Chiara De Leonibus

Update on statural growth and pubertal development in obese children

Childhood obesity is a growing and alarming problem, associated with several short-term and long-term metabolic and cardiovascular complications. In addition, it has also been suggested that excess adiposity during childhood influences growth and pubertal development. Several studies have shown that during pre-pubertal years, obese patients present higher growth velocity and that this pre-pubertal advantage tends to gradually decrease during puberty, leading to similar final heights between obese and non-obese children. Excess body weight might also influence pubertal onset, leading to earlier timing of puberty in girls. In addition, obese girls are at increased risk of hyperandrogenism and polycystic ovary syndrome. In boys, a clear evidence does not exist: some studies suggesting an earlier puberty associated with the obesity status, whereas other have found a delayed pubertal onset. Overall, the existing evidence of an association between obesity and modification of growth and pubertal patterns underlines a further reason for fighting the epidemics of childhood obesity.

Hypophosphatasia in a child with widened anterior fontanelle: lessons learned from late diagnosis and incorrect treatment

Hypophosphatasia is characterized by deficiency of serum alkaline phosphatase with defective bone and teeth mineralization. We report on an 11‐month‐old boy who developed a complex clinical picture characterized by bulging anterior fontanelle, growth failure, nephrocalcinosis and impaired bone mineralization during high‐dose calcium and vitamin D supplementation. This therapy had been started 5u2003months earlier for a presumed diagnosis of nutritional rickets established on the grounds of isolated widened anterior fontanelle. However, laboratory investigations revealed reduced alkaline phosphatase levels associated with hypercalcemia, hypercalciuria, low PTH and normal 25‐hydroxy vitamin D levels. Genetic testing detected a compound heterozygote for the novel mutation (c.262G>A) and the described mutation (c.920C>T) in the ALPL gene.

Pediatric perspective on pharmacogenomics

The advances in high-throughput genomic technologies have improved the understanding of disease pathophysiology and have allowed a better characterization of drug response and toxicity based on individual genetic make up. Pharmacogenomics is being recognized as a valid approach used to identify patients who are more likely to respond to medication, or those in whom there is a high probability of developing severe adverse drug reactions. An increasing number of pharmacogenomic studies are being published, most include only adults. A few studies have shown the impact of pharmacogenomics in pediatrics, highlighting a key difference between children and adults, which is the contribution of developmental changes to therapeutic responses across different age groups. This review focuses on pharmacogenomic research in pediatrics, providing examples from common pediatric conditions and emphasizing their developmental context.

Brugada Syndrome Unmasked by Febrile Illness in an Asymptomatic Child

4-year-old boy was admitted to the hospital for fever, cough, and chest pain in the last 2 days. Chest radiograph showed pneumonia of the lower left lobe, and antimicrobial medication was administered. Of note, an electrocardiogram (ECG) was performed while the patient had a fever, which revealed coved ST-segment elevation >2 mm in right precordial V1-V2 leads and incomplete right bundlebranch block, compatible with type 1 Brugada syndrome pattern (Figure). This ECG pattern disappeared as the patient’s fever subsided. Echocardiogram excluded structural anomalies. Family history revealed sudden death in a maternal 9-month-old sister and a 5-month-old cousin; no episodes of syncope or arrhythmia were referred. The whole family was screened for Brugada syndrome, and his mother resulted positive. Genetic analysis in the child excluded SCN5A gene mutations. No long-term treatment was started because the patient was asymptomatic and at low risk for sudden death, given his asymptomatic Brugada syndrome ECGpatternduringfeverandhisnegativehistoryforsyncope. Brugada syndrome accounts for 20% of sudden death in young adults, with a prevalence in children of 3 per 10000. 1 Brugada syndrome is inherited in an autosomal-dominant manner 2 and is attributable to cardiac sodium channel muta

Influence of inhaled corticosteroids on pubertal growth and final height in asthmatic children.

Controversial data exist on the possibility that inhaled corticosteroids (ICs) affect growth in children with mild‐to‐moderate asthma. We assessed whether ICs affect growth and final height (FH) in asthmatic children compared to controls.

Growth Hormone Deficiency in Prepubertal Children: Predictive Markers of Cardiovascular Disease

Background: Cardiovascular (CV) risk factors have been identified in adults with untreated growth hormone deficiency (GHD). Existing evidence suggests that the development of the atheromatous plaque begins early in childhood. Previous reports have shown that GHD children are prone to increased CV risks including impaired cardiac function, dyslipidemia and abnormalities in body composition. Recent studies in epigenetics and metabolomics have defined specific fingerprints that might be associated with an increased risk of CV disease. Aim: The aim of this review is to point out the most significant biochemical and clinical predictive markers of CV disease in prepubertal children and to evaluate the effect of recombinant human growth hormone therapy on most of these alterations. The novel findings in epigenetics and metabolomics are also reviewed, with a particular focus on translating them into clinical practice.

Network analysis and juvenile idiopathic arthritis (JIA): a new horizon for the understanding of disease pathogenesis and therapeutic target identification

Juvenile idiopathic arthritis (JIA) is a clinically diverse and genetically complex autoimmune disease. Currently, there is very limited understanding of the potential underlying mechanisms that result in the range of phenotypes which constitute JIA.The elucidation of the functional relevance of genetic associations with phenotypic traits is a fundamental problem that hampers the translation of genetic observations to plausible medical interventions. Genome wide association studies, and subsequent fine-mapping studies in JIA patients, have identified many genetic variants associated with disease. Such approaches rely on ‘tag’ single nucleotide polymorphisms (SNPs). The associated SNPs are rarely functional variants, so the extrapolation of genetic association data to the identification of biologically meaningful findings can be a protracted undertaking. Integrative genomics aims to bridge the gap between genotype and phenotype.Systems biology, principally through network analysis, is emerging as a valuable way to identify biological pathways of relevance to complex genetic diseases. This review aims to highlight recent findings in systems biology related to JIA in an attempt to assist in the understanding of JIA pathogenesis and therapeutic target identification.

The in vitro functional analysis of single-nucleotide polymorphisms associated with growth hormone (GH) response in children with GH deficiency

Response to recombinant human growth hormone (r-hGH) in the first year of therapy has been associated with single-nucleotide polymorphisms (SNPs) in children with GH deficiency (GHD). Associated SNPs were screened for regulatory function using a combination of in silico techniques. Four SNPs in regulatory sequences were selected for the analysis of in vitro transcriptional activity (TA). There was an additive effect of the alleles in the four genes associated with good growth response. For rs3110697 within IGFBP3, rs1045992 in CYP19A1 and rs2888586 in SOS1, the variant associated with better growth response showed higher TA with r-hGH treatment. For rs1024531 in GRB10, a negative regulator of IGF-I signalling and growth, the variant associated with better growth response had a significantly lower TA on r-hGH stimulation. These results indicate that specific SNP variants have effects on TA that provide a rationale for their clinical impact on growth response to r-hGH therapy.

Transcriptomics and machine learning predict diagnosis and severity of growth hormone deficiency

BACKGROUNDnThe effect of gene expression data on diagnosis remains limited. Here, we show how diagnosis and classification of growth hormone deficiency (GHD) can be achieved from a single blood sample using a combination of transcriptomics and random forest analysis.nnnMETHODSnPrepubertal treatment-naive children with GHD (n = 98) were enrolled from the PREDICT study, and controls (n = 26) were acquired from online data sets. Whole blood gene expression was correlated with peak growth hormone (GH) using rank regression and a random forest algorithm tested for prediction of the presence of GHD and in classification of GHD as severe (peak GH <4 μg/l) and nonsevere (peak ≥4 μg/l). Performance was assessed using area under the receiver operating characteristic curve (AUC-ROC).nnnRESULTSnRank regression identified 347 probe sets in which gene expression correlated with peak GH concentrations (r = ± 0.28, P < 0.01). These 347 probe sets yielded an AUC-ROC of 0.95 for prediction of GHD status versus controls and an AUC-ROC of 0.93 for prediction of GHD severity.nnnCONCLUSIONnThis study demonstrates highly accurate diagnosis and disease classification for GHD using a combination of transcriptomics and random forest analysis.nnnTRIAL REGISTRATIONnNCT00256126 and NCT00699855.nnnFUNDINGnMerck and the National Institute for Health Research (CL-2012-06-005).

Acquired cross-linker resistance associated with a novel spliced BRCA2 protein variant for molecular phenotyping of BRCA2 disruption

BRCA2 encodes a protein with a fundamental role in homologous recombination that is essential for normal development. Carrier status of mutations in BRCA2 is associated with familial breast and ovarian cancer, while bi-allelic BRCA2 mutations can cause Fanconi anemia (FA), a cancer predisposition syndrome with cellular cross-linker hypersensitivity. Cancers associated with BRCA2 mutations can acquire chemo-resistance on relapse. We modeled acquired cross-linker resistance with an FA-derived BRCA2-mutated acute myeloid leukemia (AML) platform. Associated with acquired cross-linker resistance was the expression of a functional BRCA2 protein variant lacking exon 5 and exon 7 (BRCA2ΔE5+7), implying a role for BRCA2 splicing for acquired chemo-resistance. Integrated network analysis of transcriptomic and proteomic differences for phenotyping of BRCA2 disruption infers impact on transcription and chromatin remodeling in addition to the DNA damage response. The striking overlap with transcriptional profiles of FA patient hematopoiesis and BRCA mutation associated ovarian cancer helps define and explicate the ‘BRCAness’ profile.