A Novel FGFR1 Missense Mutation in a Portuguese Family with Congenital Hypogonadotropic Hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a rare reproductive endocrine disorder characterized by complete or partial failure of pubertal development and infertility due to deficiency of the gonadotropin-releasing hormone (GnRH). CHH has a significant clinical heterogeneity and can be caused by mutations in over 30 genes. The aim of this study was to investigate the genetic defect in two siblings with CHH. A woman with CHH associated with anosmia and her brother with normosmic CHH were investigated by whole exome sequencing. The genetic studies revealed a novel heterozygous missense mutation in the Fibroblast Growth Factor Receptor 1 (FGFR1) gene (NM_023110.3: c.242T>C, p.Ile81Thr) in the affected siblings and in their unaffected father. The mutation affected a conserved amino acid within the first Ig-like domain (D1) of the protein, was predicted to be pathogenic by structure and sequence-based prediction methods, and was absent in ethnically matched controls. These were consistent with a critical role for the identified missense mutation in the activity of the FGFR1 protein. In conclusion, our identification of a novel missense mutation of the FGFR1 gene associated with a variable expression and incomplete penetrance of CHH extends the known mutational spectrum of this gene and may contribute to the understanding of the pathogenesis of CHH.

Antithyroid Drug-Induced Agranulocytosis: State of the Art on Diagnosis and Management.

Agranulocytosis is a rare but serious complication of antithyroid drug therapy, and an up-to-date understanding of this topic is important. Both direct toxicity and immune-mediated responses have been described as possible mechanisms. Some major susceptibility loci have recently been identified, which may lead the diagnosis of agranulocytosis into a genomic era. Onset is acute and patients present with symptoms and signs of infection together with high fever. Clinical suspicion is pivotal and should prompt blood sampling. An absolute neutrophil count of <500/µl in the presence of antithyroid drugs establishes the diagnosis. The causative drug should immediately be stopped to prevent further damage. Treatment includes broad-spectrum antibiotics and granulocyte-colony stimulation factor in selected patients. Later, patients will need definitive treatment for hyperthyroidism, usually with radioactive iodine or surgery. The best way to avoid the mortality associated with antithyroid drug-induced agranulocytosis is patient education.

Controversies in the management of hyperglycaemic emergencies in adults with diabetes.

Hyperglycaemic emergencies are associated with significant morbi-mortality and healthcare costs. Management consists on fluid replacement, insulin therapy, and electrolyte correction. However, some areas of patient management remain debatable. In patients without respiratory failure or haemodynamic instability, arterial and venous pH and bicarbonate measurements are comparable. Fluid choice varies upon replenishment phase and patient's condition. If patient is severely hypovolaemic, normal saline solution should be the first option. However, if patient has mild/moderate dehydration, fluid choice must take in consideration sodium concentration. Insulin therapy should be guided by ß-hydroxybutyrate normalization and not by blood glucose. Variations of conventional insulin infusion protocols emerged recently. Priming dose of insulin may not be required, and fixed rate insulin infusion represents the best option to suppress hepatic glucose production, ketogenesis, and lipolysis. Concomitant administration of basal insulin analogues with regular insulin infusion accelerates ketoacidosis resolution and prevents rebound hyperglycaemia. Simpler protocols using subcutaneous rapid-acting insulin analogues for mild/moderate diabetic ketoacidosis treatment have proven to be safe and effective, but further studies are required to confirm these results. Treatment with bicarbonate, phosphate, and low-molecular-weight heparin is still disputable, and randomized controlled trials are urgently needed to optimize patient management and decrease the morbi-mortality of hyperglycaemic emergencies.

The role of ablative treatment in differentiated thyroid cancer management.

INTRODUCTION: The role of ablative treatment in differentiated thyroid cancer management has been evolving over the years. After its introduction in clinical practice, the use of postsurgical radioiodine treatment was generalized to almost every patient with differentiated thyroid cancer, with the exception of unifocal microcarcinomas. However, in the last decade several studies questioned its benefit in low- and intermediate-risk patients. Areas covered: In this review we discuss the role of postsurgical radioiodine treatment at the present time. Expert commentary: Although there is general consensus about the recommendation for very low-risk (microcarcinomas) and high-risk patients - no indication for routine postoperative radioiodine and clear indication for radioiodine treatment, respectively, the recommendation for low- and intermediate-risk patients is still under debate. The most recent guidelines from the American Thyroid Association make a statement against routine postoperative radioiodine in both low- and intermediate-risk cases, recommending an individualized approach that takes into consideration the risk of disease persistence or recurrence after surgery. We consider that these recommendations are in accordance with the best evidence available today, and we would like to emphasize that radioiodine is generally favored for most intermediate-risk patients, especially in the presence of extensive lymph node disease or older age.

GNRHR biallelic and digenic mutations in patients with normosmic congenital hypogonadotropic hypogonadism.

OBJECTIVE: Normosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare disorder characterised by lack of pubertal development and infertility, due to deficient production, secretion or action of gonadotropin-releasing hormone (GnRH) and, unlike Kallmann syndrome, is associated with a normal sense of smell. Mutations in the GNRHR gene cause autosomal recessive nCHH. The aim of this study was to determine the prevalence of GNRHR mutations in a group of 40 patients with nCHH. DESIGN: Cross-sectional study of 40 unrelated patients with nCHH. METHODS: Patients were screened for mutations in the GNRHR gene by DNA sequencing. RESULTS: GNRHR mutations were identified in five of 40 patients studied. Four patients had biallelic mutations (including a novel frameshift deletion p.Phe313Metfs*3, in two families) in agreement with autosomal recessive inheritance. One patient had a heterozygous GNRHR mutation associated with a heterozygous PROKR2 mutation, thus suggesting a possible role of synergistic heterozygosity in the pathogenesis of the disorder. CONCLUSIONS: This study further expands the spectrum of known genetic defects associated with nCHH. Although GNRHR mutations are usually biallelic and inherited in an autosomal recessive manner, the presence of a monoallelic mutation in a patient should raise the possibility of a digenic/oligogenic cause of nCHH.