To evaluate the effect of different initial levothyroxine (LT₄) replacement doses on growth and intellectual outcome in patients with congenital hypothyroidism (CH) detected by neonatal screening program, the longitudinal growth and intelligence quotient (IQ) were assessed and compared at 4 years of age in 83 patients with CH. The patients were divided into three groups according to the initial LT₄ dose used: (1) group 1 (n = 42) received the previously recommended dose of 6.0-8.0 μg/kg per day; (2) group 2 (n = 21) received a dose of 8.1-10.0 μg/kg per day; (3) Group 3 (n = 20) a dose of 10.1-15.0 μg/kg per day. The IQ, evaluated by the Wechsler Preschool and Primary Scale of Intelligence test at 4 years of age, was significantly higher in group 3 (IQ 98 ± 9) compared to group 1 (IQ 88 ± 13; p < 0.05) but not compared to group 2 (IQ 94 ± 13). However, the IQs were below the normal range (< 85) in six patients from group 2 (28%), but in none of the patients from group 3 (p = 0.03). Patients from group 3, with severe CH at diagnosis, had an IQ (97 ± 9) at 4 years of age, which was not different from that of patients from the same group with moderate CH at diagnosis (IQ 99 ± 9). Similar results were also observed in patients from group 2 however, mean IQ scores in these patients (93 ± 12) were several points lower than those observed in patients from group 3 (95 ± 15). After the first month of treatment, optimal serum levels of thyroxine (T4) and free thyroxine (FT₄) were achieved in all groups, however, only patients from group 3 were able to normalize thyrotropin (TSH) (group 1, 16.0 ± 12.0; group 2, 9.2 ± 10.0; and group 3, 2.4 ± 3.3 mU/L; p < 0.0001). Twelve patients from group 2 treated with an initial LT₄ dose above 9 μg/kg per day were able to normalize TSH levels within the first 3 months of life and this resulted in a better IQ (97 ± 16) compared to the remaining patients from the same group (IQ 90 ± 9). In the whole group of 83 patients the IQ at 4 years of age was positively correlated to both initial LT₄ dosage (r = 0.27, p < 0.02) and FT₄ concentrations after the first month of treatment (r = 0.29, p < 0.02), and negatively correlated to TSH concentrations after the first month of treatment (r = -0.27, p < 0.02). No significant differences were observed in height, weight, head circumference, and bone age maturation among the three groups of patients. No clinical signs or symptoms of overtreatment were observed during follow-up in patients receiving the higher LT₄ dosage. Our results indicate that high LT₄ starting doses rapidly normalize serum TSH concentrations resulting in an improvement of the IQ at 4 years of age, even in patients with severe CH at diagnosis. Growth and bone age maturation are not affected by such a high dose.

MicroRNAs (miRNA) are small-non coding RNAs endowed with great regulatory power, thus playing key roles not only in almost all physiological pathways, but also in the pathogenesis of several diseases. Surprisingly, genomic distribution analysis revealed the highest density of miRNA sequences on the X chromosome; this evolutionary conserved mammalian feature equips females with a larger miRNA machinery than males. However, miRNAs contribution to some X-related conditions, properties or functions is still poorly explored. With the aim to support and focus research in the field, this review analyzes the literature and databases about X-linked miRNAs, trying to understand how miRNAs could contribute to emerging gender-biased functions and pathological mechanisms, such as immunity and cancer. A fine map of miRNA sequences on the X chromosome is reported, and their known functions are discussed; in addition, bioinformatics functional analyses of the whole X-linked miRNA targetome (predicted and validated) were performed. The emerging scenario points to different gaps in the knowledge that should be filled with future experimental investigations, also in terms of possible implications and pathological perspectives for X chromosome aneuploidy syndromes, such as Turner and Klinefelter syndromes.

Context: GH deficiency (GHD) in adults is associated with a cluster of cardiovascular risk factors that may contribute to an increased mortality for cardiovascular disease. Objective: The aim of this study was to evaluate the effect of GHD and GH replacement therapy on cardiac performance, lipid profile, and insulin resistance in children. Design: This was a 2-yr case-control prospective study. Patients: Thirty children with GHD aged 9.3 ± 0.5 yr and 30 healthy matched controls were studied. Intervention: Children were studied before and after 1 and 2 yr of GH replacement (GHD children) or no treatment (controls). Main Outcome Measures: Lipid profile, serum insulin levels, homeostasis model of assessment (HOMA) index, and left ventricular (LV) mass and function by echocardiography were the main outcome measures. Results: At study entry, the LV mass index was significantly lower in GHD children (50.2 ± 1.7) than in controls (60.3 ± 2.5 g/m²; P < 0.002), whereas LV systolic and diastolic function, lipid profile, insulin levels, and HOMA index were similar. In GHD children LV mass index significantly increased (66.3 ± 2.4 g/m²; P < 0.0001) after 1 yr of GH replacement and remained stable thereafter. LV systolic and diastolic function did not change during treatment. After 2 yr of GH replacement, total cholesterol (P < 0.007) and the atherogenic index (P < 0.0001) significantly decreased, whereas fasting insulin levels (P < 0.001) and HOMA index (P < 0.0001) significantly increased compared with both pretreatment and control values. Conclusions: GHD in children is associated with a reduced cardiac size but with a normal cardiac function, lipid profile, and insulin sensitivity. Two years of GH replacement normalizes cardiac morphology, improves lipid profile, and slightly impairs insulin sensitivity.

Objective: To investigate the effect of levothyroxine (L-T4) treatment on early markers of atherosclerotic disease in children with mild idiopathic subclinical hypothyroidism (SH). Design: Two-year, open, case–control prospective study. Methods: A total of 39 children, aged 9.18±3.56 years, with SH and 39 healthy controls were enrolled in the study. Waist-to-height ratio (WHtR), blood pressure, triglycerides, total cholesterol (total-C), HDL-C, LDL-C, non-HDL-C, triglycerides/HDL-C, atherogenic index (AI), homocysteine (Hcy), asymmetric dimethylarginine (ADMA), flow-mediated dilation (FMD) and intima–media thickness (IMT) were evaluated at baseline and after 2 years of L-T4 treatment in SH children and after 2 years of follow-up in controls. Results: At study entry WHtR was higher in SH subjects compared with controls (0.56±0.08 vs 0.49±0.07, P=0.04) and significantly decreased after 2 years of treatment (0.50±0.06, P<0.0001). Mean HDL-C levels (50.47±11.43 vs 61.06±13.83mg/dL, P=0.002) were lower, while triglycerides/HDL-C (1.63±1.07 vs 1.19±0.69, P=0.05), AI (3.32±0.90 vs 2.78±0.68, P=0.005), and Hcy (9.35±2.61 vs 7.71±1.94μmol/L, P=0.01) were higher in SH subjects compared with controls and improved after 2 years of treatment (HDL-C 56.26±13.76mg/dL, P<0.0001; triglycerides/HDL-C 1.23±0.78, P=0.006; AI 2.82±0.68, P<0.0001; and Hcy 8.25±2.09μmol/L, P=0.06). ADMA concentrations at baseline were higher in SH subjects compared with controls (0.77±0.21 vs 0.60±0.16μmol/L, P=0.001) and decreased after therapy (0.58±0.13μmol/L, P<0.0001). FMD, IMT and other metabolic parameters were not different among SH subjects and controls at baseline and after 2 years. Conclusions: Children with SH may have subtle pro-atherogenic abnormalities. Although L-T4 treatment exerts some beneficial effects, the long-term impact of therapy on metabolic outcomes in SH children still remains unclear.

Subclinical hypothyroidism (SH) is biochemically defined as serum TSH levels above the upper limit of the reference range in the presence of normal free T4 (FT4) concentrations. While there is a general agreement to treat subjects with serum TSH levels above 10 mU/L, the management of mild form (TSH concentrations between 4.5 and 10 mU/L) is still a matter of debate. In children, mild SH is often a benign and remitting condition and the risk of progression to overt thyroid dysfunction depends on the underlying condition, being higher in the autoimmune forms. The major concern is to establish whether SH in children should always be considered an expression of mild thyroid dysfunction and may deserve treatment. Current data indicate that children with mild SH have normal linear growth, bone health and intellectual outcome. However, slight metabolic abnormalities and subtle deficits in specific cognitive domains have been reported in children with modest elevation of TSH concentration. Although these findings are not sufficient to recommend levothyroxine treatment for all children with mild SH, they indicate the need for regular monitoring to ensure early identification of children who may benefit from treatment. In the meanwhile, the decision to initiate therapy in children with mild SH should be based on individual factors.