PUS3-related disorder: Report of a novel patient and delineation of the phenotypic spectrum.

PUS3 encodes the pseudouridylate synthase 3, an enzyme catalyzing the formation of tRNA pseudouridine, which plays a critical role in tRNA structure, function, and stability. Biallelic pathogenic variants of PUS3 have been previously associated with severe intellectual disability, microcephaly, epilepsy, and short stature. We identified a novel homozygous PUS3 frameshift variant in a child with facial dysmorphisms, growth failure, microcephaly, retinal dystrophy, cerebellar hypoplasia, congenital heart defect, and right kidney hypoplasia. This patient further expands the phenotypic spectrum of PUS3-related disorders to include a more severe syndromic presentation.

A rare case of discrete aortic coarctation in Williams-Beuren syndrome. Diagnostic and therapeutic considerations.

Williams-Beuren syndrome (WBS) is a genetic disorder caused by elastin gene deletions, and is characterized by cardiovascular malformations, primarily including supravalvular aortic stenosis and peripheral pulmonary stenosis. We report a case of a neonate who developed severe discrete aortic coarctation, underwent multiple surgical interventions, and was subsequently diagnosed with WBS. Severe discrete aortic coarctation is a rare event in WBS newborns. An abnormally thick aortic wall is present in these patients and is the basis of the failure of the classical approach towards coarctation repair, which consists of end-to-end anastomosis as first surgical choice. Our case, and a very few similar previously documented cases, have all demonstrated recoarctation, which only aortic patch implantation was able to successfully repair. In light of this, we would also like to underline the importance of early WBS diagnosis. Therefore, even in mild syndromic phenotype such as low birth weight or facial dysmorphism that raise the suspicion of a genetic syndrome, it is advisable to perform fluorescent in situ hybridization analysis rather than merely karyotypic one.

Propranolol for the treatment of infantile hemangiomas: a nine-year monocentric experience from a tertiary hospital.

BACKGROUND: Propranolol is currently considered the first-line therapy for problematic infantile hemangiomas (IH), the most common benign vascular neoplasm of infancy. OBJECTIVES: We present a retrospective observational study aimed at assessing the efficacy of propranolol in 44 IH patients. MATERIALS & METHODS: A nine-year retrospective review considering clinicodemographical and therapy-related variables was performed on medical records of infants treated for IH with oral propranolol. Each lesion was assessed through a numeric severity score based on size and colour both at baseline and after treatment conclusion (p <0.05 was considered statistically significant). RESULTS: Complete remission was achieved in 90.7% cases of IH with a general mean improvement in severity of 94.94%. No severe adverse effects were reported. Preterm patients showed a superior response compared to term infants, even though the difference was not significant (p=0.185). CONCLUSION: Propranolol showed high efficacy in terms of safety profile and cosmetic results. Prematurity and precocious therapy could be linked to a superior response.

Efficacy of Anakinra on Multiple Coronary Arteries Aneurysms in an Infant with Recurrent Kawasaki Disease, Complicated by Macrophage Activation Syndrome.

Kawasaki disease (KD) is rare in infants less than 3 months of age, and its recurrence is exceptional. Infants with KD are at higher risk of severe clinical presentation, therapy failure, complications and coronary aneurysms (CAAs), and this is the reason they deserve more aggressive therapy and a strict clinical follow-up. We report a 2-month-old male with KD, complicated by Macrophage Activation Syndrome (MAS). Despite timely and aggressive therapy with immunoglobulins, steroids and aspirin, multiple CAAs developed. Two-month therapy with anakinra completely reverted all the aneurysms. After six months, the infant experienced KD relapse and was successfully re-treated with immunoglobulins, steroids and aspirin. A strict echocardiographic follow-up did not show recurrence of aneurysms. Two years later, the child is healthy, without cardiac sequelae. In our experience, anakinra was effective in reverting multiple aneurysms and its effect proved to be long-lasting, even in front of KD recurrence. Based on this evidence, it seems reasonable to hypothesize not to limit the use of anakinra as rescue therapy for complicated or refractory KD, but to consider the possibility of adding it to first-line therapies for some subgroups of very-high-risk patients, in order to strengthen the prevention of CAAs.

Hypertrophic cardiomyopathy in infant newborns of diabetic mother: a heterogeneous condition, the importance of anamnesis, physical examination and follow-up.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) in neonates is a rare and heterogeneous disorder. HCM accounts for 25 to 40% of all pediatric cardiomyopathy cases and the highest incidence in pediatric population is reported in children < 1 year. CASE PRESENTATION: we report two clinical cases of neonates, born to mothers respectively with a pre-pregnancy insulin-dependent diabetic mellitus type 2 and a suspected diabetes, with inadequate prenatal glycemic control for the first and underestimated glycemic control for the second case, with a different evolution. In the first case, a slow evidence of improvement of the HCM was observed, persuading us to the diagnosis of a diabetes-related HCM; In the second case the progressive worsening of the HCM during follow-up in association with further investigations, resulted in the diagnosis of Pompe disease. CONCLUSIONS: Hypertrophic cardiomyopathy in newborns can be the clinical expression of different underlying disorders. We aim to show the importance both to reassess maternal and family history and critically evaluate the physical examination in order to address the correct differential diagnosis. Furthermore it is important to continue a regular cardiologic follow-up for this pathology with neonatal onset to prevent a poor prognosis.

Inferior vena cava, abdominal aorta, and IVC-to-aorta ratio in healthy Caucasian children: Ultrasound Z-scores according to BSA and age.

The pediatric ultrasound measurement of the inferior vena cava (IVC) and aorta (AO) with the study of the collapsibility index (CI) and of IVC-to-AO ratio (IVC/AO) can provide clinicians in the acute care setting with information on abnormal volume status but one of the major limitations is a lack of reference normal values by body surface area (BSA) and age. The aim of this study was to provide reference ranges for the sonographic measurement of IVC, AO, and IVC/AO ratio in healthy Caucasian Italian children. METHODS: We enrolled prospectively 516 healthy Caucasian Italian children aged between 1 month and 16 years. Echocardiographic IVC and AO diameters were collected and presented separately for children aged ≤1 year and for children aged over 1 year. For children >1 year we categorized subjects into 3 years classes. CI and IVC/AO for the systolic aortic diameter were then calculated. For children over 1 year, age reference ranges were age-related or BSA-related; for children of ≤1 year, reference ranges were determined with their 90% confidence intervals regardless of age and of BSA. RESULTS: Tables and charts with reference ranges for all the echocardiographic measurements are presented for children aged >1 year according to age and BSA. The equations to obtain percentile and Z-score for each echocardiographic measurement are provided. The reference ranges for children aged ≤1 year are shown considering the small 90% confidence intervals for upper and lower limits. CI was 30% (SD 17%) in children >1 year and 36% (SD 16%) in children <1 year. IVC/AOs showed age-dependent values from 0.83 (SD 0.20) age <1 year to 1.22 (SD 0.31) in older subjects. CONCLUSIONS: We report reliable reference ranges for echocardiographic measurement of IVC, AO, CI, and IVC/AO for a Caucasian Italian healthy pediatric population.

Kinetic and Angiogenic Activity of Circulating Endothelial Colony Forming Cells in Patients with Infantile Haemangioma Receiving Propranolol.

Endothelial progenitor cells (EPCs) have been suggested to contribute to the neovascularization of infantile haemangioma (IH). There is strong evidence of the efficacy of propranolol in the treatment of IH, possibly by inhibiting both vasculogenesis and angiogenesis in the tumour. We evaluate the frequency of circulating endothelial colony forming cells (ECFCs), as the best EPC surrogate, in patients with IH at diagnosis and while receiving propranolol by an ex vivo 12-month longitudinal study. Biological aspects of the ECFCs, such as their in vitro angiogenic potential, membrane CXCR4 expression and Ca2+ signalling, were investigated. Circulating ECFCs were isolated by in vitro culture and expanded for 2 to 3 passages in 23 patients with IH (median age: 5.5 months, range: 5.5 weeks-11 months) before and 3, 6, 9 and 12 months after receiving propranolol. Twenty-four healthy subjects comparable for age were also assessed (CTRLs). Untreated patients with IH had a circulating ECFC frequency lower (p = 0.001) than CTRLs; nevertheless, in in vitro starving conditions, ECFCs showed enhanced capacity to form tube-like structures than those of CTRLs. Patients with IH following the therapy with propranolol had a significantly increased (p = 0.022) circulating ECFC frequency, that showed a diminished tube-like formation capacity in vitro, and an altered constitutive store-operated Ca2+ entry. ECFCs play a role in IH pathogenesis; the response to propranolol therapy is associated with their increased frequency in the peripheral blood and a reduction of their vasculogenic activity.

Constitutive Store-Operated Ca(2+) Entry Leads to Enhanced Nitric Oxide Production and Proliferation in Infantile Hemangioma-Derived Endothelial Colony-Forming Cells.

Clonal endothelial progenitor cells (EPCs) have been implicated in the aberrant vascular growth that features infantile hemangioma (IH), the most common benign vascular tumor in childhood that may cause ulceration, bleeding, and/or permanent disfigurement. Endothelial colony-forming cells (ECFCs), truly endothelial EPCs endowed with clonal ability and capable of forming patent vessels in vivo, remodel their Ca(2+) toolkit in tumor-derived patients to acquire an adaptive advantage. Particularly, they upregulate the proangiogenic store-operated Ca(2+) entry (SOCE) pathway due to the overexpression of its underlying components, that is, stromal interaction molecule 1 (Stim1), Orai1, and transient receptor potential canonical 1 (TRPC1). The present work was undertaken to assess whether and how the Ca(2+) signalosome is altered in IH-ECFCs by employing Ca(2+) and nitric oxide (NO) imaging, real-time polymerase chain reaction, western blotting, and functional assays. IH-ECFCs display a lower intracellular Ca(2+) release in response to either pharmacological (i.e., cyclopiazonic acid) or physiological (i.e., ATP and vascular endothelial growth factor) stimulation. Conversely, Stim1, Orai1, and TRPC1 transcripts and proteins are normally expressed in these cells and mediate a constitutive SOCE, which is sensitive to BTP-2, La(3+), and Pyr6 and recharges the intracellular Ca(2+) pool. The resting SOCE in IH-ECFCs is also associated to an increase in their proliferation rate and the basal production of NO compared to normal cells. Likewise, the pharmacological blockade of SOCE and NO synthesis block IH-ECFC growth. Collectively, these data indicate that the constitutive SOCE activation enhances IH-ECFC proliferation by augmenting basal NO production and sheds novel light on the molecular mechanisms of IH.

BNP concentrations and cardiovascular adaptation in preterm and fullterm newborn infants.

To evaluate and compare cardiovascular adaptation of 36 preterm and 34 fullterm newborns, we analyzed BNP concentration and echocardiographic parameters at day 3 of life and at day 28 (+/-2). On day 3 BNP concentrations (pg/ml) resulted higher in PDA preterm group (n=11; 125, IQR 56.1-301) than preterm without PDA (n=25; 25.5 IQR 10.9-49; p<0.001) than fullterms (n=34; 55.1 IQR 23.6-82.7; p=0.013). No difference resulted in all groups at 28days (respectively: 12.7 IQR 4.9-23.8; 15.6 IQR 10-22; 8.9 IQR 5.6-20.6). Because of the newborns' growth, all echocardiographic parameters increased with linear relationship with body weight. On day 3 BNP concentration and echocardiographic parameters were not correlated besides LA/AO in preterms with PDA (p=0.0015). On day 28, BNP was significantly correlated with mVTI (p=0.019), M (p=0.007) and LA (p=0.005) in fullterms and only with LA (p=0.007) in preterms. In conclusion, BNP concentrations and echocardiographic measures confirm that preterm, and fullterm newborns conduct themselves in a similar manner during the transition from foetal to post-natal circulation, reaching low levels at a month of life. The presence of PDA during first days of life has no significant impact in this adaptation. LA is the echocardiographic parameter mostly related to BNP concentration in the newborns.