Context: Congenital hypothyroidism (CH) is a common endocrine disorder with an incidence of 1:3000–4000 at birth. In 80–85% of cases, CH is caused by defects in thyroid organogenesis, resulting in absent, ectopically located, and/or severely reduced gland [thyroid dysgenesis (TD)]. Mutations in genes controlling thyroid development have demonstrated that in a few cases, TD is a Mendelian trait. However, accumulating evidence supports the view that the genetics of TD are complex, possibly with a polygenic/multifactorial basis. A higher prevalence of congenital heart disease has been documented in children with CH than in the general population. Such an association suggests a possible pathogenic role of genes involved in both heart and thyroid development. NKX2–5 encodes a homeodomain-containing transcription factor with a major role in heart development, and mutations affecting this gene have been reported in individuals with congenital heart disease. Objective: In the present work we investigated the possible involvement of NKX2–5 mutations in TD. Results: Our results indicate that Nkx2–5^−/− embryos exhibit thyroid bud hypoplasia, providing evidence that NKX2–5 plays a role in thyroid organogenesis and that NKX2–5 mutations contribute to TD. NKX2–5 mutational screening in 241 patients with TD allowed the identification of three heterozygous missense changes (R25C, A119S, and R161P) in four patients with TD. Functional characterization of the three mutations demonstrated reduced DNA binding and/or transactivation properties, with a dominant-negative effect on wild-type NKX2–5. Conclusion: Our results suggest a previously unknown role of NKX2–5 in the pathogenesis of TD.

Subclinical hypothyroidism of chronic autoimmune thyroiditis must be distinguished from the rare condition of thyroid resistance to TSH in which variable degrees of congenital insensitivity of the thyroid to a biologically active TSH molecule are present. We studied 42 subjects with slight to moderate elevations of circulating TSH and normal free thyroid hormone levels in whom the diagnosis of autoimmune thyroid disease had been excluded using the best of the currently available laboratory and instrumental techniques. In three families (A, B, and C), which included 8 of the 42 cases, other members besides the propositus were found to have isolated hyperthyrotropinemia. The entire coding regions of the TSH receptor (TSHr) gene were sequenced, and TSHr mutations were found in five subjects from families A and B. No mutations were identified in the two members of family C, in one member of family A, and in the 34 remaining cases of isolated hyperthyrotropinemia. A previously described P162A mutation was found in the proband (homozygous state), the son, and the mother of family A (both in the heterozygous state). A new inactivating heterozygous mutation was found in the proband and the mother of family B and consisted of the substitution of a leucine in place of a highly conserved proline at position 252 (L252P) in the extracellular portion of the TSHr. After transfection in COS-7 cells, the mutant L252P displayed a low expression at the cell surface and a reduced response to bovine TSH in terms of cAMP production. A structural defect of the mutant TSHr protein was probably responsible for the poor routing of the receptor to the cell membrane. In conclusion, in two of three families, but in none of 34 sporadic cases of isolated hyperthyrotropinemia, inactivating mutations of the TSHr were identified. The question of whether the latter cases represent subtle forms of autoimmune thyroiditis or might bear as yet unidentified genetic defects remains a matter of future studies.

During chronic kidney disease, the progressive deterioration of renal function induces several biological/clinical dysfunctions, including enhancement of synthesis of inflammation/oxidative stress mediators. Impaired renal function is an independent cardiovascular risk factor; indeed, cardiovascular complications dominate the landscape of both chronic kidney disease and end-stage renal disease. The aim of this study is to explore the correlation between the global oxidative balance in hemodialysis patients and both inflammatory markers and cardiovascular events. Using photometric tests, this study explored plasmatic oxidative balance in 97 hemodialysis patients compared to a healthy population. In the hemodialysis patients, we showed that oxidative stress values were significantly lower than in controls while effectiveness in the antioxidant barrier was significantly increased in the hemodialysis group. Furthermore, we highlighted a strong correlation between oxidative index and blood levels of C-reactive protein. When patients were divided into two groups based on previous cardiovascular events, we found that subjects with previous cardiovascular events had higher values of both oxidative stress and antioxidant barrier than patients without cardiovascular events. Our results indicated that in hemodialysis patients, the clinical and prognostic significance of oxidative status is very different from general population. As cardiovascular complications represent a strong negative factor for survival of hemodialysis patients, the research of new cardiovascular risk biomarkers in these patients takes on particular importance in order to translate them into clinical practice/primary care.

The de novo occurrence of germline-activating thyrotropin receptor (TSHR) gene mutations has been reported as the cause of sporadic nonautoimmune neonatal hyperthyroidism in eight children. We report the case of an Italian infant girl who presented at birth with severe hyperthyroidism and goiter. Ultrasonografic examination of the infant's thyroid showed a diffuse goiter with a normal echogenic pattern. Serum antithyroglobulin, antithyroperoxidase, and antithyrotropin receptor antibodies were undetectable. Treatment with propylthiouracyl, propranolol, and saturated potassium iodide solution started at 44 days of life with the resolution of thyrotoxic symptoms. Once euthyroidism was achieved, the dose of propylthiouracyl was tapered, but hyperthyroidism recurred. Auxological parameters showed an acceleration of linear growth and bone age. DNA was extracted from peripheral white blood cells of the patient, the sister, and the two parents. All of exon 10 of the TSHR gene was amplified by polymerase chain reaction (PCR) and subjected to direct sequencing. In the thyrotoxic infant girl, a substitution of cytosine to thymine was detected, changing isoleucine 568 into a threonine (I568T), located in the second extracellular loop. The normal sequence could also be detected, indicating heterozygosis of the mutated allele. This mutation was previously described as a somatic mutation in a patient with toxic thyroid adenoma. The sister and the parents of the propositus, all euthyroid, showed the wild-type TSHR gene. In conclusion, we describe a case of a de novo germinal mutation of the TSHR causing severe congenital hyperthyroidism.