Pendred Syndrome Wémeau, Jean-Louis; Kopp, Peter
Best Practice & Research Clinical Endocrinology & Metabolism,
03/2017, Letnik:
31, Številka:
2
Journal Article
Recenzirano
Abstract Pendred syndrome is an autosomal recessive disorder that is classically defined by the combination of sensorineural deafness/hearing impairment, goiter, and an abnormal organification of ...iodide with or without hypothyroidism. The hallmark of the syndrome is the impaired hearing, which is associated with inner ear malformations such as an enlarged vestibular aqueduct (EVA). The thyroid phenotype is variable and may be modified by the nutritional iodine intake. Pendred syndrome is caused by biallelic mutations in the SLC26A4/PDS gene, which encodes the multifunctional anion exchanger pendrin. Pendrin has affinity for chloride, iodide, and bicarbonate, among other anions. In the inner ear, pendrin functions as a chloride/bicarbonate exchanger that is essential for maintaining the composition and the potential of the endolymph. In the thyroid, pendrin is expressed at the apical membrane of thyroid cells facing the follicular lumen. Functional studies have demonstrated that pendrin can mediate iodide efflux in heterologous cells. This, together with the thyroid phenotype observed in humans (goiter, impaired iodine organification) suggests that pendrin could be involved in iodide efflux into the lumen, one of the steps required for thyroid hormone synthesis. Iodide efflux can, however, also occur in the absence of pendrin suggesting that other exchangers or channels are involved. It has been suggested that Anoctamin 1 (ANO1/TMEM16A), a calcium-activated anion channel, which is also expressed at the apical membrane of thyrocytes, could participate in mediating apical efflux. In the kidney, pendrin is involved in bicarbonate secretion and chloride reabsorption. While there is no renal phenotype under basal conditions, severe metabolic alkalosis has been reported in Pendred syndrome patients exposed to an increased alkali load. This review provides an overview on the clinical spectrum of Pendred syndrome, the functional data on pendrin with a focus on its potential role in the thyroid, as well as the controversy surrounding the relative physiological roles of pendrin and anoctamin.
Aims
To investigate the performance of two proposed methods for assessing the prognosis of poorly differentiated thyroid carcinomas (PDTC): the Turin proposal and Hiltzik's histological grade (HHG). ...This was done using a series of 82 thyroid carcinomas of follicular origin.
Results
The two methods were able to classify patients accurately into two different prognosis groups. Although the Turin proposal and HHG displayed discrepant cases, they provided similar prognostic information. The Turin proposal gave accurate numbers and thresholds of PTDC criteria (loss of follicular architecture and mitoses, necrosis or convoluted nuclei). One Turin criterion, convoluted nuclei, failed to provide any prognostic value. Hiltzik's histological grade was also a simple and reliable method, allowing detection of tumours with high‐grade features (mitosis and/or tumour necrosis), notably some papillary carcinomas that displayed an intermediate prognosis. We show that Ki67 labelling (≥ 4%) was an independent factor and predictor of cause‐specific survival.
Conclusion
With similar performances in predicting prognosis, the Turin proposal and HHG provided complementary results in identifying a larger group of ‘intermediate prognosis’ thyroid carcinomas, which require adequate treatment and follow‐up.
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene, characterized by the clinical ...triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency. CMC can be complicated by systemic candidiasis or oral squamous cell carcinoma (SCC), and may lead to death. The role of chronic
infection in the etiopathogenesis of oral SCC is unclear. Long-term use of fluconazole has led to the emergence of
strains with decreased susceptibility to azoles. CMC is associated with an impaired Th17 cell response; however, it remains unclear whether decreased serum IL-17 and IL-22 levels are related to a defect in cytokine production or to neutralizing autoantibodies resulting from mutations in the
gene.
Abstract Purpose Patients with advanced radioactive iodine resistant differentiated (MDTC) or medullary (MMTC) thyroid cancer had an unmet need. Early data showed promising efficacy of vascular ...endothelial growth factor receptor inhibitors. We investigated sunitinib in this setting. Patients and methods This phase 2 trial enrolled MDTC, anaplastic (MATC) and MMTC patients in 1st line anti-angiogenic therapy with sunitinib at 50 mg/d, 4/6w. Objective response rate was the primary end-point. Secondary end-points were progression-free survival, overall survival and safety. Results Seventy-one patients were enrolled from August 2007 to October 2009, 41 MDTC/4 MATC patients and 26 MMTC patients. Patients received a median of 8 and 9 cycles, respectively. In the MDTC/MATC group, 13% of patients and 43% of cycles and in the MMTC group, 23% of the patients and 48.8% of cycles remained at 50 mg/d, respectively. The primary end-point was reached with an objective response rate of 22% (95% CI: 10.6–37.6) in MDTC patients and in 38.5% (95% CI: 22.6–56.4) in MMTC patients. No objective response was seen in MATC patients. Median progression-free survival and overall survival were 13.1 and 26.4 months in MDTC patients, 16.5 and 29.4 months in MMTC patients. The most frequent side effects were asthenia/fatigue (27.8% ≥ grade 3), mucosal (9.9% ≥ grade 3), cutaneous toxicities, hand-foot syndrome (18.3% ≥ grade 3). Of all, 14.1% had a cardiac event. Nine unexpected side effects were reported, out of which, five induced deaths. Conclusion Sunitinib is active in MDTC and MMTC patients. Side effects were more severe than with previous reports. If using sunitinib, alternative schedule/dosage should be considered.
Graves’ disease is the most frequent cause of hyperthyroidism. Many questions remain about the choice of diagnostic evaluations and treatment strategy according to clinical context (age, gender, ...pregnancy, etc.) and about the best management of the main extrathyroidal complication that is Graves orbitopathy. The exact pathogenic mechanisms are not fully clear. They associate genetic factors, interactions between endogenous and environmental factors, and immune system dysregulation. Graves’ orbitopathy is one of the consequences of this partial understanding. Iatrogenic Graves’ disease induced by the new targeted therapies are described and could help to better understand the molecular pathways involved in the disease and to develop new therapeutic approaches.
Postoperative hypocalcemia is a common and most often transient event after extensive thyroid surgery. It may reveal iatrogenic injury to the parathyroid glands and permanent hypoparathyroidism. We ...prospectively evaluated the incidence of hypocalcemia and permanent hypoparathyroidism following total or subtotal thyroidectomy in 1071 consecutive patients operated during 1990–1991. We then determined in a cross‐sectional study which early clinical and biochemical characteristics of patients experiencing postoperative hypocalcemia correlated with the long‐term outcome. Postoperative calcemia under 2 mmol/l was observed in 58 patients (5.4%). In 40 patients hypocalcemia was considered severe (confirmed for more than 2 days, symptomatic or both). At 1 year after surgery five patients (0.5%) had persistent hypocalcemia. We found that patients carried a high risk for permanent hypoparathyroidism if fewer than three parathyroid glands were preserved in situ during surgery or the early serum parathyroid hormone level was ≤ 12 pg/ml, the delayed serum calcium levels ≤ 8 mg/dl, or the delayed serum phosphorus level ≥ 4 mg/dl under oral calcium therapy. When one or more of these criteria are present, long‐term follow‐up should be enforced to check for chronic hypocalcemia and to avoid its severe complications by appropriate supplement therapy.
Background
Laparoscopic adrenalectomy (LA) is the standard treatment for benign adrenal lesions. The laparoscopic approach has also been increasingly accepted for adrenal metastases but remains ...controversial for adrenocortical carcinoma (ACC). In a retrospective cohort study we compared the outcome of LA versus open adrenalectomy (OA) in the treatment of stage I and II ACC.
Methods
This was a double cohort study comparing the outcome of patients with stage I/II ACC and a tumor size <10 cm submitted to LA or OA at Lille University Hospital referral center from 1985 to 2011. Main outcomes analyzed were: postoperative morbidity, overall survival, and disease-free survival.
Results
Among 111 consecutive patients operated on for ACC, 34 met the inclusion criteria. LA and OA were performed in 13 and 21 patients, respectively. Baseline patient characteristics (gender, age, tumor size, hormonal secretion) were similar between groups. There was no difference in postoperative morbidity, but patients in LA group were discharged earlier (
p
< 0.02). After a similar follow-up (66 ± 52 for LA and 51 ± 43 months for OA), Kaplan–Meier estimates of disease-specific survival and disease-free survival were identical in both groups (
p
= 0.65,
p
= 0.96, respectively).
Conclusions
LA was associated with a shorter length of stay and did not compromise the long-term oncological outcome of patients operated on for stage I/II ACC ≤ 10 cm ACC. Our results suggest that LA can be safely proposed to patients with potentially malignant adrenal lesions smaller than 10 cm and without evidence of extra-adrenal extension.
The aim of this review was to delineate the characteristics of antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis associated with antithyroid drugs (ATD). A PubMed search ...was made for English language articles using the search terms antithyroid drugs AND ANCA OR ANCA-associated vasculitis.
The literature includes approximately 260 case reports of ANCA-associated small-vessel vasculitis related to ATD, with 75% of these associated with thiouracil derivatives (propylthiouracil PTU) and 25% with methyl-mercapto-imidazole derivatives (MMI/TMZ). The prevalence of ANCA-positive cases caused by ATD varied between 4% and 64% with PTU (median 30%), and 0% and 16% with MMI/TMZ (median 6%). Young age and the duration of ATD therapy were the main factors contributing to the emergence of ANCA positivity. Before ATD therapy initiation, the prevalence of ANCA-positive patients was 0-13%. During ATD administration, 20% of patients were found to be positive for ANCA. Only 15% of ANCA-positive patients treated with ATD exhibited clinical evidence of vasculitis, corresponding to 3% of all patients who received ATD. Clinical manifestations of ANCA-associated vasculitis related to ATD were extremely heterogeneous. When vasculitis occurred, ATD withdrawal was usually followed by rapid clinical improvement and a favorable prognosis.
ANCA screening is not systematically recommended for individuals on ATD therapy, particularly given the decreasing use of PTU in favor of TMZ/MMI. Particular attention should be given to the pediatric population with Graves' disease who receive ATD, as well as patients treated with thiouracil derivatives and those on long-term ATD therapy.
In non-diabetic adult patients, hypoglycaemia may be related to drugs, critical illness, cortisol or glucagon insufficiency, non-islet cell tumour, insulinoma, or it may be surreptitious. ...Nevertheless, some hypoglycaemic episodes remain unexplained, and inborn errors of metabolism (IEM) should be considered, particularly in cases of multisystemic involvement. In children, IEM are considered a differential diagnosis in cases of hypoglycaemia. In adulthood, IEM-related hypoglycaemia can persist in a previously diagnosed childhood disease. Hypoglycaemia may sometimes be a presenting sign of the IEM. Short stature, hepatomegaly, hypogonadism, dysmorphia or muscular symptoms are signs suggestive of IEM-related hypoglycaemia. In both adults and children, hypoglycaemia can be clinically classified according to its timing. Postprandial hypoglycaemia can be an indicator of either endogenous hyperinsulinism linked to non-insulinoma pancreatogenic hypoglycaemia syndrome (NIPHS, unknown incidence in adults) or very rarely, inherited fructose intolerance. Glucokinase-activating mutations (one family) are the only genetic disorder responsible for NIPH in adults that has been clearly identified so far. Exercise-induced hyperinsulinism is linked to an activating mutation of the monocarboxylate transporter 1 (one family). Fasting hypoglycaemia may be caused by IEM that were already diagnosed in childhood and persist into adulthood: glycogen storage disease (GSD) type I, III, 0, VI and IX; glucose transporter 2 deficiency; fatty acid oxidation; ketogenesis disorders; and gluconeogenesis disorders. Fasting hypoglycaemia in adulthood can also be a rare presenting sign of an IEM, especially in GSD type III, fatty acid oxidation medium-chain acyl-CoA dehydrogenase (MCAD), ketogenesis disorders (3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) lyase deficiency, and gluconeogenesis disorders (fructose-1,6-biphosphatase deficiency).
PDF
