Genetic defects of hydrogen peroxide generation in the thyroid gland.

Hydrogen peroxide (H2O2) is a key element in thyroid hormone biosynthesis. It is the substrate used by thyroid peroxidase for oxidation and incorporation of iodine into thyroglobulin, a process known as organification. The main enzymes composing the H2O2-generating system are the dual oxidase 2 (DUOX2) and the recently described DUOX maturation factor 2 (DUOXA2). Defects in these reactions lead to reduced thyroid hormone synthesis and hypothyroidism, with consequent increased TSH secretion and goiter. Since the first report in 2002 of DUOX2 mutations causing congenital hypothryoidism (CH), to date 25 different mutations have been described. Affected patients show a positive perchlorate discharge test and high phenotypic variability, ranging from transient to permanent forms of CH. Up to now, only two cases of CH due to DUOXA2 defects have been published. They also suggest the existence of a great genotype-phenotype variability. The phenotypic expression is probably influenced by genetic background and environmental factors. DUOX and DUOXA constitute a redundant system in which DUOX1/DUOXA1 can at least partially replace the function of DUOX2/DUOXA2. Furthermore, increased nutritional iodide could ensure a better use of H2O2 provided by DUOX1.

Identification of a novel polymorphism in the fibronectin type II domain of the SEL1L gene and possible relation to the persistent hyperinsulinemic hypoglycemia of infancy.

SEL1L, a human gene located on chromosome 14q24.3-q31, is highly expressed in adult pancreas. It is proximal to D14S67 (IDDM11) a proposed type I diabetes susceptibility locus. Considering the organ specific expression of SEL1L, a fundamental role of SEL1L in pancreatic growth can be hypothesized. While screening for mutations in young diabetic patients, in children affected by persistent hyperinsulinemic hypoglycemia of infancy (PHHI), in patients with non-functional endocrine tumours and in over 100 control subjects, we identified a novel polymorphism (D162G) residing on the fourth exon of the gene. This exon encodes for the fibronectin type II domain and the nucleotide change involves a highly conserved amino acid. The D162G polymorphism induces a major change in the amino acid composition producing a possible disruptive role in collagen binding.

The clinical and molecular characterization of patients with dyshormonogenic congenital hypothyroidism reveals specific diagnostic clues for DUOX2 defects.

CONTEXT: Mutations in the DUOX2 gene have been associated with transient or permanent congenital hypothyroidism due to a dyshormonogenic defect. OBJECTIVE: This study aimed to verify the prevalence of DUOX2 mutations and the associated clinical features in children selected by criteria supporting a partial iodide organification defect (PIOD). PATIENTS AND METHODS: Thirty children with PIOD-like criteria were enrolled and genotyped. A detailed clinical characterization was undertaken together with the functional analysis of the DUOX2 variations and the revision of the clinical and molecular data of the literature. RESULTS: In this large selected series, the prevalence of the DUOX2 mutations was high (37%). We identified 12 missense variants, one splice site, and three frameshift DUOX2 mutations. Functional analyses showed significant impairment of H2O2 generation with five missense variants. Stop-codon mutants were shown to totally abolish DUOX2 activity by nonsense-mediated RNA decay, exon skipping, or protein truncation. DUOX2 mutations, either mono- or biallelic, were most frequently associated with permanent congenital hypothyroidism. Moreover, the present data suggested that, together with goiter and PIOD, the most significant features to select patients for the DUOX2 analysis are the low free T4 and the high TSH concentrations at the first postnatal serum sampling, despite borderline blood spot TSH. Interestingly, the analysis of previously described DUOX2 mutated cases confirmed the validity of these findings. CONCLUSIONS: The defects in the peroxide generation system are common among congenital hypothyroidism patients with PIOD. The most robust clinical parameters for selecting patients for DUOX2 analysis have been identified, and several DUOX2 variants have been functionally characterized.

Analysis of bone mineral content in horizontally HIV-infected children naïve to antiretroviral treatment.

Low bone mass is a frequent finding in HIV-infected individuals. Reduced bone mass has been found in vertically infected children who are receiving antiretroviral treatment. Little is known about bone mass in horizontally infected young patients who are naïve to antiretroviral therapy. We measured the bone mineral content (BMC) at the lumbar spine and in the whole skeleton by using dual-energy X-ray absorptiometry (DXA) in 16 HIV-infected children (age 9.3 +/- 3.9 years) naïve to antiretroviral treatment, and in 119 healthy children (age 9.7 +/- 3.3 years). Thirteen patients were also pair-matched by anthropometric measures, sex, and age with healthy children. Median spine BMC of HIV-infected children was 14.9 g (8.2-39.2 g), and whole body BMC was 1106.1 g (55.5-2344.1 g). Spine BMC of healthy children was 18.6 g (6.8-52.2 g), and whole body BMC was 1213.5 g (541.0-2722.0 g). Multivariate analysis showed a mean difference of spine BMC values of 0.004 g (P = 0.64) between the two groups. Similarly, the whole body BMC difference between the two groups (0.001 g) was not statistically significant (P = 0.55). Mean spine BMC measurements in the case-control evaluation were 21.1 g (9.7 g) (patients), and 22.3 g (6.9 g) (controls). Whole body BMC measurements of patients and controls were 1258.5 g (539.6 g) and 1311.1 g (479.2 g), respectively. In both cases the differences were not significant. The duration of HIV infection did not relate to BMC values. In conclusion, horizontally HIV-infected children naïve to antiretroviral therapy have bone mineral measurements comparable to those of healthy children.