Endocrine disorders in childhood and adolescence. Natural history of subclinical hypothyroidism in children and adolescents and potential effects of replacement therapy: a review.

OBJECTIVE: Subclinical hypothyroidism (SH) is quite common in children and adolescents. The natural history of this condition and the potential effects of replacement therapy need to be known to properly manage SH. The aim of this review is to analyse: 1) the spontaneous evolution of SH, in terms of the rate of reversion to euthyroidism the persistence of SH or the progression to over hypothyroidism; 2) the effects of replacement therapy, with respects to auxological data, thyroid volume and neuropsychological functions. Methods: We systematically searched PubMed, Cochrane and EMBASE (1990 to 2012) and identified 39 potentially relevant articles of which only 15 articles were suitable to be included. Results and Conclusions: SH in children is a remitting process with a low risk of evolution toward overt hypothyroidism. Most of the subjects reverted to euthyroidism or remained SH, with a rate of evolution toward overt hypothyroidism ranging between 0% to 28.8%, being 50% in only one study (9 articles). The initial presence of goiter and elevated thyroglobulin-antibodies, the presence of coeliac disease and a progressive increase in thyroperoxidase-antibodies and TSH value predict a progression toward overt hypothyroidism. Replacement therapy is not justified in children with SH but with TSH 5-10 mIU/L, no goiter and negative anti-thyroid antibodies. An increased growth velocity was shown in children treated with levothyroxine (2 articles). Levothyroxine reduced thyroid volume in 25% to 100% of children with SH and autoimmune thyroiditis (2 studies). No effects on neuropsychological functions (one study) and post-treatment evolution of SH (one study) were reported

Pediatric obesity and vitamin D deficiency: a proteomic approach identifies multimeric adiponectin as a key link between these conditions.

Key circulating molecules that link vitamin D (VD) to pediatric obesity and its co-morbidities remain unclear. Using a proteomic approach, our objective was to identify key molecules in obese children dichotomized according to 25OH-vitamin D (25OHD) levels. A total of 42 obese children (M/F = 18/24) were divided according to their 25OHD3 levels into 25OHD3 deficient (VDD; n = 18; 25OHD<15 ng/ml) or normal subjects (NVD; n = 24; >30 ng/ml). Plasma proteomic analyses by two dimensional (2D)-electrophoresis were performed at baseline in all subjects. VDD subjects underwent a 12mo treatment with 3000 IU vitamin D3 once a week to confirm the proteomic analyses. The proteomic analyses identified 53 "spots" that differed between VDD and NVD (p<0.05), amongst which adiponectin was identified. Adiponectin was selected for confirmational studies due to its tight association with obesity and diabetes mellitus. Western Immunoblot (WIB) analyses of 2D-gels demonstrated a downregulation of adiponectin in VDD subjects, which was confirmed in the plasma from VDD with respect to NVD subjects (p<0.035) and increased following 12mo vitamin D3 supplementation in VDD subjects (p<0.02). High molecular weight (HMW) adiponectin, a surrogate indicator of insulin sensitivity, was significantly lower in VDD subjects (p<0.02) and improved with vitamin D3 supplementation (p<0.042). A direct effect in vitro of 1α,25-(OH)2D3 on adipocyte adiponectin synthesis was demonstrated, with adiponectin and its multimeric forms upregulated, even at low pharmacological doses (10(-9) M) of 1α,25-(OH)2D3. This upregulation was paralleled by the adiponectin interactive protein, DsbA-L, suggesting that the VD regulation of adiponectin involves post-transciptional events. Using a proteomic approach, multimeric adiponectin has been identified as a key plasma protein that links VDD to pediatric obesity

Pediatric obesity and vitamin D deficiency: a proteomic approach identifies multimeric adiponectin as a key link between these conditions.

Key circulating molecules that link vitamin D (VD) to pediatric obesity and its co-morbidities remain unclear. Using a proteomic approach, our objective was to identify key molecules in obese children dichotomized according to 25OH-vitamin D (25OHD) levels. A total of 42 obese children (M/F = 18/24) were divided according to their 25OHD3 levels into 25OHD3 deficient (VDD; n = 18; 25OHD<15 ng/ml) or normal subjects (NVD; n = 24; >30 ng/ml). Plasma proteomic analyses by two dimensional (2D)-electrophoresis were performed at baseline in all subjects. VDD subjects underwent a 12mo treatment with 3000 IU vitamin D3 once a week to confirm the proteomic analyses. The proteomic analyses identified 53 "spots" that differed between VDD and NVD (p<0.05), amongst which adiponectin was identified. Adiponectin was selected for confirmational studies due to its tight association with obesity and diabetes mellitus. Western Immunoblot (WIB) analyses of 2D-gels demonstrated a downregulation of adiponectin in VDD subjects, which was confirmed in the plasma from VDD with respect to NVD subjects (p<0.035) and increased following 12mo vitamin D3 supplementation in VDD subjects (p<0.02). High molecular weight (HMW) adiponectin, a surrogate indicator of insulin sensitivity, was significantly lower in VDD subjects (p<0.02) and improved with vitamin D3 supplementation (p<0.042). A direct effect in vitro of 1α,25-(OH)2D3 on adipocyte adiponectin synthesis was demonstrated, with adiponectin and its multimeric forms upregulated, even at low pharmacological doses (10(-9) M) of 1α,25-(OH)2D3. This upregulation was paralleled by the adiponectin interactive protein, DsbA-L, suggesting that the VD regulation of adiponectin involves post-transciptional events. Using a proteomic approach, multimeric adiponectin has been identified as a key plasma protein that links VDD to pediatric obesity

A novel familial variation of the thyroid hormone receptor beta gene (I276N) associated with resistance to thyroid hormone.

Background: Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome characterized by reduced organ responsiveness to thyroid hormone, with elevated thyroid hormone levels and unsuppressed TSH concentrations, and a widely variable clinical phenotype. RTH is most frequently caused by point mutations in the thyroid hormone receptor beta gene (THRB). We report the case of a child and her mother with different clinical signs in presence of high thyroid hormone and normal TSH levels with positive anti-thyroid antibodies, both carrying a novel variation of THRB. Patient findings: A 3-year-old girl presented to our Pediatric Endocrinology Unit with statural and ponderal growth retardation since the first months of life and biochemical findings of elevated thyroid hormone levels with unsuppressed TSH, in presence of an unusual positivity to anti-thyroperoxidase antibodies for age. Molecular analysis of THRB gene identified a novel missense variation in exon 8 in the heterozygous state (I276N). The child's mother, a 42-year-old women, reported from 25-years of age a history of tachycardia, high stool frequency and goiter, elevated fT3 and fT4 with normal TSH, increased levels of anti-thyroperoxidase and anti-thyroglobulin antibodies and a thyroid ultrasound and cytological pattern suggestive for lymphocytic thyroiditis. The same THRB variation was identified also in the mother in the heterozygous state. Summary: We described the case of a child and her mother affected by RTH presenting with different clinical phenotype even if they carried an identical novel THRB missense variation. In both of them RTH was associated with the presence of anti-thyroid antibodies. Conclusions: RTH should be suspected every time elevated thyroid hormones and unsuppressed TSH are found, independently of the clinical phenotype, even in association with an autoimmune thyroiditis

Compound heterozygosity for two GHR missense mutations in a patient affected by Laron Syndrome: a case report

Abstract Background Mutations localized in the Growth Hormone Receptor (GHR) gene are often associated with the pathogenesis of Laron Syndrome, an autosomal recessive hereditary disorder characterized by severe growth retardation. Biochemically, patients present normal to high circulating GH levels, in presence of very low or undetectable IGF-I levels, which do not rise after rhGH treatment. Case presentation We describe the case of a 3.8 years old girl with symmetrical short stature (−3.76 SDS), low IGF-1 and IGFBP-3, in presence of normal GH levels. Parents were not relatives and there was no family history of short stature. During the second day of birth, she developed severe hypoglycaemia that required glucose infusion. She presented frontal bossing and depressed nasal bridge. IGF-1 generation test showed no response, suggesting a GH resistance evidence. In the hypothesis of Laron Syndrome, we decided to perform a molecular analysis of Growth Hormone Receptor (GHR) gene. This analysis demonstrated that the patient was compound heterozygote for two missense mutations. Conclusions GHR gene mutations are a well demonstrated cause of GH insensitivity. In heterozygous patients, probably the normal stature may be achieved by a compensatory mechanism of GH secretion or signalling. On the contrary, in homozygous or compound heterozygous patients these compensatory mechanisms are inadequate, and short stature may be the consequence

Obestatin levels are associated with C-peptide and anti-insulin antibodies at the onset whereas unacylated and acylated ghrelin levels are not predictive of long-term metabolic control in children with type 1 diabetes.

Context and objective: Ghrelin secretion is altered at the onset and after the start of insulin therapy in children with type 1 diabetes. Contemporary regulation of acylated (AG), unacylated ghrelin (UAG) and obestatin (OBST) remains undefined in this disease. It is unknown as to whether they could be good predictors of changes in glucose and metabolic control. Design, setting and subjects: A longitudinal study in a tertiary care center. AG, UAG and OBST were measured at baseline and after 2 years of follow-up in 51 children and adolescents with a history of type 1 diabetes extending beyond 1 year. A total of 33 healthy matched subjects were used as controls. Results: Age, puberty and BMI adjusted UAG levels were lower (p<0.005) and OBST levels were higher (p<0.009) in children with type 1 diabetes, with respect to controls. AG levels were similar to controls, but all ratios of three peptides are altered in diabetic patients. OBST (p<0.05) was negatively correlated with C-peptide (p<0.05) and IAA (p<0.008) at the onset of diabetes. In diabetic patients, baseline AG and UAG levels were negatively correlated with insulin dosage in the short- and long-term (p<0.001). AG, but not OBST, was positively correlated with C-peptide levels 2 years after diagnosis (p<0.05). Overall, the peptides were not predictive of glucose and metabolic control. Conclusions: UAG, AG, OBST and their ratios are differently regulated in children with type 1 diabetes suggesting a role in the metabolic balance of the disease, with insulin a likely regulator of AG and UAG. The peptides do not appear to be good long-term predictors of glucose control, with further investigations needed to explain if OBST could be a precocious predictor of islet dysfunction

Adiponectin oligomers are similarly distributed in adequate-for-gestational-age obese children irrespective of feeding in their first year

Nutrition and growth in early postnatal life have a role in future diseases. Our aim was to investigate adiponectin oligomers in adequate-for-gestational-age obese children with respect to type and duration of feeding in the first year of life

WIB of proteomic analyses and plasma samples confirms that total adiponectin is decreased in VD deficient pediatric obese subjects (VDD) when compared to pediatric obese with normal VD levels (NVD).

<p><b>A.</b> A WIB of 2D-electrophoretic analyses was performed in VDD (n = 10) and NVD (n = 10) subjects using anti-adiponectin antibody. <b>B.</b> A WIB analysis under reduced conditions of total adiponectin in the plasma of representative VDD (<15 ng/ml) and NVD (>30 ng/ml) subjects.</p