Plasma and urine metabolic fingerprinting of type 1 diabetic children.

Type 1 diabetes mellitus is one of the most common chronic disorders of childhood. The metabolic control is lost due to the lack of insulin, which is the main treatment for the disease. Nevertheless, long-term complications appear even under good glycemic control. Metabolomics, an emerging strategy, can help in diagnosis, prognosis, and monitoring of metabolic disorders. The objective of the present study was to investigate the alterations in plasma (by LC-MS) and urine (CE-MS) of type 1 diabetic children that were under insulin treatment and good glycemic control. Even without remarkable biochemical differences between the two groups (diabetic and control) except for glucose level and glycosilated hemoglobin, metabolomic tools were able to capture subtle metabolic differences. The main changes in plasma were associated to lipidic metabolism (nonesterified fatty acids, lysophospholipids, and other derivatives of fatty acids), and some markers of the differential activity of the gut microflora were also found (bile acids, p-cresol sulfate). In urine, changes associated to protein and amino acid metabolism were found (amino acids, their metabolites and derivatives), and among them one advanced glycation end product (carboxyethylarginine) and one early glycation end product (fructosamine) were excreted in higher proportion in the diabetic group.

CDKN1C (p57(Kip2)) analysis in Beckwith-Wiedemann syndrome (BWS) patients: Genotype-phenotype correlations, novel mutations, and polymorphisms.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by macroglossia, macrosomia, and abdominal wall defects. It is a multigenic disorder caused in most patients by alterations in growth regulatory genes. A small number of individuals with BWS (5-10%) have mutations in CDKN1C, a cyclin-dependent kinase inhibitor of G1 cyclin complexes that functions as a negative regulator of cellular growth and proliferation. Here, we report on eight patients with BWS and CDKN1C mutations and review previous reported cases. We analyzed 72 patients (50 BWS, 17 with isolated hemihyperplasia (IH), three with omphalocele, and two with macroglossia) for CDKN1C defects with the aim to search for new mutations and to define genotype-phenotype correlations. Our findings suggest that BWS patients with CDKN1C mutations have a different pattern of clinical malformations than those with other molecular defects. Polydactyly, genital abnormalities, extra nipple, and cleft palate are more frequently observed in BWS with mutations in CDKN1C. The clinical observation of these malformations may help to decide which genetic characterization should be undertaken (i.e., CDKN1C screening), thus optimizing the laboratory evaluation for BWS.

Follow-up and risk of tumors in overgrowth syndromes.

A striking feature of the overgrowth syndromes (OGS) is the risk of cancer. In some OGS (Beckwith-Wiedemann, Perlman, Simpson-Golabi-Behmel syndromes and hemihypertrophy) tumors appeared mostly in the abdomen (more than 94% of tumors), are usually diagnosed before 10 years, and most of them are embryonal. Conversely, in other OGS, such as Sotos syndrome, the most frequent type is lympho-hematological tumors, about two-thirds are extra-abdominal and some of these tumors may appear after the second decade of life. Based on a previous literature review, a specific schedule protocol for tumor screening was suggested for many OGS. In this article we briefly review some aspects of the current knowledge of OGS and tumors, emphasizing the follow-up of these disorders.

Individualised vs fixed dose of oral 17ß-oestradiol for induction of puberty in girls with Turner syndrome: an open-randomised parallel trial.

CONTEXT: Oestrogen induction of pubertal changes in Turner girls may reinforce their psychological well-being and may also optimise final height; however, oestrogen type, dose, and route are not well established. OBJECTIVE: To induce normal pubertal development in Turner girls and ovarian insufficiency with oral 17ß-oestradiol (E(2)), either as individualised dose (ID) or as fixed dose (FD), and to determine whether growth is affected. DESIGN: Open-label randomised, parallel groups, multicentre clinical trial in 48 GH-treated Turner girls. Oral E(2) was given in tablets, either as an ID of 5-15 µg/kg per day during 2 years or as a FD of 0.2 mg daily during the first year followed by 0.5 mg daily during the second year. Main outcome measures were the event of attaining a Tanner breast staging ≥4 (primary), FSH, and auxological variables (secondary). RESULTS: Shorter median time to Tanner staging ≥ B4 in the FD group (733 days) compared with the ID group (818 days) (P=0.046). Higher proportion of girls with Tanner staging ≥ B4 (65%) in the FD group compared with the ID group (42%) (P=0.068). Bone age did not show inadequate acceleration and adult height prediction was maintained in both groups. No oestrogen-related adverse events were reported. CONCLUSIONS: Two-year treatment with oral E(2) can progressively induce normal pubertal development in Turner syndrome. Low-dose oral E(2) given as a FD produces a satisfactory pubertal development not inferior to ID. Treatment was well tolerated and did not interfere with the growth-promoting effect of GH.

Beckwith-Wiedemann syndrome and uniparental disomy 11p: fine mapping of the recombination breakpoints and evaluation of several techniques.

Beckwith-Wiedemann syndrome (BWS) is a phenotypically and genotypically heterogeneous overgrowth syndrome characterized by somatic overgrowth, macroglossia and abdominal wall defects. Other usual findings are hemihyperplasia, embryonal tumours, adrenocortical cytomegaly, ear anomalies, visceromegaly, renal abnormalities, neonatal hypoglycaemia, cleft palate, polydactyly and a positive family history. BWS is a complex, multigenic disorder associated, in up to 90% of patients, with alteration in the expression or function of one or more genes in the 11p15.5 imprinted gene cluster. There are several molecular anomalies associated with BWS and the large proportion of cases, about 85%, is sporadic and karyotypically normal. One of the major categories of BWS molecular alteration (10-20% of cases) is represented by mosaic paternal uniparental disomy (pUPD), namely patients with two paternally derived copies of chromosome 11p15 and no maternal contribution for that. In these patients, in addition to the effects of IGF2 overexpression, a decreased level of the maternally expressed gene CDKN1C may contribute to the BWS phenotype. In this paper, we reviewed a series of nine patients with BWS because of pUPD using several methods with the aim to evaluate the percentage of mosaicism, the methylation status at both loci, the extension of the pUPD at the short arm and the breakpoints of recombination. Fine mapping of mitotic recombination breakpoints by single-nucleotide polymorphism-array in individuals with UPD and fine estimation of epigenetic defects will provide a basis for understanding the aetiology of BWS, allowing more accurate prognostic predictions and facilitating management and surveillance of individuals with this disorder.

Metabolomic approach to the nutraceutical effect of rosemary extract plus Ω-3 PUFAs in diabetic children with capillary electrophoresis.

Type 1 diabetes mellitus is a major endocrine disorder, affecting approximately 5% of the world's population. It not only leads to hyperglycaemia but also causes many complications, and numerous studies have demonstrated that oxidative stress contributes to these complications. As a new strategy to improve the oxidative damage in diabetes, interest has grown in the usage of natural antioxidants, even more in the long term. Among them, Rosmarinus officinalis (rosemary) has been widely accepted as one of the species with the highest antioxidant activity. In addition, omega-3 polyunsaturated fatty acids were efficient in delaying and decreasing cardiovascular risk factors associated with diabetes. Type 1 diabetic children and the corresponding controls were enrolled in the assay. The aim was evaluating the effect of a special additive containing rosemary extract, vitamin E and PUFAs added to their standard diet through the meat. In the analytical point of view, a metabolomic approach with CE-UV was used to detect possible differences in urine of diabetic children as compared to controls. After the application of the appropriate multivariate statistical tools, clear differences could be observed between treated and non-treated diabetic children and some of the metabolites associated could be identified. This was specially challenging as most of the clinical biochemical parameters measured by target analysis showed no differences between the groups.

Impact of heterozygosity for acid-labile subunit (IGFALS) gene mutations on stature: results from the international acid-labile subunit consortium.

CONTEXT: To date, 16 IGFALS mutations in 21 patients with acid-labile subunit (ALS) deficiency have been reported. The impact of heterozygosity for IGFALS mutations on growth is unknown. OBJECTIVE: The study evaluates the impact of heterozygous expression of IGFALS mutations on phenotype based on data collected by the International ALS Consortium. SUBJECTS/METHODS: Patient information was derived from the IGFALS Registry, which includes patients with IGFALS mutations and family members who were either heterozygous carriers or homozygous wild-type. Within each family, the effect of IGFALS mutations on stature was analyzed as follows: 1) effect of two mutant alleles (2ALS) vs. wild-type (WT); 2) effect of two mutant alleles vs. one mutant allele (1ALS); and 3) effect of one mutant allele vs. wild-type. The differences in height sd score (HtSDS) were then pooled and evaluated. RESULTS: Mean HtSDS in 2ALS was -2.31 +/- 0.87 (less than -2 SDS in 62%); in 1ALS, -0.83 +/- 1.34 (less than -2 SDS in 26%); and in WT, -1.02 +/- 1.04 (less than -2 SDS in 12.5%). When analyses were performed within individual families and pooled, the difference in mean HtSDS between 2ALS and WT was -1.93 +/- 0.79; between 1ALS and WT, -0.90 +/- 1.53; and between 2ALS and 1ALS, -1.48 +/- 0.83. CONCLUSIONS: Heterozygosity for IGFALS mutations results in approximately 1.0 SD height loss in comparison with wild type, whereas homozygosity or compound heterozygosity gives a further loss of 1.0 to 1.5 SD, suggestive of a gene-dose effect. Further studies involving a larger cohort are needed to evaluate the impact of heterozygous IGFALS mutations not only on auxology, but also on other aspects of the GH/IGF system.