Arianna Maiorana

Impact of Growth Hormone Therapy on Adult Height of Children Born Small for Gestational Age

CONTEXT: Use of growth hormone (GH) therapy to promote growth in short children born small for gestational age (SGA) was recently approved in the United States and Europe, but there is still disagreement about the magnitude of effectiveness of GH. OBJECTIVE: To determine the impact of GH therapy on adult height in short SGA children by a meta-analysis of randomized, controlled trials (RCTs). METHODS: We performed a systematic review of controlled studies using as data sources the Cochrane Central Register of Controlled Trials, Medline, and the bibliographic references from all retrieved articles describing RCTs up to November 2008. A meta-analysis of all RCT studies conducted up to the achievement of adult height was performed. Inclusion criteria were birth weight and/or length below −2 SD score (SDS), initial height less than −2 SDS, and GH dose range of 33 to 67 μg/kg per day. Adult height SDS and overall height gain SDS were the primary outcome measures. RESULTS: Four RCTs (391 children) met the inclusion criteria. The adult height of the GH-treated group significantly exceeded controls by 0.9 SDS. Mean height gain was 1.5 SDS in treated versus 0.25 SDS in untreated SGA subjects. No significant difference in adult height was observed between the 2 GH dose regimens. CONCLUSIONS: GH therapy seems to be an effective approach to partially reduce the adult height deficit in short SGA children. However, the response to therapy is highly variable, and additional studies are needed to identify the responders.

Insulin Resistance and Insulin-Like Growth Factors in Children with Intrauterine Growth Retardation

Aims: To investigate (a) the prevalence of insulin resistance in children with intrauterine growth retardation (IUGR); (b) whether catch-up growth is associated with a higher risk of insulin resistance; (c) the insulin-like growth factor (IGF) system status. Methods: 49 children with IUGR aged 9.1 ± 3.3 years underwent anthropometric measurements, and assessment of insulin resistance and IGF system parameters. A fasting glucose/insulin ratio (G/I) <6 was chosen as suggestive of insulin resistance. Results: 11/49 (22%) children had a G/I <6. Postnatal growth closely correlated with birth size and actual body mass index (BMI). None of the insulin resistance parameters was related to linear growth and BMI. Liver function markers were significantly related to insulin sensitivity status. The IGF system status was normal and did not correlate with insulin resistance indicators. Conclusions: (a) Children with IUGR have a high prevalence of reduced insulin sensitivity; (b) postnatal catch-up growth is related to intrauterine growth and actual nutritional status; (c) insulin sensitivity status is not related to postnatal growth but to liver function; (d) IGF system is normal and not related to the insulin resistance parameters during childhood.

Preemptive liver transplantation in a child with familial hypercholesterolemia

Maiorana A, Nobili V, Calandra S, Francalanci P, Bernabei S, El Hachem M, Monti L, Gennari F, Torre G, de Ville de Goyet J, Bartuli A. Preemptive liver transplantation in a child with familial hypercholesterolemia.
Pediatr Transplantation 2011: 15:E25–E29.

Adipose Tissue: A Metabolic Regulator. Potential Implications for the Metabolic Outcome of Subjects Born Small for Gestational Age (SGA).

Adipose tissue is involved in the regulation of glucose and lipid metabolism, energy balance, inflammation and immune response. Abdominal obesity plays a key role in the development of insulin resistance because of the high lipolytic rate of visceral adipose tissue and its secretion of adipocytokines. Low birth weight subjects are prone to central redistribution of adipose tissue and are at high risk of developing metabolic syndrome, type 2 diabetes and cardiovascular disease. Intrauterine adipogenesis may play a key role in the fetal origin of the pathogenesis of metabolic syndrome, type 2 diabetes and cardiovascular disease. Therefore, knowledge of the behavior of visceral adipose tissue-derived stem cells could provide a greater understanding of the metabolic risk related to intrauterine growth retardation, with potential clinical implications for the prevention of long-term metabolic alterations.

Congenital hyperinsulinism and glucose hypersensitivity in homozygous and heterozygous carriers of Kir6.2 (KCNJ11) mutation V290M mutation: KATP channel inactivation mechanism and clinical management

OBJECTIVE The ATP-sensitive K+ channel (KATP) controls insulin secretion from the islet. Gain- or loss-of-function mutations in channel subunits underlie human neonatal diabetes and congenital hyperinsulinism (HI), respectively. In this study, we sought to identify the mechanistic basis of KATP-induced HI in two probands and to characterize the clinical course. RESEARCH DESIGN AND METHODS We analyzed HI in two probands and characterized the course of clinical treatment in each, as well as properties of mutant KATP channels expressed in COSm6 cells using Rb efflux and patch-clamp methods. RESULTS We identified mutation V290M in the pore-forming Kir6.2 subunit in each proband. In vitro expression in COSm6 cells supports the mutation resulting in an inactivating phenotype, which leads to significantly reduced activity in intact cells when expressed homomerically, and to a lesser extent when expressed heteromerically with wild-type subunits. In one heterozygous proband, a fluoro-DOPA scan revealed a causal focal lesion, indicating uniparental disomy with loss of heterozygosity. In a second family, the proband, homozygous for the mutation, was diagnosed with severe diazoxide–unresponsive hypersinsulinism at 2 weeks of age. The patient continues to be treated successfully with octreotide and amlodipine. The parents and a male sibling are heterozygous carriers without overt clinical HI. Interestingly, both the mother and the sibling exhibit evidence of abnormally enhanced glucose tolerance. CONCLUSIONS V290M results in inactivating KATP channels that underlie HI. Homozygous individuals may be managed medically, without pancreatectomy. Heterozygous carriers also show evidence of enhanced glucose sensitivity, consistent with incomplete loss of KATP channel activity.

Riboflavin responsive mitochondrial myopathy is a new phenotype of dihydrolipoamide dehydrogenase deficiency. The chaperon-like effect of vitamin B2

Dihydrolipoamide dehydrogenase (DLD, E3) is a flavoprotein common to pyruvate, α-ketoglutarate and branched-chain α-keto acid dehydrogenases. We found two novel DLD mutations (p.I40Lfs*4; p.G461E) in a 19 year-old patient with lactic acidosis and a complex amino- and organic aciduria consistent with DLD deficiency, manifesting progressive exertional fatigue. Muscle biopsy showed mitochondrial proliferation and lack of DLD cross-reacting material. Riboflavin supplementation determined the complete resolution of exercise intolerance with the partial restoration of the DLD protein and disappearance of mitochondrial proliferation in the muscle. Morphological and functional studies support the riboflavin chaperon-like role in stabilizing DLD protein with rescue of its expression in the muscle.

Isolation and Characterization of Omental Adipose Progenitor Cells in Children: A Potential Tool to Unravel the Pathogenesis of Metabolic Syndrome

Background/Aim: Visceral adipose tissue plays a pivotal role in the pathogenesis of metabolic syndrome. Several investigations refer to the physiology of subcutaneous and visceral adipose tissue of adult obese subjects, focusing on the characterization of adipose-derived stem cells and their differentiation capacity. To date, no study has been carried out on visceral adipose tissue of children, the main limitation being the amount of fat tissue available. The aim of this investigation was to establish a method to successfully isolate adipose progenitor cells from very small specimens of omental fat obtained from children undergoing abdominal surgery. Methods: A previously described procedure employed to extract adipose progenitors from large amounts of lipoaspirate was modified. 0.5-cm3 specimens of omental fat were collected from 13 children and 2 newborns. Primary, secondary and higher passaged adipocytic progenitor cell cultures were established. Immunophenotyping of the generated lines was carried out by flow cytometry analysis. Differentiation experiments concerning the adipogenic phenotype were conducted. Results: A feasible method for isolating adipose progenitors from pediatric specimens of omental fat was established. Cells showed a fibroblast-like appearance consistent with that of mesenchymal stem cells obtained from bone marrow. The mesenchymal phenotype was confirmed by the surface antigenic profile of these cells. Cells also underwent adipogenic differentiation in vitro. Conclusion: The availability of progenitor primary cell lines from omental adipose tissue of children may allow future investigations aimed at unraveling whether fetal programming of adipogenesis is responsible for the pathogenesis of the metabolic syndrome that develops during adulthood in subjects, born with low birth weight, typically showing central fat redistribution.

Low Birth Weight for Gestational Age Associates with Reduced Glucose Concentrations at Birth, Infancy and Childhood

Background/Aims: Our aim was to investigate glucose homeostasis, insulin sensitivity and insulin-like growth factor (IGF) system status in children born small for gestational age (SGA). Methods: A case-control study was carried out at birth, infancy and childhood, comparing SGA with children appropriate for gestational age strictly matched for age, gender, pubertal status and body mass index. Ninety newborns, 52 infants, and 68 children were studied. Fasting insulin (IF), fasting glucose (GF) to IF ratio (GF/IF), the homeostasis model assessment of insulin sensitivity, the quantitative insulin sensitivity check index, insulinogenic index and the triglyceride/high-density lipoprotein-cholesterol ratio were measured. IGF-I, IGF-binding protein-3 and the IGF-I/IGF-binding protein-3 molar ratio were assessed. Results: Glucose concentrations were lower in SGA newborns (p < 0.0001), infants (p = 0.01), and children (p = 0.001). Birth weight correlated with glucose levels at birth (r = 0.59, p < 0.0001), 12 months (r = 0.29, p = 0.04) and childhood (r = 0.44, p < 0.0001). Conclusion: Our results provide evidence for a developmental adaptation of glucose metabolism in SGA children leading to reduced glucose concentrations.

Acute thiamine deficiency and refeeding syndrome: Similar findings but different pathogenesis

OBJECTIVE Refeeding syndrome can occur in several contexts of relative malnutrition in which an overaggressive nutritional support is started. The consequences are life threatening with multiorgan impairment, and severe electrolyte imbalances. During refeeding, glucose-involved insulin secretion causes abrupt reverse of lipolysis and a switch from catabolism to anabolism. This creates a sudden cellular demand for electrolytes (phosphate, potassium, and magnesium) necessary for synthesis of adenosine triphosphate, glucose transport, and other synthesis reactions, resulting in decreased serum levels. Laboratory findings and multiorgan impairment similar to refeeding syndrome also are observed in acute thiamine deficiency. The aim of this study was to determine whether thiamine deficiency was responsible for the electrolyte imbalance caused by tubular electrolyte losses. METHODS We describe two patients with leukemia who developed acute thiamine deficiency with an electrolyte pattern suggestive of refeeding syndrome, severe lactic acidosis, and evidence of proximal renal tubular dysfunction. RESULTS A single thiamine administration led to rapid resolution of the tubular dysfunction and normalization of acidosis and electrolyte imbalance. This demonstrated that thiamine deficiency was responsible for the electrolyte imbalance, caused by tubular electrolyte losses. CONCLUSIONS Our study indicates that, despite sharing many laboratory similarities, refeeding syndrome and acute thiamine deficiency should be viewed as separate entities in which the electrolyte abnormalities reported in cases of refeeding syndrome with thiamine deficiency and refractory lactic acidosis may be due to renal tubular losses instead of a shifting from extracellular to intracellular compartments. In oncologic and malnourished patients, individuals at particular risk for developing refeeding syndrome, in the presence of these biochemical abnormalities, acute thiamine deficiency should be suspected and treated because it promptly responds to thiamine administration.

Wolman disease associated with hemophagocytic lymphohistiocytosis: attempts for an explanation.

The lysosomal acid lipase (LAL) is the enzyme responsible of the hydrolysis of cholesteryl esters and triglycerides within endo-lysosomes. Loss of enzyme activity leads to accumulation of cholesteryl esters and triglycerides in the lysosome of most tissues. The complete deficiency of LAL is responsible of Wolman disease (WD), a severe systemic disease manifesting in the first days of life with vomiting, diarrhea, failure to thrive, hepatosplenomegaly, jaundice, anemia, and thrombocytopenia. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition which may be genetically determined or secondary to infections, malignancies, immune deficiencies, and rheumatologic disorders. So far, some inborn errors of metabolism have been associated with HLH (e.g., lysinuric protein intolerance, Gaucher’s disease), and it has been anecdotally described in three WD patients, without any specific pathogenetic hypothesis. Here, we report on a WD patient, showing clear clinical, biochemical, and histological features indicative of HLH. We discuss the pathophysiological role of cholesteryl ester-induced inflammasome activation in macrophages, leading to a secondary HLH. Conclusion: This case indicates that WD can cause secondary HLH and suggests that a careful metabolic workup should be performed when facing to a pediatric patient with HLH.