Alessia Claudia Codazzi

Constitutive Store-Operated Ca2+ 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.

Hypertension During Therapy with Triptorelin in a Girl with Precocious Puberty

To the Editor: GnRH-receptor agonists are used for treatment of central precocious puberty (CPP) and relative safety and tolerability in children are reported [1]. In experimental studies, hypertensive crisis during treatment with triptorelin is described and attributed to hypoestrogenism [2]. Postmenopause is associated with increased incidence of hypertension; estrogen low levels have important effects on venous system that reverse in animal model by hormone replacement therapy [3]. We report a “suggested” association between hypertension and triptorelin therapy in a girl with CPP. A 5-y-old girl presented with breast enlargement (Tanner B2), without any other sign of sexual maturation and with prepubertal hormonal status. At the age of 7y, she showed progressive breast development (Tanner B3), bone age advancement (SDS-BA 2.5), elevated height velocity (SDS-v 3.17). Blood pressure (BP) was 105/70 mmHg (50th centile for systolic and 90th centile for diastolic [4]). Endocrine examination revealed GnRH-stimulated serum LH peak 14.7 mIU/ml and β-estradiol level 25.6 pg/ml. Magnetic Resonance Imaging showed a 1.8×1.0×1.2 cm pineal cyst, with homogeneous content and slightly thickened wall with focal irregularity. Alpha-feto-protein and human-chorionic-gonadotropin levels were negative. Therapy with Triptorelin 3.75 mg/4 wk was started. No neurosurgical intervention was planned immediately. At the age of 10y–8 mo, we noted asymptomatic hypertension (150/110 mmHg, >99th centile [4]). Ambulatory BP monitoring confirmed severe hypertension, with 24-h mean systolic and diastolic BP>3SD [5]. Transthoracic echocardiographic evaluation showed concentric hypertrophy of the left ventricle, with increased thickness of interventricular septum and posterior wall. Renovascular and renal parenchymal diseases, endocrine causes of hypertension, coartaction of aorta were excluded. We discontinued GnRH-analog and started anti-hypertensive therapy (ramipril 5mg/die and nifedipine retard 40 mg/die). Progressively, the girl showed normalization of BP values and reduction of left ventricle wall thickness. Anti-hypertensive treatment was modified during follow-up; nifedipine retard and ramipril were stopped after 4 and 8 mo, respectively. At the age of 11y-8-mo the girl had menarche. Normal BP values persist. Considering the normotensive condition at the start therapy, the reversibility of hypertension and cardiac hypertrophy after discontinuation of triptorelin and the persistence of V. Calcaterra :D. Larizza Department of Internal Medicine, University of Pavia and Department of Pediatrics, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy

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.

Efficacia della terapia con propranololo negli emangiomi infantili: studio di un caso difficile

The infantile hemangiomas are the most common tumor of childhood, occurring in 4-5% of children under the age of one year and in 10% of Caucasian children. Most of them appear in the first four weeks of life, in a minority of cases the lesions are already present at birth. The disease is more frequent in females than in males, with a ratio of 3:1. The lesions are characterized by a rapid neonatal growth, followed by a phase of slow regression, with disappearance of the lesions within the first few years of life. Although the benign capillary hemangiomas have a tendency to spontaneous involution their management should be carefully considered. In most cases the preferred approach is wait and see, but in cases of problematic hemangiomas with complications risk, a therapeutic approach should be taken into consideration. For over forty years corticosteroids have been used as first-line therapy, with vincristine and interferon alpha. However all these drugs had many side effects. After the discovery of the usefulness of propranolol in the treatment of infantile hemangiomas numerous studies have confirmed the efficacy of the drug in inducing regression of hemangiomatous lesions, with no evidence of significant side effects. We present the case of a patient with a problematic hemangioma treated with propranolol, showing a steady regression of the lesion after 12 months of total treatment.

Diagnosi prenatale di aneurisma o diverticolo del ventricolo destro

Right ventricular aneurysms or diverticula are very rare congenital heart diseases. They are outpouchings arising from ventricular wall and being connected with the ventricle. Prenatal diagnosis is made by fetal echocardiogra-phy. We describe the case of a male fetus presenting, at the echocardiography made at 20 weeks of gestational age, an outpouching of the right ventricle posterolateral wall. The intrauterine and postnatal (17 months) follow-up shows a favourable progression, without the need for medical or surgical therapies.

Cuore e mucopolisaccaridosi: descrizione di quattro casi pediatrici

Mucopolysaccharidoses are lysosomal storage diseases characterized by the deficiency of enzymes involved in the degradation of the glycosaminoglycans, important constituents of connective tissue. Glycosaminoglycan storage involves different organs and systems: the most frequent cardiac changes are represented by valvular lesions. We describe four cases of cardiac involvement in patients with three different types of mucopolysaccharidoses. The variability of cardiac damage and the complexity of the patients affected by these diseases makes a close cardiological follow-up necessary to identify the appearance or the worsening particularly of valvular changes.

Cardiomiopatia ipertrofica nella glicogenosi tipo III: tre casi in età pediatrica

Il coinvolgimento cardiaco e costantemente presente nella glicogenosi tipo IIIa, il sottotipo piu frequente (85%) di glicogenosi tipo III o malattia di Cori (deficit di enzima deramificante). La cardiomiopatia ipertrofica generalmente insorge nell’infanzia, ma diventa rilevante nell’adolescenza e nell’eta adulta. Rari sono i casi in cui la cardiomiopatia ipertrofica si rende clinicamente manifesta in eta pediatrica. Riportiamo tre casi di cardiomiopatia ipertrofica in bambini affetti da glicogenosi tipo IIIa. Risulta evidente come la stessa forma di glicogenosi possa portare a interessamento cardiaco di entita variabile, talvolta severo gia nei primi anni di vita. Altri fattori, oltre al deficit di enzima deramificante, potrebbero essere implicati nel determinare una forma severa di cardiomiopatia ipertrofica durante l’infanzia.

Diagnosi e follow-up dei disturbi del ritmo cardiaco fetale

Alterazioni della frequenza cardiaca fetale si riscontrano in una percentuale compresa tra lo 0.2 e il 2% delle gravidanze e nel 10% di questi casi si tratta di aritmie significative. I disturbi del ritmo cardiaco fetale vengono distinti in bradiaritmie, tachiaritmie e battiti ectopici (o extrasistoli). Lo scopo di questo lavoro e descrivere le caratteristiche e l’outcome dei disturbi del ritmo cardiaco fetale. Sono state prese in considerazione 29 gravidanze complicate da disturbi del ritmo cardiaco fetale. Le anomalie di piu frequente riscontro sono state le extrasistolie, presenti nel 65.5% dei casi; non raramente sono state rilevate ai controlli ecocardiografici effettuati fino alla fine della gravidanza, senza tuttavia inficiare la prognosi fetale. In alcuni casi il disturbo del ritmo si e presentato anche nel periodo postnatale, comunque con una tendenza alla risoluzione nei primi mesi di vita. Le tachiaritmie sono state diagnosticate nel 24.1% dei casi; il ricorso alla terapia antiaritmica in utero e stato necessario nella maggior parte di questi, permettendo la sopravvivenza fetale e il raggiungimento di un’eta gestazionale sufficientemente avanzata per evitare importanti danni da prematurita. La terapia antiaritmica, somministrata alla gestante in modo da raggiungere il feto per via transplacentare, e stata efficace nella maggior parte dei casi. Talvolta, nonostante la buona risposta clinica in utero, la gestione di questi disturbi del ritmo e stata difficile a causa del verificarsi di recidive postnatali. Le bradiaritmie, riscontrate nel 10.4% dei casi, hanno presentato un andamento analogo a quanto generalmente riportato: in particolare si e verificata la risoluzione in utero nei casi di bradicardia sinusale e da extrasistolia atriale bloccata, mentre il blocco atrioventricolare completo associato a isomerismo atriale sinistro e risultato a prognosi severa.

Follow-up delle complicanze cardiache nella malattia reumatica

La malattia reumatica e una complicanza tardiva infiammatoria non suppurativa di un’infezione a carico delle alte vie aeree sostenuta da streptococchi beta-emolitici di gruppo A. Dopo una diminuzione dell’incidenza osser-vata nei paesi industrializzati nel corso del XX secolo, negli ultimi 20 anni si e assistito ad una recrudescenza della malattia. Nello studio da noi condotto abbiamo analizzato l’entita del coinvolgimento cardiaco e la sua evoluzione in 43 pazienti pediatrici affetti da malattia reumatica in fase acuta e correttamente trattati. E stato possibile osservare che: 1) nella maggior parte dei casi l’interessamento cardiaco si manifesta sottoforma di endocardite valvolare; 2) attualmente rappresenta anche in fase acuta la manifestazione piu frequente della malattia (83.3% dei pazienti); 3) la diagnosi precoce e una terapia adeguata consentono un miglioramento dell’insufficienza valvolare nella maggior parte dei casi (70% dei casi) o addirittura una remissione completa (53% delle insufficienze aortiche).

Compromissione cardiovascolare nella malattia di Kawasaki

La malattia di Kawasaki e una vasculite acuta sistemica che colpisce i vasi di medio calibro, tipica dell’eta pe-diatrica e soprattutto dei bambini di eta inferiore ai 5 anni, la cui complicanza principale e rappresentata dallo sviluppo di aneurismi coronarici. La diagnosi e essenzialmente clinica e la terapia si basa sulla somministrazione di immunoglobuline per via endovenosa (IVIG). Questo lavoro ha lo scopo di descrivere la malattia di Kawasaki in una popolazione di 60 pazienti e valutare i principali fattori di rischio per lo sviluppo del danno coronarico. La malattia si e presentata in forma tipica nel 77% dei pazienti, in forma incompleta nel 18%, in forma atipica nel 5%. Nel 77% dei pazienti si e ottenuta la remissione dopo un solo ciclo di IVIG e nella maggior parte dei casi (81%) le IVIG sono state somministrate entro 10 giorni dall’esordio della malattia. La compromissione coronari-ca e stata riscontrata nel 55% dei pazienti, ma solo il 21% di questi (12% di tutti i pazienti) ha presentato un danno coronarico permanente. Fattori di rischio per lo sviluppo del danno coronarico sono risultati: il sesso maschile, la forma incompleta o atipica, la mancata risposta a un solo ciclo di IVIG e la somministrazione delle IVIG oltre il 10° giorno dall’esordio.