A somatic mutation in the thyrotropin receptor gene in a patient with an autonomous nodule within a multinodular goiter

ABSTRACT Thyrotropin (TSH) is the prime regulator of thyroid cell growth and function and acts through the thyrotropin receptor (TSHR) located on the surface membrane of thyrocytes. Somatic heterozygous mutations that cause TSHR activation in the absence of TSH have been found in toxic adenomas and in hot nodules of multinodular goiters. Clinically and histologically heterogeneous nodules can share common gain-of-function mutations. Mutation prevalence varies greatly and is inversely related to iodine intake of the population. We report a Greek patient presenting with subclinical hyperthyroidism due to a fast-growing autonomous hyperplastic nodule in a long-standing multinodular goiter. Direct DNA sequencing showed that the hot nodule harbored a somatic heterozygous activating TSHR mutation: substitution of glutamine for leucine in the third transmembrane helix. This mutation (L512Q) was recently described in two solitary toxic adenomas. This report expands the spectrum of mutations shared by dissimilar hot nodules, supporting a common mechanism for nonautoimmune thyroid autonomy. The identification of the L512Q substitution demonstrates that gainof-function TSHR mutations are encountered in Greece, although iodine deficiency has been significantly corrected over the last three decades

Congenital Hypogonadotropic Hypogonadism Due to GNRH Receptor Mutations in Three Brothers Reveal Sites Affecting Conformation and Coupling

Congenital hypogonadotropic hypogonadism (CHH) is characterized by low gonadotropins and failure to progress normally through puberty. Mutations in the gene encoding the GnRH receptor (GNRHR1) result in CHH when present as compound heterozygous or homozygous inactivating mutations. This study identifies and characterizes the properties of two novel GNRHR1 mutations in a family in which three brothers display normosmic CHH while their sister was unaffected. Molecular analysis in the proband and the affected brothers revealed two novel non-synonymous missense GNRHR1 mutations, present in a compound heterozygous state, whereas their unaffected parents possessed only one inactivating mutation, demonstrating the autosomal recessive transmission in this kindred and excluding X-linked inheritance equivocally suggested by the initial pedigree analysis. The first mutation at c.845 C>G introduces an Arg substitution for the conserved Pro 282 in transmembrane domain (TMD) 6. The Pro282Arg mutant is unable to bind radiolabeled GnRH analogue. As this conserved residue is important in receptor conformation, it is likely that the mutation perturbs the binding pocket and affects trafficking to the cell surface. The second mutation at c.968 A>G introduces a Cys substitution for Tyr 323 in the functionally crucial N/DPxxY motif in TMD 7. The Tyr323Cys mutant has an increased GnRH binding affinity but reduced receptor expression at the plasma membrane and impaired G protein-coupling. Inositol phosphate accumulation assays demonstrated absent and impaired Gαq/11 signal transduction by Pro282Arg and Tyr323Cys mutants, respectively. Pretreatment with the membrane permeant GnRHR antagonist NBI-42902, which rescues cell surface expression of many GNRHR1 mutants, significantly increased the levels of radioligand binding and intracellular signaling of the Tyr323Cys mutant but not Pro282Arg. Immunocytochemistry confirmed that both mutants are present on the cell membrane albeit at low levels. Together these molecular deficiencies of the two novel GNRHR1 mutations lead to the CHH phenotype when present as a compound heterozygote

The nonthyroidal illness syndrome in the non-critically ill patient

P>Background The nonthyroidal illness syndrome (NTIS) is a very common clinical entity among hospitalized patients and has been reported in practically every severe illness and acute or chronic stressful event. There is a large body of data associating the presence of NTIS with the severity of the underlying disease. Most of these studies concern intensive care unit (ICU) patients, whereas the non-critically ill patients outside the ICU setting are less well studied. Design We provide a review of the existing literature focusing on studies examining NTIS in non-critically ill patients and attempt to summarize the pathophysiological pathways underlying the syndrome, its prognostic role, as well as the current intervention studies mainly from a clinical standpoint. Results The aetiology of the NTIS is multifactorial and varies among different groups of patients. Experimental and clinical findings suggest that inflammatory cytokines are implicated in the pathogenesis of the syndrome, whereas recent evidence re-evaluate the role of deiodinases in thyroid hormone metabolism not only in the periphery but also in the hypothalamus and the pituitary and thus in the alterations accompanying NTIS. Clinical data examining the effectiveness of thyroid hormone supplementation in NTIS remain controversial. Conclusions As long as there is no clear evidence of benefit from thyroid hormone replacement and until well-designed studies confirm its efficacy, thyroxine supplementation should not be recommended for the treatment of NTIS

The failure of physiologic doses of reverse T3 to effect thyroid-pituitary function in man

Reverse T3 (3,3',5'-triiodothyronine, rT3), a major product of the peripheral monodeiodination of thyroxine (T4), was administered to normal male volunteers in doses sufficient to sustain an elevated serum rT3 concentration similar to that frequently observed in patients with nonthyroidal illness. No changes in basal serum T4, T3, TSH and prolactin concentrations, nor in the T3, TSH and prolactin responses to iv TRH were observed during rT3 administration. These findings suggest that physiologic increases in serum rT3 concentration probably do not inhibit T4 to T3 conversion or the anterior pituitary TSH and prolactin responses to thyrotropin-releasing hormone (TRH)

Studies of serum triiodothyronine, thyroxine and thyrotropin concentrations in endemic goiter in greece

ABSTRACT. The serum concentrations of triiodothyronine (T3) and thyrotropin (TSH) measured by radioimmunoassay, and that of thyroxine (T4), measured by competitive protein binding assay, were assessed in goitrous and non- goitrous subjects residing in an area of moderate iodine deficiency in Greece. Results were compared to those obtained in a group of age-matched control subjects residing in Boston, an area of adequate iodine intake. Serum T4 concentrations were within the normal range in both goitrous and non-goitrous Greek subjects, but were nevertheless significantly lower than in the Boston con trols. Serum T3 concentrations in the nongoitrous Greek subjects were similar to those in the Boston group, but values in the goitrous Greek subjects were significantly increased. Serum TSH concentrations in the Greek subjects were, with one exception, within the normal range and were almost identical to those in the Boston controls. It is suggested that endemic iodine deficient goiter in Greece is the result of an increased sensitivity of the iodine-deficient thyroid to the stimulatory effect of TSH on thyroid size and on the secretion of T3 relative to T4. © 1973 by The Endocrine Society

The expression of Omental 11β-HSD1 is not increased in severely obese women with metabolic syndrome

Objective: Plasma cortisol in obese subjects does not differ from that in normoweight subjects. Extra-adrenal cortisol production by 11β- hydroxysteroid dehydrogenase type 1 (11β-HSD1) can result in local hypercortisolemia. The aim of the present study was to examine the role of visceral hypercortisolemia in the development of metabolic syndrome in severe obesity. Methods: Eight lean women during hysterectomy (controls) and 19 severely obese women during bariatric surgery were studied, 8 without metabolic syndrome (OM- group) and 11 with it (OM+ group). Biopsies of omental and subcutaneous fat were performed in the severely obese women during surgery, but only omental biopsies in the controls. Expression of 11β-HSD1, glucocorticoid receptor α (GRα) and glucocorticoid receptor β (GRβ) was evaluated using real-time PCR.Results: Omental 11β-HSD1 expression was different between groups (one-way ANOVA, p < 0.01). Post-hoc analysis revealed that mean omental 11β-HSD1 mRNA levels were higher in the OM- group compared to controls, whereas they were similar when comparing the OM+ group with lean controls. Expression of 11β-HSD1 in subcutaneous fat was not different between OM+ and OM- groups. GRα expression in omental fat did not differ among groups or between omental and subcutaneous fat in severely obese patients. An expression of GRβ was not detected.Conclusion: Contrary to our original hypothesis, omental 11β-HSD1 expression is not increased in the OM+ group. Copyright © 2012 S. Karger GmbH, Freiburg