Deborah Mannavola

BRAF mutations in an Italian cohort of thyroid cancers

objective  Recently, a somatic point mutation of the BRAF gene (V599E) has been identified as the most common genetic event in papillary thyroid carcinoma (PTC) with a variable frequency (about 25–70%) in different series from USA, Japan, Portugal and Ukraine.

Different responses to chronic somatostatin analogues in patients with central hyperthyroidism

Objective  Central hyperthyroidism is mainly due to two different causes, TSH‐secreting pituitary adenoma (TSH‐oma) and resistance to thyroid hormone in its pituitary variant, i.e. patients presenting with signs and symptoms of hyperthyroidism (PRTH). Because therapeutic approach and the clinical follow‐up are extremely different in these two disorders, a correct differential diagnosis is mandatory. Unfortunately, no definite pathognomonic tool is presently available and an extensive biochemical and instrumental workup is frequently needed in order to reach the correct diagnosis. Aim of the present study was to investigate the use of somatostatin analogues in the differential diagnosis between TSH‐omas and PRTH, as well as the possible treatment of PRTH with these analogues.

Differential diagnosis between Pendred and pseudo-Pendred syndromes: Clinical, radiologic, and molecular studies

The disease gene for Pendred syndrome has been recently characterized and named PDS. It codes for a transmembrane protein called pendrin, which is highly expressed at the apical surface of the thyroid cell and functions as a transporter of chloride and iodide. Pendrin is also expressed at the inner ear level, where it appears to be involved in the maintenance of the endolymph homeostasis in the membranous labyrinth, and in the kidney, where it mediates chloride-formate exchange and bicarbonate secretion. Mutations in the PDS gene and the consequent impaired function of pendrin leads to the classic phenotype of Pendred syndrome, i.e. dyshormonogenic goiter and congenital sensorineural hearing loss. In the present study, we performed a detailed clinical, radiologic, and molecular analysis of six families presenting with clinical diagnosis of Pendred syndrome. In two families a homozygous pattern for PDS mutations was found, whereas the affected members of the other four families were compound heterozygotes. One family did not harbor PDS mutations. Among the four novel mutations described, one is a transversion in exon 2 (84C>A), leading to the substitution S28R. Two other novel mutations lie in exon 4 (398T>A) and in exon 16 (1790T>C), leading to the substitutions S133T and L597S, respectively. The fourth novel mutation (1614+1G>A) is located in the first base pair of intron 14, probably affecting the splicing of the PDS gene. Clinically, all patients had goiter with positive perchlorate test, hypothyroidism, and severe or profound sensorineural hearing loss. In all the individuals harboring PDS mutations, but not in the family without PDS mutations, inner ear malformations, such as enlargement of the vestibular aqueduct and of the endolymphatic duct and sac, were documented. The pseudo-Pendred phenotype exhibited by the family without PDS mutations is likely caused by an autoimmune thyroid disease associated with a sensorineural hearing loss of different origin.

Multigenerational familial medullary thyroid cancer (FMTC): evidence for FMTC phenocopies and association with papillary thyroid cancer

background Occurrence in a familial setting is well established for medullary thyroid carcinoma (MTC) and has been more recently reported for papillary thyroid cancer (PTC). Germline mutations or rearrangements of the RET proto‐oncogene are the genetic background of the majority of hereditary MTCs and of about 25–40% of PTCs.

Recombinant human TSH testing is a valuable tool for differential diagnosis of congenital hypothyroidism during l‐thyroxine replacement

objective The differential diagnosis of congenital hypothyroidism (CH) is aimed to distinguish transitory from permanent forms, to optimize l‐thyroxine (l‐T4) therapy to replacement or TSH‐suppressive regimens, and to reach accurate definition of the clinical and biochemical phenotype for subsequent genetic investigations and counselling. Therefore, l‐T4 therapy is presently withdrawn in most instances and investigations are performed in a disturbing hypothyroid state.

Resistance to Thyroid Hormone

The concept of a hormone-resistant disease has been introduced around the 1940s by Fuller Albright by studying the rickets resistant to Vitamin D therapy and the “Pseudohypoparathyroidism—an example of Seabright-Bantam syndrome” (1,2).He called the disease “pseudo,” as the patients showed clinical features of hypoparathyroidism, but the injection of parathyroid hormone was not followed by the expected increases of serum calcium levels and urinary phosphate excretion. Thus, the term “pseudo” entered into the medical vocabulary to indicate an endocrine disorder resembling a known disease, but accompanied by failure of the end-organ to respond to the specific hormone. Several examples of insensitivity to many hormones, including insulin, corticosteroids, androgens, estrogens, anterior and posterior pituitary hormones, have been reported in the last 50 yr. Moreover, it is now clearly demonstrated that genetic mutations of hormone receptor proteins or proteins involved in the signal transduction are the underlying cause of most clinical conditions that we prefer today to call not “pseudo,” but “resistance to thyroid hormone action.”

TGB Deficiency: description of two novel mutations associated with complete TBG deficiency and review of the literature

Thyroxine-binding globulin (TBG) is the main thyroid hormone transport protein in serum. Inherited TBG defects lead to a complete (TBG-CD) or a partial (TBG-PD) deficiency and have a diagenic transmission, being clinically fully expressed only in hemizygous males and in homozygous females. In the present study, seven patients from two unrelated families with TBG-CD were studied and two novel TBG mutations were documented. In particular, a T insertion at the 5′ donor splice site of exon 0, between nucleotides 2 and 3 at the beginning of intron 1 (g.IVS1+2_3insT) was found in one family and was named TBG-Milano. The other novel mutation is a T deletion at nucleotide 214 of exon 1, which leads to a frameshift at codon 50 with a premature stop codon at position 51 (c.214delT, P50fsX51) and was named TBG-Nikita. According to the X-linked transmission of the defect, females harboring the mutation showed a reduction in TBG levels with normal TSH and total thyroid hormone values at the lower limit of normal. Males harboring either TBG-Milano or TBG-Nikita, showed normal TSH values and low levels of total thyroid hormones and lacked TBG. In conclusion, we report two novel mutations of the TBG gene associated with a complete TBG defect. The first mutation lies at the 5′ donor splice site of exon 0 and probably alters the start of translation, while the second is a single nucleotide deletion and leads to a premature stop codon.

Syndromes of Resistance to Thyroid Hormone: Clinical Aspects

Resistance to thyroid hormone (RTH) is a rare syndrome caused by a molecular defect of the thyroid hormone receptor β (TRβ) leading to a decreased responsiveness of target tissues to the action of thyroid hormones. Despite of the specific biochemical presentation, characterized by elevated thyroid hormone levels in the presence of detectable concentration of TSH, the resulting clinical phenotype is extremely variable. Early recognition of RTH is mandatory, since its diagnostic procedures, as well as its management and follow-up differs from that of other forms of hyperthyroidism, i.e. TSH-secreting pituitary adenoma, Graves’ disease and uni- or multinodular toxic goiter. The increasing awareness of the existence of RTH syndrome along with the introduction of ultrasensitive immunometric TSH assay led to duplicate the number of reported new cases every 5 years (Figure 1). In fact, since the first case described in 1967 (1), more than 700 individuals with RTH belonging to about 250 unrelated families have been identified up to day (2, 3). RTH patients have been described all over the world, without apparent geographical and ethnic predominance or preferential sex distribution. The use of TSH measurement, rarely associated with that of total T4, in the neonatal screening for congenital hypothyroidism does not help to understand the real prevalence of RTH, which is indirectly estimated to be around 1 in 50,000 live births (4).

Genetic analyses and evaluation of peripheral parameters of thyroid hormone action for the differential diagnosis of RTH. A novel heterozygous missense mutation (M334T) discovered.

Resistance to thyroid hormone (RTH) is a rare disease characterized by goiter and elevated free thyroid hormone (TH) levels in the presence of detectable concentrations of TSH. Most RTH patients harbor mutations in the ligand binding domain (LBD) of thyroid hormone receptor ß (TRß) gene, without a clear correlation between genotype and phenotype. Clinical, biochemical and genetic analyses were performed in several members of one family, because the index case presented with elevated free TH, measurable TSH and no hyperthyroid manifestations, but with a pituitary lesion at MRI. High free TH levels and TSH concentrations in the normal range were found also in 4 relatives. The presence of euthyroidism in all patients together with peripheral parameters of TH action in the normal range led to the diagnosis of generalized RTH (GRTH). In the five affected members, the genetic analysis revealed a novel heterozygous missense mutation at codon 334 (M334T). A different mutation at codon 334 was previously described in association with selective pituitary resistance to thyroid hormone (PRTH). Therefore, we confirm that substitutions at Methionine 334 are critical for the structural integrity of TRß LBD. The association of different phenotypes with substitutions affecting the same codon is another contribution confirming that RTH phenotype does not generally depend upon the site of the mutation in the LBD of TRß1.

Syndromes of thyroid hormone resistance due to mutations in the T3β receptor: progress in our understanding

nant disorder, characterized clinically by goiter and biochemically by elevated circulating free thyroid hormone levels in the presence of measurable serum thyroid-stimulating hormone (TSH) concentrations. About 85% of patients with RTH harbor mutations in thyroid hormone receptor β (TRβ). These mutations cluster in three different “hot spots” in the ligand (T3) binding domain of the receptor. When mapped to their homologous residues in the thyroid hormone receptor (TR) crystal structure, these three clusters of mutations border the T3binding pocket. As a consequence, most TRβ mutations impair the hormone binding to the receptor and interfere with the mechanisms of corepressor release and consequent recruitment of coactivators. Thus, the remodeling of chromatin structure throughout the process of histone acetylation is prevented and the transcriptional activity of the mutant receptor on both positively and negatively regulated genes is severely disrupted. The lack of interaction with coactivators appears to be an additional mechanism for the dominant negative effects of mutant TRβ on the transcriptional activity of the normal (wildtype) TRs. Curr Opin Endocrinol Diabetes 2000, 7:281–287