differentiated thyroid cancer patients: analysis of risk factors and review of modern trends.

In the last years, especially thanks to a large diffusion of ultrasound-guided FNBs, a surprising increased incidence of differentiated thyroid cancer (DTC), "small" tumors and microcarcinomas have been reported in the international series. This led endocrinologists and surgeons to search for "tailored" and "less aggressive" therapeutic protocols avoiding risky morbidity and useless "overtreatment". Considering the most recent guidelines of referral endocrine societies, we analyzed the role of routine or so-called prophylactic central compartment lymph node dissection (RCLD), also considering its benefits and risks. Literature data showed that the debate is still open and the surgeons are divided between proponents and opponents of its use. Even if lymph node metastases are commonly observed, and in up to 90% of DTC cases micrometastases are reported, the impact of lymphatic involvement on long-term survival is subject to intensive research and the best indications of lymph node dissection are still controversial. Identification of prognostic factors for central compartment metastases could assist surgeons in determining whether to perform RLCD. Considering available evidence, a general agreement to definitely reserve RCLD to "high-risk" cases was observed. More clinical researches, in order to identify risk factors of meaningful predictive power and prospective long-term randomized trials, should be useful to validate this selective approach.

A Gelatin-Thrombin Matrix Topical Hemostatic Agent (Floseal) in Combination With Harmonic Scalpel Is Effective in Patients Undergoing Total Thyroidectomy: A Prospective, Multicenter, Single-Blind, Randomized Controlled Trial.

BACKGROUND: Hemostasis during thyroidectomy is essential; however, the safest, most efficient, and most cost-effective way to achieve this is unclear. This randomized, multicenter, single-blind, prospective study evaluated the efficacy and safety of using different hemostatic approaches in patients undergoing total thyroidectomy. METHODS: Patients aged ≥18 to 70 years were randomized to Floseal + a harmonic scalpel (HS), Floseal alone, HS alone, or standard total thyroidectomy. Primary endpoint was 24-hour drain output. Secondary endpoints included surgery duration and complications. RESULTS: Two hundred and six patients were randomized to Floseal + HS (n = 52), Floseal alone (n = 54), HS alone (n = 50), and standard total thyroidectomy (n = 50). The 24-hour drain output was lower in the Floseal + HS group compared with standard thyroidectomy. Floseal + HS also had a shorter surgery time (P < .0001) versus the other 3 treatments. CONCLUSION: Floseal + HS can be effective at reducing postsurgical drain output and provides a complementary hemostatic approach in patients undergoing total thyroidectomy.

Prognostic role of the CDNK1B V109G polymorphism in multiple endocrine neoplasia type 1.

CDKN1B encodes the cyclin-dependent kinase inhibitor p27/Kip1. CDKN1B mutations and polymorphisms are involved in tumorigenesis; specifically, the V109G single nucleotide polymorphism has been linked to different tumours with controversial results. Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant syndrome, characterized by the development of different types of neuroendocrine tumours and increased incidence of other malignancies. A clear genotype-phenotype correlation in MEN1 has not been established yet. In this study, we assessed whether the CDKN1B V109G polymorphism was associated with the development of aggressive tumours in 55 consecutive patients affected by MEN1. The polymorphism was investigated by PCR amplification of germline DNA followed by direct sequencing. Baseline and follow-up data of tumour types and their severity were collected and associated with the genetic data. MEN1-related aggressive and other malignant tumours of any origin were detected in 16.1% of wild-type and 33.3% of polymorphism allele-bearing patients (P = NS). The time interval between birth and the first aggressive tumour was significantly shorter in patients with the CDKN1B V109G polymorphism (median 46 years) than in those without (median not reached; P = 0.03). Similarly, shorter was the time interval between MEN1 diagnosis and age of the first aggressive tumour (P = 0.02). Overall survival could not be estimated as 96% patients were still alive at the time of the study. In conclusion, CDKN1B V109G polymorphism seems to play a role in the development of aggressive tumours in MEN1.

Mortality in patients with adrenal insufficiency: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Adrenal insufficiency (AI) is a rare disorder characterised by an impaired secretion of glucocorticoids from the adrenal glands. Treatment strategies for AI have developed over time with reduced glucocorticoid replacement doses and improved circadian exposure regimens, but whether this has resulted in better survival is unknown. The main purpose of this systematic review is to gather and synthesise available evidence on long-term mortality in patients with AI. The secondary aim is to study causes of death, with focus on cardiovascular and infectious diseases, in AI patients. METHODS AND ANALYSIS: Studies published from the inception of respective databases (Medline, Embase, Cochrane and Web of Science) until the end of May 2023 will be systematically synthetised. Observational studies with a reference population will be included, and their quality will be assessed using the Newcastle-Ottawa scale. Data collected will be narratively integrated and a meta-analysis will be performed to pool data from studies considered homogeneous. The systematic review will be reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. This will be the first systematic review assessing mortality and causes of death in AI patients. The findings of this systematic review will be of value for both patients and healthcare providers. ETHICS AND DISSEMINATION: This systematic review does not require ethical approval or informed consent because it will be based on previously published data only and does not implicate any direct contact with individual patients. The research results will be presented at scientific conferences and submitted for publication in an internationally recognised peer-reviewed scientific journal. PROSPERO REGISTRATION NUMBER: CRD42023416253.

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.

Predictive value of nodal metastases on local recurrence in the management of differentiated thyroid cancer. Retrospective clinical study.

BACKGROUND: The significance of nodal metastases, very common in papillary thyroid cancer, and the role of lymph node dissection in the neoplasm management, are still controversial. The impact of lymph node involvement on local recurrence and long-term survival remains subject of active research. With the aim to better analyze the predictive value of lymph node involvement on recurrence and survival, we investigated the clinico-pathological patterns of local relapse following total thyroidectomy associated with lymph node dissection, for clinical nodal metastases papillary thyroid cancer, in order to identify the preferred surgical treatment. METHODS: Clinical records, between January 2000 and December 2006, of 69 patients undergoing total thyroidectomy associated with selective lymph node dissection for clinical nodal metastases papillary thyroid cancer, were retrospectively evaluated. Radioiodine ablation, followed by Thyroid Stimulating Hormone suppression therapy was recommended in every case. In patients with loco regional lymph nodal recurrence, a repeated lymph node dissection was carried out. The data were compared with those following total thyroidectomy not associated with lymph node dissection in 210 papillary thyroid cancer patients without lymph node involvement, at preoperative ultrasonography and intra operative inspection. RESULTS: Incidence of permanent hypoparathyroidism (iPTH < 10 pg/ml) and permanent monolateral vocal fold paralysis were respectively 1.4 % (1/69) and 1.4% (1/69), similar to those reported after total thyroidectomy "alone". The rate of loco regional recurrence, with positive cervical lymph nodes, following 8 year follow-up, was 34.7% (24/69), higher than that reported in patients without nodal metastases (4.2%). A repeated lymph node dissection was carried out without significant complications. CONCLUSIONS: Nodal metastases are a predictor of local recurrence, and a higher rate of lymph node involvement is expected after therapeutic lymph node dissection associated with total thyroidectomy. The prognostic significance of nodal metastases on long-term survival remains unclear, and more prospective randomized trials are requested to better evaluate the benefits of different therapeutic approaches.

Laparoscopic adrenal surgery: ten-year experience in a single institution.

BACKGROUND: Minimal invasive adrenalectomy has become the procedure of choice to treat adrenal tumors with a benign appearance, ≤ 6 cm in diameter and weighing < 100 g. Authors evaluated medium- and long-term outcomes of laparoscopic adrenalectomy (LA), performed for ten years in a single endocrine surgery unit. METHODS: We retrospectively reviewed 88 consecutive patients undergone LA for lesions of adrenal glands from 2003 to 2013. The first 30 operations were considered part of the learning curve. Doxazosin was preoperatively administered in case of pheochromocytoma (PCC), while spironolactone and potassium were employed to treat Conn's disease. Perioperative cardiovascular status modifications and surgical and medium- and long-term results were analyzed. RESULTS: Forty nine (55.68%) functioning tumors, and one (1.13%) bilateral adrenal disease were identified. In 2 patients (2.27%) a supposed adrenal metastasis was postoperatively confirmed, while in no patients a diagnosis of incidental primitive malignancy was performed. There was no mortality or major post operative complication. The mean operative time was higher during the learning curve. Conversion and morbidity rates were respectively 1.13% and 5.7%. Intraoperative hypertensive crises (≥180/90 mmHg) were observed in 23.5% (4/17) of PCC patients and were treated pharmacologically with no aftermath. There was no influence of age, size and operative time on the occurrence of PCC intraoperative hypertensive episodes. Surgery determined a normalization of the endocrine profile. One single PCC persistence was observed, while in a Conn's patient, just undergone right LA, a left sparing adrenalectomy was performed for a contralateral metachronous aldosteronoma. CONCLUSIONS: LA, a safe, effective and well tolerated procedure for the treatment of adrenal neoplasms ≤ 6 cm, is feasible for larger lesions, with a similar low morbidity rate. Operative time has improved along with the increase of the experience and of the technological development. Preoperative adrenergic blockade did not prevent PCC intraoperative hypertensive crises, but facilitated the control of the hemodynamic stability.

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.

Impact of Current Technology in Laparoscopic Adrenalectomy: 20 Years of Experience in the Treatment of 254 Consecutive Clinical Cases.

BACKGROUND: Laparoscopic adrenalectomy (LA), which avoids large abdomen incisions, is considered the gold standard technique for the treatment of benign small- and medium-size adrenal masses (<6 cm) and weighing < 100 g. A trascurable mortality and morbidity rate, short hospitalization and patient rapid recovery are the main advantages compared to traditional surgery. During the past decade, a new surgical technology has been developed that expedites a "clipless" adrenalectomy. Here, the authors analyze a clinical series of 254 consecutive patients who were affected by adrenal gland neoplasms and underwent LA by the transabdominal lateral approach over the two last decades. A literature review is also presented. METHODS: Preoperative, intraoperative and postoperative data from 254 patients who underwent LA between January 2003 and December 2022 were retrospectively collected and reviewed. Diagnosis was obtained on the basis of clinical examination, laboratory values and imaging techniques. Doxazosin was preoperatively administered in the case of pheochromocytoma (PCC) while spironolactone and potassium were employed to treat Conn's disease. The same surgeon (CG) performed all the LA and utilized the same laparoscopic transabdominal lateral approach. Different dissection tools-ultrasonic, bipolar or mixed scissors-and hemostatic agents were used during this period. The following results were obtained: 254 patients were included in the study; functioning tumors were diagnosed in 155 patients, 52 patients were affected by PCCs, 55 by Conn's disease, 48 by Cushing's disease. Surgery mean operative time was 137.33 min (range 100-180 min) during the learning curve adrenalectomies and 98.5 min (range 70-180) in subsequent procedures. Mean blood loss was respectively 160.2 mL (range 60-280) and 96.98 mL (range 50-280) in the first 30 procedures and the subsequent ones. Only three conversions (1.18%) to open surgery occurred. No mortality or postoperative major complications were observed, while minor complications occurred in 19 patients (3.54%). In 153 out of 155 functioning neoplasms, LA was effective in the normalization of the endocrine profile. According to our experience, a learning curve consisting of 30 cases was identified. In fact, a lower operative time and a lower complication rate was reported following 30 LA. CONCLUSIONS: LA is a safe procedure, even for masses larger than 6 cm and PCCs. Undoubtedly, the development of surgical technology has made it possible reducing operative times, performing a "clipless" adrenalectomy and extending the indications in the treatment of more complex patients. A multidisciplinary team, in referral high-volume centers, is recommended in the management of adrenal pathology. A 30-procedure learning curve is necessary to improve surgical outcomes.

Rare PHEX intron variant causes complete and severe phenotype in a family with hypophosphatemic rickets: a case report.

OBJECTIVES: Lower limb deformities in children need careful orthopedic evaluation to distinguish physiological forms from pathological ones. X-linked hypophosphatemia (XLH) is a rare hereditary condition caused by PHEX gene mutations where tibial varum can be the first sign. CASE PRESENTATION: We report a family presenting with severe tibial varum, harbouring a rare PHEX intron mutation, c.1586+6T>C. This is the first clinical description available in literature for this variant. Despite the previous prediction of a mild phenotype in functional study, our patients showed important bone deformities, rickets and impaired growth since infancy followed by severe bone pain, hearing loss and reduced life quality in adulthood. Burosumab therapy improved biochemical and radiological findings in children and ameliorated quality of life in adults. CONCLUSIONS: This case demonstrated c.1586+6T>C causes a severe XLH phenotype, responsive to Burosumab. Familial genetic screening, enlarged to intronic region analysis, when XLH is suspected, allows precocious diagnosis to start timely the appropriate treatment.

Tumor Inflammatory Microenvironment of the Thyroid Cancer: Relationship between Regulatory T-Cell Imbalance, and p-NFΚB (p65) Expression-A Preliminary Study.

BACKGROUND: Inflammatory microenvironment is an essential component of all tumors, including thyroid cancer. Autoimmune thyroid diseases are often associated with thyroid cancer. CD25, expressed in Treg cells and B cells, has been found to be associated with autoimmune thyroid diseases and the NFkB pathway is critical to tumor formation, regulating immune-related genes, and pro-inflammatory cytokine. METHODS: Protein expression of CD25 and NFkB and its phosphorylated form was analyzed by immunohistochemistry in 80 patients with thyroid cancer (10 cases of cancers with Hashimoto's thyroiditis and 70 cases without). RESULTS: CD25 was mainly detected in the nucleus of the inflammatory cells such as in the thyrocytes and neoplastic cells. Protein staining was detected in the T-lymphocytes of the outermost zone of the lymphoid follicles. Moreover, in all cancer alterations, there were a higher level of p-NFkB than in the surrounding tissues. Again, p-NFkB staining was evident in neoplastic cells but not evident in inflammatory cells. CONCLUSIONS: Strong inflammatory infiltrate in the tumor microenvironment is correlated with an invasive phenotype. CD25 and p-NFkB levels were statistically significantly overexpressed in cancer cells.

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.

Patients with chronic autoimmune thyroiditis are not at higher risk for developing clinically overt thyroid cancer: a 10-year follow-up study.

OBJECTIVE: The association between chronic autoimmune thyroiditis (CAT) and differentiated thyroid cancer (DTC) remains controversial. The incidence of DTC increases when screening procedures are implemented, as typically occurs in CAT patients being routinely submitted to thyroid ultrasound (US). The aim of this study was to longitudinally evaluate the long-term development of DTC in patients with CAT. DESIGN AND METHODS: A retrospective longitudinal cohort study was designed. For the study, 510 patients with chronic autoimmune thyroiditis (CAT) with a 10-year follow-up were enrolled. Patients were divided in two groups according to the presence (CAT+ NOD+; n = 115) or absence (CAT+ NOD-; n = 395) of co-existent nodules at diagnosis. The main outcome measures were appearance of new thyroid-nodules and development of DTC during follow-up. RESULTS: During a 10-year median follow-up period, new thyroid-nodules were detected in 34/115 (29.5%) patients in the CAT+ NOD+ group and in 41/395 (10.3%) in the CAT+ NOD- group (P < 0.001). Logistic regression analysis showed that thyroid-volume at diagnosis and belonging to the CAT+ NOD+ group significantly predicted the appearance of a new thyroid nodule during follow-up, independently of baseline age and sex. Among the 75 patients experiencing the appearance of a new nodule, 27 (39%) met the criteria for fine-needle-aspiration-cytology (FNAC). A benign cytological diagnosis was rendered in all cases. CONCLUSIONS: In our series of CAT patients, the appearance of new thyroid-nodules was frequent, but none of them were found to be malignant. The presence of CAT appears to be associated with a negligible risk of developing clinically overt DTC.

The Human Microbiota in Endocrinology: Implications for Pathophysiology, Treatment, and Prognosis in Thyroid Diseases.

The human microbiota is an integral component in the maintenance of health and of the immune system. Microbiome-wide association studies have found numerous diseases associated to dysbiosis. Studies are needed to move beyond correlations and begin to address causation. Autoimmune thyroid diseases (ATD) are one of the most common organ-specific autoimmune disorders with an increasing prevalence, higher than 5% worldwide. Most frequent manifestations of ATD are Hashimoto's thyroiditis and Graves' disease. The exact etiology of ATD remains unknown. Until now it is not clear whether bacterial infections can trigger ATD or modulate the efficacy of treatment and prognosis. The aim of our review is to characterize the microbiota and in ATD and to evaluate the impact of dysbiosis on treatment and prognosis. Moreover, variation of gut microbiome has been associated with thyroid cancer and benign nodules. Here we will characterize the microbioma in benign thyroid nodules, and papillary thyroid cancer to evaluate their implications in the pathophysiology and progression.

Selenium supplementation in patients with subclinical hypothyroidism affected by autoimmune thyroiditis: Results of the SETI study.

OBJECTIVE: The purpose of this prospective study was to assess the effects of selenium supplementation on TSH and interferon-γ inducible chemokines (CXCL9, CXCL10 and CXCL11) levels in patients with subclinical hypothyroidism due to Hashimoto's thyroiditis. PATIENTS AND METHODS: Patients with subclinical hypothyroidism due to Hashimoto thyroiditis were prospectively enrolled in the SETI study. They received 83mcg of selenomethionine/day orally in a soft gel capsule for 4 months with water after a meal. No further treatment was given. All patients were measured thyroid hormone, TPOAb, CXCL9, CXCL10, CXCL11, iodine, and selenium levels at baseline and at study end. RESULTS: 50 patients (43/7 female/male, median age 43.9±11.8 years) were enrolled, of which five withdrew from the study. At the end of the study, euthyroidism was restored in 22/45 (48.9%) participants (responders), while 23 patients remained hypothyroid (non-responders). There were no significant changes in TPOAb, CXCL9, CXCL10, CXCL11, and iodine levels from baseline to the end of the study in both responders and non-responders. TSH levels were re-tested six months after selenomethionine withdrawal: 83.3% of responding patients remained euthyroid, while only 14.2% of non-responders became euthyroid. CONCLUSIONS: The SETI study shows that short-course supplementation with selenomethionine is associated to a normalization of serum TSH levels which is maintained 6 months after selenium withdrawal in 50% of patients with subclinical hypothyroidism due to chronic autoimmune thyroiditis. This TSH-lowering effect of selenium supplementation is unlikely to be related to changes in humoral markers of autoimmunity and/or circulating CXCL9.