Safety of Rotavirus Vaccination in Preterm Infants Admitted in Neonatal Intensive Care Units in Sicily, Italy: A Multicenter Observational Study

Rotavirus (RV) is among the most common vaccine-preventable diseases in children under five years of age. Despite the severity of rotavirus pathology in early childhood, rotavirus vaccination for children admitted to the neonatal intensive care unit (NICU), who are often born preterm and with various previous illnesses, is not performed. This multicenter, 3-year project aims to evaluate the safety of RV vaccine administration within the six main neonatal intensive care units of the Sicilian Region to preterm infants. Methods: Monovalent live attenuated anti-RV vaccination (RV1) was administered from April 2018 to December 2019 to preterm infants with gestational age ≥ 28 weeks. Vaccine administrations were performed in both inpatient and outpatient hospital settings as a post discharge follow-up (NICU setting) starting at 6 weeks of age according to the official immunization schedule. Any adverse events (expected, unexpected, and serious) were monitored from vaccine administration up to 14 days (first assessment) and 28 days (second assessment) after each of the two scheduled vaccine doses. Results: At the end of December 2019, 449 preterm infants were vaccinated with both doses of rotavirus vaccine within the six participating Sicilian NICUs. Mean gestational age in weeks was 33.1 (±3.8 SD) and the first dose of RV vaccine was administered at 55 days (±12.9 SD) on average. The mean weight at the first dose was 3388 (SD ± 903) grams. Only 0.6% and 0.2% of infants reported abdominal colic and fever above 38.5 ◦C in the 14 days after the first dose, respectively. Overall, 1.9% EAEs were observed at 14 days and 0.4% at 28 days after the first/second dose administration. Conclusions: Data obtained from this study confirm the safety of the monovalent rotavirus vaccine even in preterm infants with gestational age ≥ 28 weeks, presenting an opportunity to improve the vaccination offer both in Sicily and in Italy by protecting the most fragile infants who are more at risk of contracting severe rotavirus gastroenteritis and nosocomial RV infection

Genetic and clinical profile of a sicilian population with R92Q mutation

Gene TNFRSF1A mutation is linked to TRAPS, autosomal dominant Autoinflammatory Disease (AID) with recurrent attacks of fever (2-3 weeks long), abdominal pain, vomiting, serositis, arthralgia and/or arthritis, myalgia, fasciitis, rash. The disease starts precociously and amyloidosis is reported in the 25% of the patients. Patients carrying the mutation R92Q usually show a mild clinical phenotype, with an extreme interindividual variability. Arthralgia and serositis are frequently less severe, however oral ulcers and pharyngitis are recurrent. Objectives: We studied the clinical and biochemical impact of the mutation R92Q in our population and the treatment outcome in all the patients with clinical relevant symptoms

Genetic and clinical profile of a paediatric population with FMF in Sicily

Familial Mediterranean fever (FMF) is an Autoinflammatory syndrome that is common in children in Mediterranean countries. The real prevalence of FMF in Sicilian children is unknown and need a wide population study. Furthermore, there are no data on the real prevalence of the different mutations between FMF patients and the concordance and/or discordance in clinical and biochemical parameters between patients of different generations

MECASERMIN TREATMENT OF A CHILD WITH CONGENITAL HYPERINSULINISM LINKED TO INS-R MUTATION

Objectives: Mecasermin is recombinant human insulin-like growth factor 1 (IGF1) which is approved for the treatment of short stature in children with documented primary IGF1 deficiency. Leprechaunism, also known as Donohue syndrome, is a severe disease, secondary to a severe congenital insulin resistance, with prenatal and neonatal growth retardation, typical dysmorphic features, glycaemic dysregulation characterized by hyperinsulinemia and hyperandrogenism. These patients have a poor prognosis with death in the first year of life. Methods: We describe the case of a 3.5 years child, born at 35,4 weeks, with severe fetal growth restriction (weight 1149 gr; length: 38 cm; cranial circumference: 28 cm), typical facial features with low implant ears, low implant hairs, hypertrichosis, hypertrophic external genitalia, postnatal growth failure, and severe hyperglycaemia (327 mg/dl) alternated with hypoglycaemia (10 mg/dl) also during i.v. infusion of glucose; significant hyperinsulinism (1000 mcU/dl) with elevated C peptide levels (43,41 ng/ml), persistent hypertension (113/74 mmHg). He has consanguineous parents (cousins) and the mother underwent abortions before the baby was born. Results: A treatment with diazoxide (5 mg/kg/day) was tried with limited efficacy. He was treated with ACE-inhibitor (Captopril) at the dose of 0,02 mg/kg/day with a low response. The Captopril dose was increased at 0,04 mg/kg/day with a regulation of the blood pressure (76/54 mmHg). The genetic study of INS-R was showed a homozygote mutation in the insulin receptor (INS-R) gene. The mutation reported was c.3289C>T (CAG->TAG) p.Gln1097Stop (Q1097X). For the growth delay and the hypotrophic muscular masses he started a off-label treatment with mecasermin at increasing doses. He had no adverse events linked to the treatment. Otherwise, he improved growth and muscular strength. Conclusions: The singular case is of relieve for the rarity of the disease and for the good response to the treatment with mecasermin, the real opportunity for these children with a severe disease otherwise with a poor prognosis

TERAPIA CON MECASERMINA IN UN BAMBINO CON IPERINSULINISMO CONGENITO DA MUTAZIONE DI INS-R

PRESENTAZIONE DEL CASO, STORIA CLINICA E SINTOMATOLOGIA L’uso per fi ni terapeutici della Mecasermina, insulin-like growth factor 1 (IGF1) umano ricombinante trova indicazione nella terapia della bassa statura di bambini con un defi cit primitivo documentato di IGF-1. Il Leprecaunismo, noto come S. di Donohue, è una rara patologia congenita caratterizzata da insulino-resistenza, severo defi cit accrescitivo intra-uterino e post-natale, fenotipie caratteristiche, alterazione del controllo dell’assetto glicemico, con iperinsulinismo e iperandrogenismo associato. L’outcome prognostico è segnato da morte entro il primo anno di vita in quasi tutti i pazienti descritti. Descriviamo l’outcome di un bambino che attualmente ha 3,5 anni, nato a 35,4 settimane con un ritardo di crescita endouterino severo (peso alla nascita: 1149 gr; lunghezza: 38 cm; circonferenza cranica: 28 cm). Alla nascita presentava facies dismorfi ca caratteristica, con orecchie a basso impianto, attaccatura bassa dei capelli, ipertricosi, lipoatrofi a sottocutanea, ipotrofi a muscolare, macrogenitalismo. Dopo la nascita la crescita è stata estremamente stentata con iperglicemia (327 mg/dl) alternata a ipoglicemia (10 mg/dl) anche durante l’infusione endovenosa di glucosio, iperinsulinismo (1000 mcU/dl)ed elevato C peptide (43,41 ng/ml), ipertensione refrattaria alla terapia farmacologica (113/74 mmHg). La madre ha avuto molti aborti precedenti la nascita del piccolo e i genitori sono consanguinei. Ha iniziato terapia con diazossido alla dose di 5mg/kg/die ed ACE inibitore alla dose do 0,02 mg/kg/die con una risposta parziale. IPOTESI DIAGNOSTICHE Nel sospetto di Iperinsulinismo congenito, è stato avviato lo stidio del gene del recettore per l’insulina (INS-R). INDAGINI DI I E II LIVELLO Lo studio del gene dell’INS-R ha dimostrato una mutazione in omozigosi: c.3289C>T (CAG->TAG) p.Gln1097Stop (Q1097X). DIAGNOSI ED EVENTUALE TERAPIA Il defi cit accrescitivo ponderale e lineare e l’ipotrofi a muscolare si sono accentuate col trascorrere dei mesi epertanto è stata iniziata terapia con mecasermina (0,04 mg/kg bis in die). Non sono stati segnalati eventi avversi. La dose del farmaco è stata progressivamente aumentata con incremento della crescita e della forza muscolare. La rarità del caso clinico e la terapia off-label somministrata con buona risposta anche in termini auxologici, identificano nella mecasermina una prospettiva terapeutica in una sindrome con una prognosi estremamente severa

Efficacy of Mecasermin Treatment and Long-Term Survival in a Child with Leprechaunism

Homozygous mutation of Insulin receptor (INS-R) gene cause an extremely rare disease called Leprechaunism, and induce intrauterine growth restriction with poor postnatal growth, hyperinsulinemia, postprandial hyperglycaemia, pre-prandial hypoglycaemia, typical facies, lack of subcutaneous fat, thick skin, hypertrichosis, macrogenitosomia in males. The survival is severely compromised in these patients. Treatment with diazoxide could ameliorate glycaemic control, however these patients are signed by a high precocious lethality into the first 1-2 years of life. Anecdotical cases are described with a longer survival. We describe the clinical case of a child with Leprechaunism, born from consanguineous parents, who had a homozygous mutation of the INS-R gene: c.3289 C>T (CAG->TAG) p.Gln 10975 stop (Q1097X). He was treated with diazoxide (5 mg/kg/day) and captopril (0.04 mg/kg/day), with a reduction of hyperglycaemia and hypertension. However, the stop in ponderal and linear growth induced to try the off-label treatment with mecasermin (0.04 mg/kg bid). The dose was progressively increased to 0.06 mg/kg/bid. After 2 years of treatment with mecasermin, the child increased the weight to 5.9 kg, length to 65 cm, head circumference to 41 cm. His neuromotor development is significantly improved. He performed an encephalic MRI which showed non-specific alterations of the white matter subcortical and periventricular, possible evolution of neonatal prolonged hypoglycaemic events. The peculiar outcome of our patient is linked to the long-term survival and the clinical improvement by mecasermin