Asthma is a multifactorial disease influenced by genetic and environmental factors. In the past decade, several loci and >100 genes have been found to be associated with the disease in at least one population. Among these loci, region 12q13-24 has been implicated in asthma etiology in multiple populations, suggesting that it harbors one or more asthma susceptibility genes. We performed linkage and association analyses by transmission/disequilibrium test and case-control analysis in the candidate region 12q13-24, using the Sardinian founder population, in which limited heterogeneity of pathogenetic alleles for monogenic and complex disorders as well as of environmental conditions should facilitate the study of multifactorial traits. We analyzed our cohort, using a cutoff age of 13 years at asthma onset, and detected significant linkage to a portion of 12q13-24. We identified IRAK-M as the gene contributing to the linkage and showed that it is associated with early-onset persistent asthma. We defined protective and predisposing SNP haplotypes and replicated associations in an outbred Italian population. Sequence analysis in patients found mutations, including inactivating lesions, in the IRAK-M coding region. Immunohistochemistry of lung biopsies showed that IRAK-M is highly expressed in epithelial cells. We report that IRAK-M is involved in the pathogenesis of early-onset persistent asthma. IRAK-M, a negative regulator of the Toll-like receptor/IL-1R pathways, is a master regulator of NF- kappa B and inflammation. Our data suggest a mechanistic link between hyperactivation of the innate immune system and chronic airway inflammation and indicate IRAK-M as a potential target for therapeutic intervention against asthma.

Objective: Obesity is frequently associated with modifications of thyroid size and function. We evaluated the prevalence of thyroid function abnormalities and the effects of puberty and weight loss in obese children and adolescents. Methods: We examined 468 obese children (255 girls and 213 boys aged 3.7–17.9 years) and 52 normal-weight age-matched children as controls. TSH, fT3, fT4, fasting serum insulin and glucose were measured at baseline. fT3, fT4 and TSH were also measured after 6 months of lifestyle intervention in a subset of 43 patients. Results: 109 obese children showed abnormal circulating thyroid hormone concentrations (84 had elevated fT3 levels, 15 elevated TSH, 6 elevated fT4, 3 elevated fT3 and TSH, and 1 elevated fT3, fT4 and TSH levels). Serum TSH and fT3 concentrations were positively correlated with BMI-SDS. The prevalence of patients with abnormal thyroid hormone concentrations was similar between sexes and between prepubertal and pubertal subjects. After 6 months of lifestyle intervention, thyroid hormone concentrations normalized in 27 of the patients with decreased BMI-SDS, and in 2 patients in whom BMI-SDS increased. Conclusions: In obese children, an increased fT3 concentration is the most frequent thyroid function abnormality. Serum fT3 and TSH correlate with BMI. Moderate weight loss frequently restores these abnormalities.

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HOMA-IR in obese children increases at puberty more than in normal-weight children and does not return to pre-pubertal values at the end of puberty.

Objective: The diagnosis of GH deficiency (GHD) in children and adolescents is established when GH concentrations fail to reach an arbitrary cut-off level after at least two provocative tests. The objective of the study was to define the optimal GH cut-offs to provocative tests in children and adolescents. Design: Retrospective study in 372 subjects who underwent evaluation of GH secretion. GH and IGF-I were measured by chemiluminescence assay in all samples. Receiver operating characteristic (ROC) analysis was used to evaluate the optimal GH cut-offs and the diagnostic accuracy of provocative tests. Methods: Seventy four patients with organic GHD (GH peak <10 µg/L after two provocative tests) and 298 control subjects (GH response >10 µg/L to at least one test) were included in the study. The provocative tests used were arginine, insulin tolerance test (ITT) and clonidine. Diagnostic criteria based on cut-offs identified by ROC analysis (best pair of values for sensitivity and specificity) were evaluated for each test individually and for each test combined with IGF-I SDS. Results: The optimal GH cut-off for arginine resulted 6.5 µg/L, 5.1 µg/L for ITT and 6.8 µg/L for clonidine. IGF-I SDS has low accuracy in diagnosing GHD (AUC = 0.85). The combination of the results of provocative tests with IGF-I concentrations increased the specificity. Conclusions:The results of the ROC analysis showed that the cut-off limits which discriminate between normal and GHD are lower than those commonly employed. IGF-I is characterized by low diagnostic accuracy.

BMI affects the GH response to clonidine in children with short stature and should be considered when interpreting the results to the stimulation test.

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Adult height in patients with permanent IGHD and spontaneous puberty is similar to adult height in patients with MPHD and induced puberty.