Short stature is a frequent disorder in the pediatric population and can be caused by multiple factors. In the last few years, the introduction of Next Generation Sequencing (NGS) in the molecular diagnostic workflow led to the discovery of mutations in novel genes causing short stature including heterozygous mutations in ACAN gene. It encodes for aggrecan, a primary proteoglycan component specific for the structure of the cartilage growth plate, articular and intervertebral disc. We report a novel ACAN heterozygous pathogenic variant in a family with idiopathic short stature, early-onset osteoarthritis and osteoarthritis dissecans (SSOAOD). We also performed a literature review summarizing the clinical characteristic of ACAN's patients. The probands are two Caucasian sisters with a family history of short stature and osteoarthritis dissecans. They showed dysmorphic features such as mild midface hypoplasia, brachydactyly and broad thumbs, especially the great toes. The same phenotype was presented in the mother who had had short stature and suffered from intervertebral disc disease. DNA sequencing identified a heterozygous pathogenic variation (c.4390delG p.Val1464Ter) in the sisters, with a maternal inheritance. The nonsense mutation, located on exon 12, results in premature truncation and presumed loss of protein function. In terms of treatment, our patients underwent recombinant human growth hormone replacement therapy, associated with gonadotropin releasing hormone therapy, in order to block early growth cessation and therefore reach a better final height. Our case suggests that SSOAOD ACAN related should be considered in the differential diagnosis of children with autosomal dominant short stature and family history of joints disease.

Background: The aim of this study was to determine the effects of a 12-month healthy lifestyle intervention based on diet plus physical activity on cardiovascular structure and function in children and adolescents with obesity; Methods: In this longitudinal study we assessed changes in anthropometric, biochemical and cardiovascular variables in 55 subjects with obesity (6–16 years) before and after a 12-month behavioral program based on Mediterranean diet plus exercise regimen. Subjects were divided in two groups based on negative change in BMI z-score ≥10% from baseline: weight losers (WL) and non-weight losers (NWL); Results: After 12 months, WL showed a significant improvement of metabolic parameters. Treatment was effective in increasing the mitral peak early diastolic velocity E and the E/A ratio. In subjects with a reduction of the number of NCEP-ATPIII metabolic syndrome criteria, lifestyle intervention reduced left ventricular area and volume. Intervention reduced carotid intima-media thickness in subjects showing a decrease of the systemic blood pressure; Conclusions: In children with obesity, cardiovascular impairment could be partially reversed by a healthy lifestyle intervention. To adopt prompt behavioral programs in childhood obesity is crucial both for prevention and treatment of precocious complications and could have an exponential impact on long-term morbidity and mortality.

Background/objective Data on metabolic impairments in Cushing’s syndrome and GH deficiency all suggest that the relationship between cortisol and GH/IGF-I axis in obesity may have a role in the related diseases. However, studies focusing only on one of these hormones are often controversial in paediatrics. We aimed to explore the simultaneous relationship between cortisol and IGF-I with the metabolic alterations in paediatric obesity. Subjects/methods Retrospective cross-sectional study in a tertiary care center. We recruited 876 (441 males and 435 females) overweight and obese children and adolescents. A complete clinical and biochemical evaluation including OGTT was performed. Cortisol and IGF-I SDS were divided in quartiles and then crossed to explore the reciprocal influence of high/high, low/low, and high/low levels of each one on the metabolic alterations of obesity. Results Subjects in the higher quartiles of IGF-I-SDS and cortisol had an increased risk of hypertension, hypercholesterolemia, high levels of triglycerides, and reduced HDL cholesterol. Diversely, lower IGF-I-SDS quartiles were associated with higher blood glucose, insulin, insulin resistance, and reduced insulin sensitivity levels with the rise of cortisol quartiles. Conclusions We observed that apart from glucose metabolism that is associated with low IGF-I and high cortisol levels, the other parameters known to be associated with increased cardiovascular risk were related to high levels of both IGF-I and cortisol, even if within normal range. Cortisol and IGF-I play a complex role in the comorbidities of obesity, and the evaluation of both variables could clarify some of the discordant results.

Lipodystrophy syndromes are characterized by a progressive metabolic impairment secondary to adipose tissue dysfunction and may have a genetic background. Congenital generalized lipodystrophy type 4 (CGL4) is an extremely rare subtype, caused by mutations in the polymerase I and transcript release factor (PTRF) gene. It encodes for a cytoplasmatic protein called caveolae-associated protein 1 (Cavin-1), which, together with caveolin 1, is responsible for the biogenesis of caveolae, being a master regulator of adipose tissue expandability. Cavin-1 is expressed in several tissues, including muscles, thus resulting, when dysfunctional, in a clinical phenotype characterized by the absence of adipose tissue and muscular dystrophy. We herein describe the clinical phenotypes of two siblings in their early childhood, with a phenotype characterized by a generalized reduction of subcutaneous fat, muscular hypertrophy, distinct facial features, myopathy, and atlantoaxial instability. One of the siblings developed paroxysmal supraventricular tachycardia leading to cardiac arrest at 3 months of age. Height and BMI were normal. Blood tests showed elevated CK, a mild increase in liver enzymes and triglycerides levels, and undetectable leptin and adiponectin concentrations. Fasting glucose and HbA1c were normal, while Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was mildly elevated. Both patients were hyperphagic and had cravings for foods rich in fats and sugars. Genetic testing revealed a novel pathogenic mutation of the CAVIN1/PTRF gene (NM_012232 exon1:c T21A:p.Y7X) at the homozygous state. The diagnosis of lipodystrophy can be challenging, often requiring a multidisciplinary approach, given the pleiotropic effect, involving several tissues. The coexistence of generalized lack of fat, myopathy with elevated CK levels, arrhythmias, gastrointestinal dysmotility, and skeletal abnormalities should prompt the suspicion for the diagnosis of CGL4, although phenotypic variability may occur.

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