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Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M-) a causative genetic variant. Methods and Results An lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk-increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause but by genotype associated with high lp(a) levels. Among 765 subjects with FH/M- and 930 subjects with FH/M+, 133 (17.4%) and 95 (10.2%) were characterized by 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 (lp(a) score ≥1). Subjects with FH/M- also had lower mean levels of pretreatment low-density lipoprotein cholesterol than individuals with FH/M+ (t test for difference in means between FH/M- and FH/M+ groups

This study aimed to widen the knowledge of a recently identified, autosomal-recessive, multiple congenital anomalies syndrome to date observed in only other three children. This is the second report of biallelic mutations in MAPKAPK5 whose impairment during human development has been associated with neurological, cardiac, and facial anomalies combined with fingers and toes malformations. Through the affected patients' genetic and phenotypic features overlap, this report confirms MAPKAPK5 as causative gene and adds unique neurodevelopmental characterization. Moreover, based on the complex congenital genitourinary anomalies reported and MAPKAPK5 literature review, we also propose kidney and external genitalia involvement as a key syndromic feature whose expressivity may be more severe in males.

Pathology registers can be a useful tool to overcome obstacles in the identification and management of familial hypercholesterolemia since childhood. In 2018, the LIPIGEN pediatric group was constituted within the Italian LIPIGEN study to focus on FH subjects under 18 years. This work aimed at discussing its recent progress and early outcomes. Demographic, biochemical, and genetic baseline characteristics were collected, with an in-depth analysis of the genetic defects. The analysis was carried out on 1,602 children and adolescents (mean age at baseline 9.9 ± 4.0 years), and almost the whole cohort underwent the genetic test (93.3%). Overall, the untreated mean value of LDL-C was 220.0 ± 97.2 mg/dl, with an increasing gradient from subjects with a negative (N = 317; mean untreated LDL-C = 159.9 ± 47.7 mg/dl), inconclusive (N = 125; mean untreated LDL-C = 166.4 ± 56.5 mg/dl), or positive (N = 1,053; mean untreated LDL-C = 246.5 ± 102.1 mg/dl) genetic diagnosis of FH. In the latter group, the LDL-C values presented a great variability based on the number and the biological impact of involved causative variants. The LIPIGEN pediatric group represents one of the largest cohorts of children with FH, allowing the deepening of the characterization of their baseline and genetic features, providing the basis for further longitudinal investigations for complete details.

Pitt-Hopkins syndrome (PTHS, MIM #610954) is a rare neurodevelopmental disease characterized by the association of intellectual disability, characteristic facial gestalt and episodes of abnormal and irregular breathing. PTHS is due to heterozygous loss-of-function variants in the TCF4 gene (transcription factor 4, MIM #602272) encoding for a basic helix-loop-helix transcription factor. TCF4 is highly expressed during early development of the nervous system, and it is involved in cellular differentiation and proliferation. Since the first clinical description in 1978, less than 200 PTHS patients have been described. A comprehensive phenotype, especially regarding cancer predisposition, is not yet well defined. We report the case of a 7-year-old boy affected by PTHS with a 4-week history of progressive swelling of the frontal bones diagnosed with Langerhans cell histiocytosis.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome, caused by alterations in a cluster of imprinted genes located within the chromosome region 11p15.5. Common clinical features are overgrowth, macroglossia, lateralized overgrowth, abdominal wall defects, neonatal hypoglycemia and an increased risk of embryonal tumors, such as hepatoblastomas. Periodic screening for abdominal tumors is recommended. Vascular tumors are uncommon in BWS. Diffuse infantile hepatic hemangiomas (DIHHs) are rare vascular tumors with potentially lethal complications, in particular acquired consumptive hypothyroidism, high-output cardiac failure, liver failure and abdominal compartment syndrome. We describe a 2-month-old patient with hallmark clinical features of BWS and confirmed a genetic diagnosis with mosaic paternal uniparental disomy of chromosome 11p15.5 (UPD[11]pat). The patient developed hepatomegaly and elevated alpha-fetoprotein (AFP) and was therefore suspected of having a hepatoblastoma. Abdominal echo-color Doppler and a CT-scan allowed diagnosis of DIHHs. She was closely monitored and underwent treatment with propranolol. Oral propranolol was effective in reducing hepatic lesions without side effects. This report may suggest that vascular tumors can also be associated with BWS.

Little is known about the role of Lp(a) in the assessment of cardiovascular risk in the paediatric population. Trying to clarify the clinical relevance of Lp(a) in risk stratification, the aim of the study is to evaluate the association between Lp(a) plasma levels in children with familial hypercholesterolaemia (FH) and positive family history for premature cardiovascular disease (pCVD) in first- and second-degree relatives.653 Caucasian children and adolescents (334 females and 319 males), aged 2-17 years, with diagnosis of FH from a paediatric cohort included in the LIPIGEN Network, were selected. We compared family history of pCVD, lipid and genetic profile in two groups based on Lp(a) levels below or above 30 mg/dL. To determine the independent predictors of pCVD, a multivariate logistic regression was used, with all clinical characteristics and blood measurements as predictors.Subjects with Lp(a) 30 mg/dl more frequently reported positive family history of pCVD compared to subjects with Lp(a)≤30 mg/dl (69.90% vs 36.66%, p 0.0001), while did not show differences in terms of median [interquartile range] LDL-cholesterol level (153.00 [88.00 vs 164.50 [90.25] mg/dL, p = 0.3105). In the regression analysis, Lp(a) 30 mg/dl was an independent predictor of family history of pCVD. Comparing subjects with or without family history of pCVD, we reported significant differences for Lp(a) 30 mg/dl (46.25% vs 17.65%, p 0.0001), FH genetic mutation (50.48% vs 40.75%, p = 0,0157), as well as for LDL-cholesterol (p = 0.0013) and total cholesterol (p = 0.0101).Children/adolescents with FH and Lp(a) 30 mg/dl where more likely to have a positive family history of pCVD. Lp(a) screening in children and adolescents with FH may enhance risk assessment and help identify those subjects, children and relatives, at increased pCVD risk.

Background and aims Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated plasma levels of low density lipoprotein cholesterol (LDL-C) and high risk of premature atherosclerotic cardiovascular disease (ASCVD). HoFH is caused by pathogenic variants in several genes, such as LDLR, APOB and PCSK9, responsible for autosomal dominant hypercholesterolemia (ADH), and LDLRAP1 responsible for autosomal recessive hypercholesterolemia (ARH). Aim of this study was the review of the clinical and molecular features of patients with HoFH identified in Italy from 1989 to 2019. Methods Data were collected from lipid clinics and laboratories, which had performed molecular diagnosis in suspected HoFH. Clinical data included baseline lipid levels and ASCVD events. Results A total of 125 subjects with ADH were identified, of whom 60 were true homozygotes, 58 compound heterozygotes and 7 double heterozygotes for LDLR (likely) pathogenic variants. Compared with compound heterozygotes, true homozygotes showed a more severe lipid phenotype and more ASCVD events. ADH carriers of LDLR negative variants (R-NEG) presented with a more aggressive phenotype, as compared to carriers of LDLR defective variants (R-DEF). Kaplan-Meier analysis showed that the median age of ASCVD event-free survival was 25 years of age in R-NEG as opposed to 50 years of age in R-DEF patients. A total of 66 patients with ARH were also identified, of whom 46 were homozygotes and 20 compound heterozygotes. The phenotypic features of ARH patients were similar to those of R-DEF/ADH patients. Overall, 45% ADH patients and 33% ARH patients did not meet the classic diagnostic criteria for HoFH. Conclusions In our cohort, the phenotypic variability of HoFH was dependent on the candidate gene involved and the functional impact of its variants on the LDL receptor pathway.

BackgroundPostzygotic activatingPIK3CAvariants cause several phenotypes within thePIK3CA-related overgrowth spectrum (PROS). Variant strength, mosaicism level, specific tissue involvement and overlapping disorders are responsible for disease heterogeneity. We explored these factors in 150 novel patients and in an expanded cohort of 1007PIK3CA-mutated patients, analysing our new data with previous literature to give a comprehensive picture.MethodsWe performed ultradeep targeted next-generation sequencing (NGS) on DNA from skin biopsy, buccal swab or blood using a panel including phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway genes andGNAQ,GNA11,RASA1andTEK. Additionally, 914 patients previously reported were systematically reviewed.Results93 of our 150 patients hadPIK3CApathogenetic variants. The merged PROS cohort showed thatPIK3CAvariants span thorough all gene domains, some were exclusively associated with specific PROS phenotypes: weakly activating variants were associated with central nervous system (CNS) involvement, and strongly activating variants with extra-CNS phenotypes. Among the 57 with a wild-typePIK3CAallele, 11 patients with overgrowth and vascular malformations overlapping PROS had variants inGNAQ,GNA11,RASA1orTEK.ConclusionWe confirm that (1) molecular diagnostic yield increases when multiple tissues are tested and by enriching NGS panels with genes of overlapping ‘vascular’ phenotypes; (2) strongly activatingPIK3CAvariants are found in affected tissue, rarely in blood: conversely, weakly activating mutations more common in blood; (3) weakly activating variants correlate with CNS involvement, strong variants are more common in cases without; (4) patients with vascular malformations overlapping those of PROS can harbour variants in genes other thanPIK3CA.

Gorham-Stout disease (GSD) is a very rare disease characterized by increased bone erosion with angiomatous proliferation. The mechanisms underlying this disorder have not been deeply investigated. Due to its rarity, no guidelines are currently available for treatment and management of GSD. We recently evaluated the cellular alterations of the bone remodeling in patients showing that osteoclast precursors displayed increased ability to differentiate into osteoclasts and that affected osteoclasts resorb bone more actively than control cells. Moreover, osteoblasts isolated from a patient showed a defective ability to form mineralized nodules. In this paper, we investigated the molecular pathways involved in the cellular defects of GSD bone cells. For this study, we recruited nine patients and performed miRNome analysis of bone cells. Between the 178 miRNAs robustly expressed in GSD osteoclasts, significant modulation of three miRNAs (miR-1246, miR-1-3p, and miR-137-3p) involved in the regulation of osteoclast formation and activity or in the angiomatous proliferation was found in patients' cells. Interestingly, miR-1246 was also up-regulated in serum exosomes from patients. Analysis of miRNAs from patient osteoblasts suggested alteration of miR-204a-5p, miR-615-3p and miR-378a-3p regulating osteoblast function and differentiation. The resulting miRNA pattern may help to understand better the mechanisms involved in GSD and to identify new potential therapeutic targets for this rare disease.

Background Adenylosuccinate lyase deficiency (ADSLD) is an ultrarare neurometabolic recessive disorder caused by loss-of-function mutations in the ADSL gene. The disease is characterized by wide clinical variability. Here we provide an updated clinical profiling of the disorder and discuss genotype–phenotype correlations. Results Data were collected through "Our Journey with ADSL deficiency Association" by using a dedicated web survey filled-in by parents. Clinical and molecular data were collected from 18 patients (12 males, median age 10.9 years ± 7.3), from 13 unrelated families. The age at onset ranged from birth to the first three years (median age 0.63 years ± 0.84 SD), and age at diagnosis varied from 2 months to 17 years, (median age 6.4 years ± 6.1 SD). The first sign was a psychomotor delay in 8/18 patients, epilepsy in 3/18, psychomotor delay and epilepsy in 3/18, and apneas, hypotonia, nystagmus in single cases. One patient (sibling of a previously diagnosed child) had a presymptomatic diagnosis. The diagnosis was made by exome sequencing in 7/18 patients. All patients were definitively diagnosed with ADSL deficiency based on pathogenic variants and/or biochemical assessment. One patient had a fatal neonatal form of ADSL deficiency, seven showed features fitting type I, and nine were characterized by a milder condition (type II), with two showing a very mild phenotype. Eighteen different variants were distributed along the entire ADSL coding sequence and were predicted to have a variable structural impact by impairing proper homotetramerization or catalytic activity of the enzyme. Six variants had not previously been reported. All but two variants were missense. Conclusions The study adds more details on the spectrum of ADSLD patients’ phenotypes and molecular data.

Gorham-Stout disease (GSD) is a very rare syndrome displaying excessive bone erosion and vascular lesion. Due to the rarity of the disease and to the limited studies, its etiopathogenesis is not entirely known. The involvement of immune system in the progressive osteolysis was recently suggested. Indeed, extensive reciprocal interactions between the immune and skeletal systems have been demonstrated. This study aimed to evaluate alterations of immune cells in GSD. An increase of CD8+ cells and reduction of CD4+ and CD4+CD25+CD127low cells was revealed in patients. Interestingly, patients’ regulatory T cells maintain the ability to respond to extracellular stimuli and to regulate osteoclastogenesis; GSD cells proliferate under aCD3/CD28 signal reaching similar levels to those observed in control culture and exert their immunomodulatory activity on effector T cells. GSD Treg cells preserved their inhibitory effects on the osteoclastogenesis. These results suggest that stimulation of Treg cells could open the way for the identification and testing of new therapeutic approaches for patients affected by GSD.

Adenylosuccinate lyase deficiency is a rare neurometabolic recessive disorder of purine metabolism characterized by a wide range of clinical manifestations. We present a very mild phenotype of two siblings characterized by mild isolated cognitive disability, in absence of brain anomalies, seizures, EEG anomalies and without progression of disease. The two patients had unsuccessfully been investigated until clinical exome was performed. In both siblings, compound heterozygosity for two inherited missense variants in ADSL gene, c.76A>T (p.Met26Leu) and c.1187G>A (p.Arg396His), were detected. Analysis of the catabolic pathway of autophagy on EBV-transformed B lymphoblastoid cell derived from the male patient excluded the presence of any autophagy alterations at the basal level. Further studies are necessary to understand the pathogenesis of the disease and to elucidate the potential role of autophagy in the development of ADSL deficiency.

Background and aims Severe hypercholesterolemia associated or not with xanthomas in a child may suggest the diagnosis of homozygous autosomal dominant hypercholesterolemia (ADH), autosomal recessive hypercholesterolemia (ARH) or sitosterolemia, depending on the transmission of hypercholesterolemia in the patient's family. Sitosterolemia is a recessive disorder characterized by high plasma levels of cholesterol and plant sterols due to mutations in the ABCG5 or the ABCG8 gene leading to a loss of function of the ATP-binding cassette (ABC) heterodimer transporter G5-G8. Methods We aimed to perform the molecular characterization of two children with severe primary hypercholesterolemia. Results Case #1 was a 2 year-old girl with high LDL-cholesterol (690 mg/dl) and tuberous and intertriginous xanthomas. Case #2 was a 7 year-old boy with elevated LDL-C (432 mg/dl) but no xanthomas. In both cases, at least one parent had elevated LDL-cholesterol level. For molecular diagnosis, we applied targeted next generation sequencing (NGS), which unexpectedly revealed that both patients were compound heterozygous for nonsense mutations: Case #1 in ABCG5 gene [p.(Gln251*)/p.(Arg446*) ] and Case #2 in ABCG8 gene [p.(Ser107*)/p.(Trp361*)]. Both children had extremely high serum sitosterol and campesterol levels, thus confirming the diagnosis of sisterolemia. A low-fat/low-sterol diet was promptly adopted with and without the addition of ezetimibe for Case #1 and Case #2, respectively. In both patients, serum total and LDL-cholesterol decreased dramatically in two months and progressively normalized. Conclusions Targeted NGS allows the rapid diagnosis of sitosterolemia in children with severe hypercholesterolemia, even though their family history does not unequivocally suggest a recessive transmission of hypercholesterolemia. A timely diagnosis is crucial to avoid delays in treatment.

We present a 9-month-old boy, second child of non-consanguineous healthy parents, born after a full-term pregnancy. At 10th day of life, multiple subcutaneous nodules appeared, which progressively increased in size and number. The biggest one was evident in the forehead (figure 1); multiple subcentimetric nodules were detectable only on palpation on the trunk. Lesions were unpainful, mobile or fixed. Figure 1 Frontoparietal fixed subcutaneous nodule. Whole-body MRI showed multiple areas with stromal …

Gorham-Stout disease (GSD) is a rare disorder characterized by progressive osteolysis and angiomatous proliferation. Since the mechanisms leading to bone loss in GSD are not completely understood, we performed histological, serum, cellular and molecular analyses of 7 patients. Increased vessels, osteoclast number and osteocyte lacunar area were revealed in patients' bone biopsies. Biochemical analysis of sera showed high levels of ICTP, Sclerostin, VEGF-A and IL-6. In vitro experiments revealed increased osteoclast differentiation and activity, and impaired mineralization ability of osteoblasts. To evaluate the involvement of systemic factors in GSD, control cells were treated with patients' sera and displayed an increase of osteoclastogenesis, bone resorption activity and a reduction of osteoblast function. Interestingly, GSD sera stimulated the vessel formation by endothelial cells EA.hy926. These results suggest that bone cell autonomous alterations with the cooperation of systemic factors are involved in massive bone loss and angiomatous proliferation observed in GSD patients.

Background Homozygous familial hypercholesterolaemia is a rare life-threatening disease characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) concentrations and accelerated atherosclerosis. The presence of double gene defects in the LDL-Receptor, either the same defect (homozygous) or two different LDL-raising mutations (compound heterozygotes) or other variants, identify the homozygous phenotype (HopFH). Apheresis is a procedure in which plasma is separated from red blood cells before the physical removal of LDL-C or the LDL-C is directly removed from whole blood. It is currently the treatment of choice for patients with HopFH whose LDL-C levels are not able to be reduced to target levels with conventional lipid-lowering drug therapy. Design The aim of this study is to report a cohort of six paediatric patients and to evaluate the long term efficacy of combined medical therapy and LDL-apheresis on LDL-C reduction. Methods We collected data from six children with confirmed diagnosis of HopFH (two females and four males; age range at diagnosis 3–8 years, mean 6 ± 1 years) from a single clinical hospital in Italy from 2007 to 2017. Results Clinical manifestations and outcomes may greatly vary in children with HopFH. Medical therapy and LDL-apheresis for the severe form should be started promptly in order to prevent cardiovascular disease. Conclusions Lipoprotein apheresis is a very important tool in managing patients with HopFH at high risk of cardiovascular disease. Based on our experience and the literature data, the method is feasible in very young children, efficient regarding biological results and cardiac events, and safe with minor side-effects and technical problems. We advise treating homozygous and compound heterozygous children as soon as possible.

OBJECTIVES: To describe muscle-related statin adverse effects in real-world pediatric practice. STUDY DESIGN: Using prospectively collected quality improvement data from a pediatric preventive cardiology practice, we compared serum creatine kinase (CK) levels among patients prescribed and not prescribed statins, and pre/post statin initiation. Multivariable mixed-effect models were constructed accounting for repeated measures, examining the effect of statins on log-transformed CK levels (lnCK) adjusted for age, sex, weight, season, insurance type, and race/ethnicity. RESULTS: Among 1,501 patients seen over 3.5 years, 474 patients (14±4 years, 47% female) had at least one serum CK measured. Median (IQR) CK levels of patients prescribed (n=188 patients, 768 CK measurements) and not prescribed statins (n=351 patients, 682 CK measurements) were 107 (83) IU/L and 113 (81) IU/L, respectively. In multivariable-adjusted models, lnCK did not differ based on statin use (β=0.02 [SE 0.05], p=0.7). Among patients started on statins (n=86, 130 pre-statin and 292 post-statin CK measurements), median CK levels did not differ in adjusted models (β for statin use on lnCK=0.08 [SE 0.07], p=0.2). There was a clinically insignificant increase in CK over time (β =0.08 [SE 0.04], p=0.04 per year). No muscle symptoms or rhabdomyolysis were reported among patients with high CK levels. CONCLUSIONS: In a real-world practice, pediatric patients using statins did not experience higher CK levels, nor was there a meaningful CK increase with statin initiation. These data suggest the limited utility to checking CK in the absence of symptoms, supporting current guidelines.

Background The incidental finding of severe hypertriglyceridemia (HyperTG) in a child may suggest the diagnosis of familial chylomicronemia syndrome (FCS), a recessive disorder of the intravascular hydrolysis of triglyceride (TG)-rich lipoproteins. FCS may be due to pathogenic variants in lipoprotein lipase (LPL), as well as in other proteins, such as apolipoprotein C-II and apolipoprotein A-V (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface) and LMF1 (a factor required for intracellular formation of active LPL). Objective Molecular characterization of 5 subjects in whom HyperTG was an incidental finding during infancy/childhood. Methods We performed the parallel sequencing of 20 plasma TG-related genes. Results Three children with severe HyperTG were found to be compound heterozygous for rare pathogenic LPL variants (2 nonsense, 3 missense, and 1 splicing variant). Another child was found to be homozygous for a nonsense variant of APOA5, which was also found in homozygous state in his father with longstanding HyperTG. The fifth patient with a less severe HyperTG was found to be heterozygous for a frameshift variant in LIPC resulting in a truncated Hepatic Lipase. In addition, 1 of the patients with LPL deficiency and the patient with APOA-V deficiency were also heterozygous carriers of a pathogenic variant in LIPC and LPL gene, respectively, whereas the patient with LIPC variant was also a carrier of a rare APOB missense variant. Conclusions Targeted parallel sequencing of TG-related genes is recommended to define the molecular defect in children presenting with an incidental finding of HyperTG.

Cyclic vomiting syndrome (CVS) is an episodic disorder that may be associated with migraine. It characterized by recurrent, stereotypic episodes of vomiting and nausea separated by intervals of comparative wellness. We report the first pediatric case of 22q 11 deletion syndrome (22q11DS) and CVS.

Incidence rates for varicella and herpes zoster were similar in patients with juvenile idiopathic arthritis receiving etanercept/methotrexate (n = 85, 184.9 patient-years [PY]) or methotrexate alone (n = 71, 199.4 PY); no complicated varicella or herpes zoster cases were reported; herpes labialis incidence was higher in patients receiving etanercept/methotrexate versus methotrexate alone (0.38 vs. 0.24 PY).

Trichorhinophalangeal syndrome (TRPS) is a rare, autosomal dominant malformation syndrome characterized by hair, craniofacial and skeletal abnormalities, skin laxity, deformation of phalanges and anomalies of pelvis, femurs, and tibias. Three subtypes have been described: TRPS I, caused by mutations in TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses. We present the case of a 7-year-old boy, affected by TRPS with a severe osteoporosis and several spontaneous bone fractures, an association described only once in the literature, successfully treated with biphosphonates. Bone mineral density (BMD) at dual-energy X-ray Absorptiometry (DXA) was of 0.331 g/cm(2) at lumbar spine with. He had four spontaneous femoral fractures in a year, and for this reason he was been operated for positioning intramedullary osteosynthesis and orthopedic supports. Due to the severity of the clinical and radiological pattern it was established, after approval of the Ethical Committee, to begin off-label therapy with infusions of neridronate at a dose of 2 mg/kg IV every 3 months. The treatment was, in this patient, effective both in terms of clinical (absence of new fractures) and mineralomethric (+45% BMD ath the lumbar level). We therefore suggest that treatment with biphosponates can be taken in account as a possible therapeutic option in case of bone fragility in patients with TRPSI.

Objectives Results of epidemiological studies of lipid profiles in individuals with Down Syndrome (DS) in different settings showed discordant results but laboratory norms for this population has been lacking. The aim of our study is to evaluate lipid profiles in a large population of Italian children with DS. Methods Lipid profiles of 357 patients with diagnosis of DS were recorded. RESULTS: Multiple linear regression was employed to estimate models for each lipid fraction as a function of sex and age in patients with DS. Conclusions The main contribution of this paper is to provide data about lipid profile on a large cohort of people with Down syndrome. Long-term surveillance will be crucial to establish if this specific lipid profile may translate into increased morbidity and mortality from cardiovascular diseases (CVD)

Objective.To evaluate safety, tolerability, and efficacy of etanercept in a cohort of patients with juvenile idiopathic arthritis (JIA) under 4 years of age.Methods.Data were collected at every visit during treatment with etanercept in 25 children who began treatment at a mean age of 3 years (range 18–48 months). Safety endpoints included the incidence of any adverse events. Efficacy endpoints included the American College of Rheumatology (ACR) Pediatric 30, 50, and 70 criteria for improvement.Results.Data from 25 patients with JIA treated with etanercept for a mean period of 23 months were analyzed. All patients received concomitant medications: 24 methotrexate, 3 cyclosporin A, and 10 corticosteroids. After the first 6 months of treatment, 15 (71.4%) patients achieved an ACR Pedi30 response and at the last observation 20 (80%) achieved ACR Pedi30. ACR Pedi50 and 70 responses were, respectively, 62% and 43% at 6 months and 72% and 64% at the last followup. Five patients (20%) discontinued etanercept for lack of efficacy. Two (8%) developed adverse events, both primary varicella zoster virus (VZV) infections (both not vaccinated). One was hospitalized because of a necrotizing fasciitis secondary to VZV infection. No cases of tuberculosis, opportunistic infections, or malignancies were reported.Conclusion.In our cohort of patients etanercept proved to be safe and efficacious in the majority of children. The response in toddlers was similar to that in older children. We observed only 1 case of severe infection that required hospitalization and stopped treatment temporarily.

The aim of this study is to verify the usefulness for parents of a web evaluation framework composed of ten quality criteria to improve their ability to assess the quality level of medical web sites. We conducted a randomised controlled trial that included two groups of parents who independently evaluated five paediatric web sites by filling out two distinct questionnaires: group A with the evaluation framework, group B without it. 40 volunteers were recruited from parents referring to the General Paediatrics Out-patients Department who satisfied the following eligibility criteria: Internet users, at least 1 child under 12 months old, no professional skill in Internet and medicine. The survey was taken between February 2, 2000 and March 22, 2000. Parents evaluated each web site and assigned a score, compared with a gold standard created by a group of experts. Suggesting evaluation criteria to parents seem useful for an improvement of their ability to evaluate web sites.

Familial Hypercholesterolemia (FH) is caused by a mutation in the gene that encodes the low-density lipoprotein (LDL) receptor, resulting in very high levels of circulating LDL-cholesterol and endothelial damage during time. Apoprotein B, activated by LDL receptor, and PCSK9 (proprotein convertase subtilisin / kexin type 9 serine Protease), that impairs the clearance of LDL receptors, are important additional mechanisms that lead to increase LDL-cholesterol. The prevalence of Homozigous form (HoFH) is estimated to be 1 per 1 million individuals and, if untreated, proximal coronary disease or aortic valve disease frequently occurs during childhood and most affected patients suffer from fatal coronary disease before the age of 30. Heterozygous condition (HeFH) occurs in about 1/380-500 individuals. The levels of LDL-cholesterol in this form may greatly vary but the disease is always asymptomatic until adult age when there is a high risk of early cardiovascular disease. Lifestyle intervention and maximal statin therapy are the mainstays of treatment. In patients that not achieve LDL-C targets, primarly HoFH patients, adjunctive lipoprotein apheresis is recommended where available. Biological agents represents to date a new therapeutic approach for this not so rare condition. The PCSK9 pathway is one of the best examples of how genetics has led to identification of a new target for cholesterol management. Different PCSK9 inhibitors (alirocumab, evolocumab) are now available [1]. Mipomersen is an antisense oligonucleotide (ASO) that targets apoliporotein B-100 mRNA and disrupts its function: it is distributed mainly to the liver where it silences apoB mRNA, thereby reducing hepatic apoB-100 and giving rise to reductions in plasma total cholesterol, LDL-cholesterol, and apoB concentrations [2]. Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor. MTP resides in the lumen of the endoplasmic reticulum, thereby preventing the assembly of apo B–containing lipoproteins in enterocytes and hepatocytes. This inhibition leads to a reduction in the synthesis of chylomicrons and very low–density lipoprotein, resulting in a reduction in plasma LDL levels [3].

Background Familial chylomicronemia is a genetic defect of the intravascular lipolysis of triglyceride (TG)-rich lipoproteins. Intravascular lipolysis involves the TG-hydrolase lipoprotein lipase (LPL) as well as other factors such as apolipoprotein CII and apolipoprotein AV (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface), and LMF1 (a factor required for intracellular formation of active LPL). Methods We sequenced the familial chylomicronemia candidate genes in a neonate with chylomicronemia. Results A 3-day-old newborn was found to have chylomicronemia (plasma TG 18.8 mmol/L, 1.667 mg/dL). The discontinuation of breastfeeding for 24 hours reduced plasma TG to 2.3 mmol/L (201 mg/dL), whereas its resumption induced a sharp TG increase (7.9 mmol/L, 690 mg/dL). The child was switched to a low-fat diet, which was effective in maintaining TG level below 3.5 mmol/L (294 mg/dL) during the first months of life. The child was found to be a compound heterozygous for 2 novel mutations in GPIHBP1 gene. The first mutation was a 9-bp deletion and 4-bp insertion in exon 2, causing a frameshift that abolished the canonical termination codon TGA. The predicted translation product of the mutant messenger RNA is a peptide that contains 51 amino acids of the N-terminal end of the wild-type protein followed by 252 novel amino acids. The second mutation was a nucleotide change (c.319T>C), causing an amino acid substitution p.(Ser107Pro) predicted in silico to be damaging. Conclusions GPIHBP1 mutations should be considered in neonates with chylomicronemia negative for mutations in LPL gene.

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth syndrome associated with multiple congenital anomalies caused by a mutant X-linked recessive trait. The authors report on a 14-month-old male patient affected by hepatoblastoma. As far as is known, this is the second patient reported with SGBS and hepatoblastoma. The observations emphasize that an increased risk of neoplasia in SGBS must be kept in mind, especially in young patients.

A 9-year-old girl presented at the Pediatric Emergency Department with an acute onset of gastrointestinal symptoms due to hypercalcemia. Despite the absence of circulating blast, bone marrow biopsy was diagnostic of acute lymphoblastic leukemia. The hypercalcemia was initially treated with intravenous hydration and furosemide, and later on with bisphosphonates. However, the serum calcium levels normalized only after the beginning of specific chemotherapy. Hypercalcemia represents an emergency in children, and acute leukemia must be considered in its differential diagnosis, even when there are no circulating blasts.

A 7-year-old boy with Rubinstein-Taybi syndrome (RTS) was referred with 20-day history of coughing fits. On arrival he looked well. He had characteristic facial features (arched eyebrows, long eyelashes, oblique eye rims down, hooked nose, prominent columella down, arched palate and micrognathia), psychomotor delay and ligamentous and joint laxity compatible with the underlying condition. Chest auscultatory finding was negative, no signs of dyspnoea or swallowing problems were detected. …

You are the paediatric registrar on duty when a 12-year-old boy is admitted to your ward with a strong suspicion of septic arthritis of the left knee. He plays soccer at competitive level; the boy and his parents are concerned about the long-term consequences for his playing. While you are waiting for the result of the white count of the synovial fluid to confirm the diagnosis and promptly start antibiotic therapy, you remember a recent discussion about the use of steroids in infectious disease, and so you decide to review the literature and analyse whether the use of steroids as an adjuvant therapy could improve the prognosis of your patient. ### Structured clinical question In children with septic arthritis (population) does steroid therapy in addition to antibiotic therapy (intervention) reduce the duration of symptoms and late sequelae (outcome) compared with the antibiotic treatment only (comparison)? Medline through PubMed and The Cochrane library from start until November 2013 were searched. Keywords used were septic arthritis and steroid, dexamethasone and glucocorticoid limited to humans. Two double-blind randomised placebo-controlled studies were found and included in this analysis (see table 1). Through bibliography analysis, two additional studies based …

Bazex-Dupre-Christol syndrome (BDCS) [OMIM 301845] is an X-linked dominant disorder of the hair follicle characterized by multiple basal cell carcinomas, follicular atrophoderma, congenital hypotrichosis, and hypohidrosis. Additional features include multiple milia, trichoepitheliomas, and axillary hidradenitis suppurativa as well as a variety of other symptoms. Some patients with a diagnosis of BDCS have had poor school performance. But no other associated psychopathological disorders have been described in the literature. We describe the neuropsychological characteristics and the co-occurring psychopathological disorders in an Italian family (brother and sister, and their mother) affected by BDCS. The BDCS phenotype in this family was characterized by hypotrichosis, atrophoderma follicularis, milia, and trichoepitheliomas. No basal cell carcinomas were documented. At neuropsychological assessment the three affected family members all had a borderline cognitive level. Other identified psychopathological disorders included attention deficit hyperactivity disorder, executive deficits, academic difficulties, deficits in lexical skills, and internalizing problems. The presence of cognitive impairment in the three family members affected by BDCS suggests that cognitive impairment may be associated with the syndrome. It may be useful to assess neuropsychological performance in patients with BDCS to identify possible associated neuropsychological disorders.