Carnitine palmitoyltransferase II (CPT II) deficiency responsible for refractory cardiac arrhythmias, acute multiorgan failure and early fatal outcome.

BACKGROUND: Carnitine palmitoyltransferase II (CPT II) deficiency is a rare inborn error of mitochondrial fatty acid metabolism with autosomal recessive pattern of inheritance. Its phenotype is highly variable (neonatal, infantile, and adult onset) on the base of mutations of the CPT II gene. In affected subjects, long-chain acylcarnitines cannot be subdivided into carnitine and acyl-CoA, leading to their toxic accumulation in different organs. Neonatal form is the most severe, and all the reported patients died within a few days to 6 months after birth. Hereby, we report on a male late-preterm newborn who presented refractory cardiac arrhythmias and acute multiorgan (hepatic, renal, muscular) injury, leading to cerebral hemorrhage, hydrocephalus, cardiovascular failure and early (day 5 of life) to death. Subsequently, extended metabolic screening and target next generation sequencing (NGS) analysis allowed the CPT II deficiency diagnosis. CASE PRESENTATION: The male proband was born at 36+ 4 weeks of gestation by spontaneous vaginal delivery. Parents were healthy and nonconsanguineous, although both coming from Nigeria. Family history was unremarkable. Apgar score was 9/9. At birth, anthropometric measures were as follows: weight 2850 g (47th centile, -0.07 standard deviations, SD), length 50 cm (81st centile, + 0.89 SD) and occipitofrontal circumference (OFC) 35 cm (87th centile, + 1.14 SD). On day 2 of life our newborn showed bradycardia (heart rate around 80 bpm) and hypotonia, and was then transferred to the Neonatal Intensive Care Unit (NICU). There, he subsequently manifested many episodes of ventricular tachycardia, which were treated with pharmacological (magnesium sulfate) and electrical cardioversion. Due to the critical conditions of the baby (hepatic, renal and cardiac dysfunctions) and to guarantee optimal management of the arrythmias, he was transferred to the Pediatric Cardiology Reference Center of our region (Sicily, Italy), where he died 2 days later. Thereafter, the carnitines profile evidenced by the extended metabolic screening resulted compatible with a fatty acid oxidation defect (increased levels of acylcarnitines C16 and C18, and low of C2); afterwards, the targeted next generation sequencing (NGS) analysis revealed the known c.680 C > T p. (Pro227Leu) homozygous missense mutation of the CPTII gene, for diagnosis of CPT II deficiency. Genetic investigations have been, then, extended to the baby's parents, who were identified as heterozygous carriers of the same variant. When we meet again the parents for genetic counseling, the mother was within the first trimester of her second pregnancy. Therefore, we offered to the couple and performed the prenatal target NGS analysis on chorionic villi sample, which did not detect any alterations, excluding thus the CPT II deficiency in their second child. CONCLUSIONS: CPTII deficiency may be suspected in newborns showing cardiac arrhythmias, associated or not with hypertrophic cardiomyopathy, polycystic kidneys, brain malformations, hepatomegaly. Its diagnosis should be even more suspected and investigated in cases of increased plasmatic levels of creatine phosphokinase and acylcarnitines in addition to kidney, heart and liver dysfunctions, as occurred in the present patient. Accurate family history, extended metabolic screening, and multidisciplinary approach are necessary for diagnosis and adequate management of affected subjects. Next generation sequencing (NGS) techniques allow the identification of the CPTII gene mutation, essential to confirm the diagnosis before or after birth, as well as to calculate the recurrence risk for family members. Our report broads the knowledge of the genetic and molecular bases of such rare disease, improving its clinical characterization, and provides useful indications for the treatment of patients.

Intraoperative ultrasound-assisted endoscopic treatment of primary intermediate and high-grade vesicoureteral reflux in children in a long-term follow-up.

BACKGROUND: Endoscopic treatment of vesicoureteral reflux (VUR) is an important minimally invasive surgical approach in patients undergoing surgical treatment of VUR. In our past experience, we observed that a bulking agent mound sagittal diameter of 10 mm is the main predictor of effectiveness of the procedure. Moreover we noticed that the use of intraoperative ultrasound, allows the surgeon to better identify the site, volume and shape of the bulking agent injected, finally reducing operative time. OBJECTIVE: We aimed to evaluate if the intraoperative ultrasound assistance could definitively improve effectiveness of the endoscopic procedure. METHODS: We retrospectively compared two series treated with endoscopic procedures for intermediate and high grade primary VUR, respectively without (series A) and with (series B) intraoperative ultrasound (IO-US). In all patients VCUG was performed to assess VUR grade and to verify resolution or VUR downgrading during the follow-up. RESULTS: A total of 177 ureteric units were treated. Endoscopic procedures globally were effective in 68/96 ureters (70.8 %) in series A and in 68/81 ureters (83.9 %) in series B. No significant differences in effectiveness were observed comparing the series with regard to VUR grades, but a significant difference is shown (p < 0.05) when grouping grades III-V VUR. No significance in differences of volume injected were detected, but operative time was significantly lower in series B (27.5 min vs 19.6 min, p < 0.05). Mean sagittal mound diameter measured during cystoscopy in series B was 10.45 mm (range 8.5-14.2 mm). DISCUSSION: The intraoperative ultrasound assistance during endoscopic treatment of VUR could represent a valid tool for surgeons to better identify location, volume and shape of the bulking agent. Furthermore, the use of an objective parameter of evaluation of the implant can overcome the subjective intraoperative evaluation of the implant itself, improving results for experienced surgeons and reducing the learning-curve for inexperienced ones. CONCLUSIONS: Results of endoscopic injection of bulking-agent can be improved with intraoperative ultrasound, allowing at the same time a significant reduction of operative time.

Report and follow-up on two new patients with congenital mesoblastic nephroma.

BACKGROUND: Tumors are rare in neonatal age. Congenital mesoblastic nephroma (CMN) is a usually benign renal tumor observed at birth, or in the first months of life. It may also be identified prenatally and associated with polyhydramnios leading to preterm delivery. Effective treatment is surgical in most cases, consisting in total nephrectomy. In literature, very few studies report on the neonatal management of such a rare disease, and even less are those describing its uncommon complications. CASES PRESENTATION: We report on two single-center newborns affected with CMN. The first patient is a preterm female baby, born at 30+ 1 weeks of gestation (WG) due to premature labor, with prenatal (25 WG) identification of an intra-abdominal fetal mass associated with polyhydramnios. Once obtained the clinical stability, weight gain, instrumental (computed tomography, CT, showing a 4.8 × 3.3 cm left renal neoformation) and histological/molecular characterization of the lesion (renal needle biopsy picture of classic CMN with ETV6-NTRK3 translocation), a left nephrectomy was performed at 5 weeks of chronological age. The following clinical course was complicated by intestinal obstruction due to bowel adherences formation, then by an enterocutaneous fistula, requiring multiple surgical approaches including transitory ileo- and colostomy, before the conclusive anastomoses intervention. The second patient is a 17-day-old male term baby, coming to our observation due to postnatal evidence of palpable left abdominal mass (soon defined through CT, showing a 7.5 × 6.5 cm neoformation in the left renal lodge), feeding difficulties and poor weight gain. An intravenous diuretic treatment was needed due to the developed hypertension and hypercalcemia, which regressed after the nephrectomy (histological diagnosis of cellular CMN with ETV6-NTRK3 fusion) performed at day 26. In neither case was chemotherapy added. Both patients have been included in multidisciplinary follow-up, they presently show regular growth and neuromotor development, normal renal function and no local/systemic recurrences or other gastrointestinal/urinary disorders. CONCLUSIONS: The finding of a fetal abdominal mass should prompt suspicion of CMN, especially if it is associated with polyhydramnios; it should also alert obstetricians and neonatologists to the risk of preterm delivery. Although being a usually benign condition, CMN may be associated with neonatal systemic-metabolic or postoperative complications. High-level surgical expertise, careful neonatological intensive care and histopathological/cytogenetic-molecular definition are the cornerstones for the optimal management of patients. This should also include an individualized follow-up, oriented to the early detection of any possible recurrences or associated anomalies and to a better quality of life of children and their families.

Penile Length Assessment of Children Treated for Primary Buried Penis: Can Satisfying Penile Growth Always Be Achieved?

Primary buried (BP) penis is describes as a small penis caused by a penile ligaments anomaly; it is unclear if a primary BP could reach a normal length. We selected 49 patients treated at our institution between 2015 and 2020 in order to post-operatively evaluate the SPL after one year. SPL was evaluated according to the PH Tanner staging system for pre-pubertal patients according to age-normalized values. A micropenis was detected if the SPL was below 2.5 SD. A normal SPL was found in thirty-two patients, eighteen were in PH Stage 1, four were in PH Stage 2, six were in PH Stage 3, and four were in PH Stage 5. Seventeen patients showed a reduced SPL; in seven of these (four in PH Stage 4 and three in PH Stage 5), their SPL was <2.5 ST. The difference in micropenis prevalence between the pre-pubertal and post-pubertal patients was significant (p = 0.038). A primary BP grows normally during the pre-pubertal period, where patients frequently showed a normal SPL, but it seems to be unable to reach a normal length in the higher PH stages, where the SPL is used to detect a micropenis. We suggest that a primary BP should be considered not as a simple defect of the penile ligaments and surrounding tissues, but as an incomplete manifestation of a micropenis due to a growth slowdown of the organ in late puberty.

Useless and limits of Postmortem CT (PMCT) in a complex case of preterm infant murder.

The present case-report empathizes the usefulness of post-mortem computed tomography (PMCT) in the detection of live birth signs in a baby found dead, comparing the results with standard autoptic, histologic and immunohistochemical examinations. The report describes the case of a new-born who was thrown out on the footpath from a window of the fifth floor according to the investigative police, whilst the mother has hidden herself immediately after childbirth. PMCT showed diffusely aerated lung parenchyma with signs of severe lung distress, air in the airways with no fluid inside, and air in the upper gastro-intestinal tract, in absence any resuscitation manoeuvres performed on the baby at delivery. PMCT underlined multiple fractures of the skull with degeneration of cerebral parenchyma. All these findings were confirmed by conventional autopsy and histological and immunohistochemical examinations, clinching the usefulness of PMCT in differentiating live births from stillbirths.

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.

New insights on partial trisomy 3q syndrome: de novo 3q27.1-q29 duplication in a newborn with pre and postnatal overgrowth and assisted reproductive conception.

BACKGROUND: Duplications of the long arm of chromosome 3 are rare, and associated to a well-defined contiguous gene syndrome known as partial trisomy 3q syndrome. It has been first described in 1966 by Falek et al., and since then around 100 patients have been reported. Clinical manifestations include characteristic facial dysmorphic features, microcephaly, hirsutism, congenital heart disease, genitourinary anomalies, hand and feet abnormalities, growth disturbances and intellectual disability. Most of cases are due to unbalanced translocations, inherited from a parent carrying a balanced aberration (reciprocal translocation or inversion), and rarely the genomic anomaly arises de novo. Very few studies report on the prenatal identification of such rearrangements. CASE PRESENTATION: Hereby, we report on a newborn with a rare pure duplication of the long arm of chromosome 3. Noninvasive prenatal test (cell free fetal DNA analysis on maternal blood), performed for advanced parental age and use of assisted reproductive technique, evidenced a partial 3q trisomy. Then, invasive cytogenetic (standard and molecular) investigations, carried out through amniocentesis, confirmed and defined a 3q27.1-q29 duplication spanning 10.9 Mb, and including about 80 genes. Our patient showed clinical findings (typical facial dysmorphic features, esotropia, short neck, atrial septal defect, hepatomegaly, mild motor delay) compatible with partial trisomy 3q syndrome diagnosis, in addition to pre- and postnatal overgrowth. CONCLUSIONS: Advanced parental age increases the probability of chromosomal and/or genomic anomalies, while ART that of epigenomic defects. Both conditions, thus, deserve more careful prenatal monitoring and screening/diagnostic investigations. Among the latter, cell free fetal DNA testing can detect large segmental aneuploidies, along with chromosomal abnormalities. It identified in our patient a wide 3q rearrangement, then confirmed and defined through invasive molecular cytogenetic analysis. Neonatologists and pediatricians must be aware of the potential risks associated to duplication syndromes. Therefore, they should offer to affected subjects an adequate management and early and careful follow-up. These may be able to guarantee to patients satisfactory growth and development profiles, prevent and/or limit neurodevelopmental disorders, and timely recognition of complications.

Congenital syphilis in a preterm newborn with gastrointestinal disorders and postnatal growth restriction.

BACKGROUND: Congenital syphilis (CS) depends on the placental transmission of Treponema pallidum (TP) spirochetes from an infected mother to fetus during pregnancy. It shows a wide clinical variability with cutaneous and visceral manifestations, including stillbirths, neonatal death, and asymptomatic cases. Preterm infants with CS may have more severe features of disease than the term ones, due to the combined pathogenic effect of both CS and prematurity. CASE PRESENTATION: We report on a female preterm (32+6 weeks of gestation) newborn showing most of the typical CS manifestations, in addition to gastrointestinal disorders including feeding difficulties, colon stenosis and malabsorption leading to postnatal growth restriction. The mother resulted positive at the syphilis screening test of the first trimester of pregnancy, but she did not undergo any treatment. At birth, our newborn was VDRL positive (antibody titer four times higher compared to the mother), and she was treated with intravenous benzathine benzylpenicillin G for 10 days (50,000 IU/Kg three times per day). Poor tolerance to enteral nutrition (abdominal distension, increased biliary type gastric secretions) was observed. A barium enema X-Ray identified a colon stenosis within the descending tract. However, the poor general conditions due to a concurrent fungal sepsis did not allow to perform any surgical procedure, and a conservative approach with total parenteral nutrition was started. The following evolution was marked by difficulties in enteral feeding including refusal of food and vomiting, to which also contributed the neurological abnormalities related to a perinatal asphyxia, and the affective deprivation for the physical absence of the mother during hospitalization. At 5 months of age, after the introduction of an amino acid-based formula (Neocate LCP Nutricia ®), an improvement of enteral feeding was observed, with no further and significantly decreased episodes of abdominal distension and vomiting respectively, and regular stool emission. A psychological support offered to the family allowed a more stable bond between the mother and her baby, thus providing a significant additional benefit to food tolerance and growth. She was discharged at 5 months of age, and included in a multidisciplinary follow-up. She at present shows global growth delay, and normal development apart from mildly increased tone of lower limbs. CONCLUSIONS: Our report highlights less common clinical CS manifestations like gastrointestinal disorders including feeding difficulties, colon stenosis and malabsorption leading to postnatal growth delay. Moreover, it underlines how prematurity may worsen the clinical evolution of such congenital infection, due to the additional pathogenic effect of possible associated diseases and/or conditions like sepsis, hypoxic/ischemic injury, or use of drugs. CS may be observed also in high-income countries, with high rates of antenatal screening and availability of prenatal treatment. A multidisciplinary network must be guaranteed to the affected subjects, to ensure adequate care and improve the quality of life for patients and their families.

Intestinal malrotation in a female newborn affected by Osteopathia Striata with Cranial Sclerosis due to a de novo heterozygous nonsense mutation of the AMER1 gene.

BACKGROUND: Osteopathia Striata with Cranial Sclerosis (OS-CS), also known as Horan-Beighton Syndrome, is a rare genetic disease; about 90 cases have been reported to date. It is associated with mutations (heterozygous for female subjects and hemizygous for males) of the AMER1 gene, located at Xq11.2, and shows an X-linked pattern of transmission. Typical clinical manifestations include macrocephaly, characteristic facial features (frontal bossing, epicanthal folds, hypertelorism, depressed nasal bridge, orofacial cleft, prominent jaw), hearing loss and developmental delay. Males usually present a more severe phenotype than females and rarely survive. Diagnostic suspicion is based on clinical signs, radiographic findings of cranial and long bones sclerosis and metaphyseal striations, subsequent genetic testing may confirm it. CASE PRESENTATION: Hereby, we report on a female newborn with frontal and parietal bossing, narrow bitemporal diameter, dysplastic, low-set and posteriorly rotated ears, microretrognathia, cleft palate, and rhizomelic shortening of lower limbs. Postnatally, she manifested feeding intolerance with biliary vomiting and abdominal distension. Therefore, in the suspicion of bowel obstruction, she underwent surgery, which evidenced and corrected an intestinal malrotation. Limbs X-ray and skull computed tomography investigations did not show cranial sclerosis and/or metaphyseal striations. Array-CGH analysis revealed normal findings. Then, a target next generation sequencing (NGS) analysis, including the genes involved in skeletal dysplasias, was performed and revealed a de novo heterozygous nonsense mutation of the AMER1 gene. The patient was discharged at 2 months of age and included in a multidisciplinary follow-up. Aged 9 months, she now shows developmental and growth (except for relative macrocephaly) delay. The surgical correction of cleft palate has been planned. CONCLUSIONS: Our report shows the uncommon association of intestinal malrotation in a female newborn with OS-CS. It highlights that neonatologists have to consider such a diagnosis, even in absence of cranial sclerosis and long bones striations, as these usually appear over time. Other syndromes with cranial malformations and skeletal dysplasia must be included in the differential diagnosis. The phenotypic spectrum is wide and variable in both genders. Due to variable X-inactivation, females may also show a severe and early-onset clinical picture. Multidisciplinary management and careful, early and long-term follow-up should be offered to these patients, in order to promptly identify any associated morbidities and prevent possible complications or adverse outcomes.

Congenital hypopituitarism and multiple midline defects in a newborn with non-familial Cat Eye syndrome.

BACKGROUND: Cat eye syndrome (CES) is a rare chromosomal disease, with estimated incidence of about 1 in 100,000 live newborns. The classic triad of iris coloboma, anorectal malformations, and auricular abnormalities is present in 40% of patients, and other congenital defects may also be observed. The typical associated cytogenetic anomaly relies on an extra chromosome, derived from an inverted duplication of short arm and proximal long arm of chromosome 22, resulting in partial trisomy or tetrasomy of such regions (inv dup 22pter-22q11.2). CASE PRESENTATION: We report on a full-term newborn, referred to us soon after birth. Physical examination showed facial dysmorphisms, including hypertelorism, down slanted palpebral fissures, and dysplastic ears with tragus hypoplasia and pre-auricular pit. Ophthalmologic evaluation and heart ultrasound identified left chorioretinal and iris coloboma and ostium secundum type atrial septal defect, respectively. Based on the suspicion of cat eye syndrome, a standard karyotype analysis was performed, and detected an extra small marker chromosome confirming the CES diagnosis. The chromosomal abnormality was then defined by array comparative genome hybridization (a-CGH, performed also in the parents), which identified the size of the rearrangement (3 Mb), and its de novo occurrence. Postnatally, our newborn presented with persistent hypoglycemia and cholestatic jaundice. Endocrine tests revealed congenital hypothyroidism, cortisol and growth hormone (GH) deficiencies, which were treated with replacement therapies (levotiroxine and hydrocortisone). Brain magnetic resonance imaging, later performed, showed aplasia of the anterior pituitary gland, agenesis of the stalk and ectopic neurohypophysis, confirming the congenital hypopituitarism diagnosis. She was discharged at 2 months of age, and included in a multidisciplinary follow-up. She currently is 7 months old and shows a severe global growth failure, and developmental delay. She started GH replacement treatment, and continues oral hydrocortisone, along with ursodeoxycholic acid and levothyroxine, allowing an adequate control of glycemic and thyroid profiles as well as of cholestasis. CONCLUSIONS: CES phenotypic spectrum is wide and highly variable. Our report highlights how among the possible associated endocrine disorders, congenital hypopituitarism may occur, leading to persistent hypoglycemia and cholestasis. These patients should be promptly assessed for complete hormonal evaluations, in addition to major malformations and midline anomalies. Early recognition of such defects is necessary to decrease fatal events, as well as short and long-term related adverse outcomes.

Cutis verticis gyrata and Noonan syndrome: report of two cases with pathogenetic variant in SOS1 gene.

BACKGROUND: Noonan and Noonan-like syndromes are multisystem genetic disorders, mainly with autosomal dominant trasmission, caused by mutations in several genes. Missense pathogenetic variants of SOS1 gene are the second most common cause of Noonan syndrome (NS) and account approximately for 13% to 17% of cases. Subjects carrying a pathogenetic variant in SOS1 gene tend to exhibit a distinctive phenotype that is characterized by ectodermal abnormalities. Cutis verticis gyrata (CVG) is a rare disease, congenital or acquired, characterized by the redundancy of skin on scalp, forming thick skin folds and grooves of similar aspect to cerebral cortex gyri. Several references in the literature have reported association between nonessential primary form of CVG and NS. CASE PRESENTATION: we report two cases of newborns with CVG and phenotype suggestive for NS who have been diagnosed to harbour the same pathogenetic variant in SOS1 gene. CONCLUSIONS: previously described patients with NS presenting CVG had received only clinical diagnosis. Therefore we report the first patients with CVG in which the clinical suspicion of NS is confirmed by molecolar analysis.

Novel mutations of the ABCA12, KRT1 and ST14 genes in three unrelated newborns showing congenital ichthyosis.

BACKGROUND: Congenital ichthyosis (CI) is a heterogeneous group of genetic disorders characterized by generalized dry skin, scaling and hyperkeratosis, often associated to erythroderma. They are rare diseases, with overall incidence of 6.7 in 100,000. Clinical manifestations are due to mutations in genes mostly involved in skin barrier formation. Based on clinical presentation, CI is distinguished in non-syndromic and syndromic forms. To date, mutations of more than 50 genes have been associated to different types of CI. CASES PRESENTATION: We report on three Italian unrelated newborns showing clinical signs compatible with different forms of CI of variable severity, namely Harlequin ichtyosis (HI), epidermolytic ichtyosis (EI) and autosomal recessive ichtyosis with hypotrichosis (ARIH). Target next generation sequencing (NGS) analysis identified three novel mutations of the ABCA12, KRT1 and ST14 genes, respectively associated to such congenital ichtyoses, not reported in literature. Genomic investigation allowed to provide the more appropriate management to each patient, based on an individualized approach. CONCLUSIONS: Our report highlights the wide genetic heterogeneity and phenotypic variability of CI. It expands the current knowledge on such diseases, widening their genomic database, and providing a better clinical characterization. Furthermore, it underlines the clinical relevance of NGS, which is essential to address the management of patients. Indeed, it may guide towards the most adequate approach, preventing clinical obstinacy for subjects with more severe forms and unfavorable outcomes (together with the support, in such situations, of bioethicists included within the multidisciplinary care team), as well as reassuring families in those with milder course and favorable evolution.

Quality of life improving after propranolol treatment in patients with Infantile Hemangiomas.

Infantile hemangiomas may affect the quality of life (QoL) of patients and their family members, as anxiety and worry may commonly occur in parents, also linked to the social adversion they experience. We underline the beneficial impact of oral propranolol therapy on QoL of patients with infantile hemangiomas (IH) and of their relatives. A specific questionnaire measuring QoL was administered to parents of IH patients at beginning and end of a treatment with oral propranolol. Different aspects were investigated: site of the lesion, age of patients at starting therapy, length of treatment, occurrence of adverse effects and persistence/recurrence of the vascular anomaly. In all cases the questionnaire revealed a significant improvement of QoL, which was independent from all analyzed factors. It showed that oral propranolol administration in these patients combines optimal clinical results with relevant improvement of QoL, especially in cases of early management. The improvement of QoL seems unrelated to site of lesion, timing and duration of therapy, occurrence of drug-related adverse effects and persistence/recurrence of disease.

Novel de novo missense mutation in the interferon regulatory factor 6 gene in an Italian infant with IRF6-related disorder.

BACKGROUND: Congenital maxillomandibular syngnathia is a rare craniofacial anomaly leading to difficulties in feeding, breathing and ability to thrive. The fusion may consist of soft tissue union (synechiae) to hard tissue union. Isolated cases of maxillomandibular fusion are extremely rare, it is most often syndromic in etiology. CASE PRESENTATION: Clinical management of a female newborn with oromaxillofacial abnormities (synechiae, cleft palate, craniofacial dysmorphisms, dental anomaly) and extraoral malformations (skinfold overlying the nails of both halluces, syndactyly, abnormal external genitalia) is presented. The associated malformations addressed to molecular genetic investigations revealing an interferon regulatory factor 6 (IRF6)-related disorder (van der Woude syndrome/popliteal pterygium syndrome). A novel de novo heterozygous mutation in exon 4 of IRF6 gene on chromosome 1q32.2, precisely c.262A > G (p.Asn88Asp), was found. Similarities are discussed with known asparagine missense mutations in the same codon, which may alter IRF6 gene function by reduced DNA-binding ability. A concomitant maternal Xp11.22 duplication involving two microRNA genes could contribute to possible epigenetic effects. CONCLUSIONS: Our reported case carrying a novel mutation can contribute to expand understandings of molecular mechanisms underlying synechiae and orofacial clefting and to correct diagnosing of incomplete or overlapping features in IRF6-related disorders. Additional multidisciplinary evaluations to establish the phenotypical extent of the IRF6-related disorder and to address family counseling should not only be focused on the surgical corrections of syngnathia and cleft palate, but also involve comprehensive otolaryngologic, audiologic, logopedic, dental, orthopedic, urological and psychological evaluations.

Distal Arthrogryposis type 5 in an Italian family due to an autosomal dominant gain-of-function mutation of the PIEZO2 gene.

BACKGROUND: Arthrogryposis multiplex congenita (AMC) is a group of clinically and etiologically heterogeneous conditions, characterized by prenatal onset contractures affecting two or more joints. Its incidence is about 1 in 3000 live births. AMC may be distinguished into amyoplasia, distal and syndromic arthrogryposis. Distal arthrogryposis (DA) predominantly affects hands and feet. It is currently divided into more than ten subtypes (DA1, DA2A/B, DA3-10), based on clinical manifestations, gene mutations and inheritance pattern. Among them, only a few patients with DA5 have been reported. It is associated to a gain-of-function pathogenic variant of the PIEZO2 gene, encoding for an ion-channel necessary to convert mechanical stimulus to biological signals and crucial for the development of joints, neuromuscular and respiratory systems. Main clinical features include multiple distal contractures, short stature, ptosis, ophthalmoplegia and, in some cases, restrictive lung disease. CASE PRESENTATION: Hereby, we report on a four-generation Italian family with DA5. Our first proband was a newborn with prenatal suspicion of AMC. At birth, clinical findings were compatible with a DA diagnosis. Family history was positive for the mother with short stature, ophthalmoplegia, short neck, and contractures of the joints of distal extremities, and for three other relatives on the maternal side, including grandfather and great-grandmother, who all shared similar findings. Thus, we performed a next generation sequencing analysis (NGS) of the genes associated to AMC and of those involved in DA. The gain-of-function heterozygous mutation c.8181_8183delAGA (p.Glu2727del) of PIEZO2 was identified in the proband, and the same mutation was also found in the mother, confirming the autosomal dominant inheritance of the condition. CONCLUSIONS: Our patients contribute to the current DA5 genomic database, and to a better characterization of the disease. Clinicians may have suspicion of a DA diagnosis based on suggestive (also prenatal) clinical findings, which must be then confirmed by NGS analysis. Since natural history varies widely among different DA disorders, detection of the underlying causal variant is essential for the identification of the exact subtype, and to its adequate management, which must rely on a multidisciplinary and individualized approach.

Cardio-facio-cutaneous syndrome and gastrointestinal defects: report on a newborn with 19p13.3 deletion including the MAP 2 K2 gene.

BACKGROUND: Cardio-facio-cutaneous syndrome (CFCS) belongs to RASopathies, a group of conditions caused by mutations in genes encoding proteins of the rat sarcoma/mitogen-activated protein kinase (RAS/MAPK) pathway. It is a rare syndrome, with about 300 patients reported. Main clinical manifestations include facial dysmorphisms, growth failure, heart defects, developmental delay, and ectodermal abnormalities. Mutations (mainly missense) of four genes (BRAF, MAP 2 K1, MAP 2 K2, and KRAS) have been associated to CFCS. However, whole gene deletions/duplications and chromosomal microdeletions have been also reported. Specifically, 19p13.3 deletion including MAP 2 K2 gene are responsible for cardio-facio-cutaneous microdeletion syndrome, whose affected subjects show more severe phenotype than CFCS general population. CASE PRESENTATION: Hereby, we report on a female newborn with prenatal diagnosis of omphalocele, leading to further genetic investigations through amniocentesis. Among these, array comparative genomic hybridization (a-CGH) identified a 19p13.3 microdeletion, spanning 1.27 Mb and including MAP 2 K2 gene. Clinical features at birth (coarse face with dysmorphic features, sparse and friable hair, cutaneous vascular malformations and hyperkeratotic lesions, interventricular septal defect, and omphalocele) were compatible with CFCS diagnosis, and further postnatal genetic investigations were not considered necessary. Soon after discharge, at around 1 month of life, she was readmitted to our Neonatal Intensive Care Unit due to repeated episodes of vomiting, subtending a hypertrophic pyloric stenosis (HPS) which was promptly identified and treated. CONCLUSIONS: Our report supports the 19p13.3 microdeletion as a contiguous gene syndrome, in which the involvement of the genes contiguous to MAP 2 K2 may modify the patients' phenotype. It highlights how CFCS affected subjects, including those with 19p13.3 deletions, may have associated gastrointestinal defects (e.g., omphalocele and HPS), providing further data on 19p13.3 microdeletion syndrome, and a better characterization of its genomic and phenotypic features. The complex clinical picture of such patients may be worsened by additional, and even precocious, life-threatening conditions like HPS. Clinicians must consider, anticipate and/or promptly treat possible medical and surgical complications, with the aim of reducing adverse outcomes. Extensive diagnostic work-up, and early, continuous, and multidisciplinary follow-up, as well as integrated care, are necessary for the longitudinal clinical evolution of any single patient.

Interstitial deletions of chromosome 1p: novel 1p31.3p22.2 microdeletion in a newborn with craniosynostosis, coloboma and cleft palate, and review of the genomic and phenotypic profiles.

BACKGROUND: Rearrangements of unstable DNA sequences may alter the structural integrity or the copy number of dose-sensitive genes, resulting in copy number variations. They may lead more frequently to deletions, in addition to duplications and/or inversions, which are the underlying pathogenic mechanism of a group of conditions known as genomic disorders (or also contiguous gene syndromes). Interstitial deletions of the short arm of chromosome 1 are rare, and only about 30 patients have been reported. Their clinical features are variable, in respect of the extent of the deleted region. They include global developmental delay, central nervous system (CNS) malformations, craniosynostosis, dysmorphic face, ocular defects, cleft palate, urinary tract anomalies and hand/foot abnormalities. CASE PRESENTATION: Hereby, we report on an Italian female newborn with craniosynostosis, facial dysmorphisms including bilateral microphthalmia and coloboma, cleft palate, and a severe global developmental and growth delay, associated to a 1p31.3p22.2 deletion of 20.7 Mb. This was inherited from the healthy mother, who was carrier of a smaller (2.6 Mb) deletion included within the centromeric region (1p22.3p22.2) of the same rearrangement, in addition to a translocation between chromosomes 1p and 4q. The deleted region of the proband contains about ninety genes. We focus on the genotype-phenotype correlations. CONCLUSIONS: The results of the present study further confirm that microdeletions at 1p31.3 constitute a contiguous gene syndrome. It is hard to establish whether the critical rearrangement of such syndrome may involve the centromeric band p22.3p22.2, or more likely do not, also in light of the genomic profile of the healthy mother of our patient. Neonatologists and pediatricians should take into consideration 1p31 microdeletion in cases of developmental and growth delay associated to craniosynostosis, peculiar facial dysmorphisms, cleft palate and hand/foot abnormalities. The present report provides new data about 1p31 microdeletion syndrome, in view of a better characterization of its genomic and phenotypic profile.

Hypertrophic pyloric stenosis masked by kidney failure in a male infant with a contiguous gene deletion syndrome at Xp22.31 involving the steroid sulfatase gene: case report.

BACKGROUND: Contiguous gene deletion syndrome at Xp22.3 resulting in nullisomy in males or Turner syndrome patients typically encompasses the steroid sulfatase gene (STS) and contiguously located other genes expanding the phenotype. In large deletions, that encompass also the Kallmann syndrome 1 gene (KAL1), occasionally infantile hypertrophic pyloric stenosis (IHPS) and congenital anomalies of the kidney and urinary tract (CAKUT) have been reported. PATIENT PRESENTATION: We report on a male newborn with family history in maternal uncle of renal abnormalities and short stature still without ichthyosiform dermatosis. The baby presented CAKUT with kidney failure and progressive vomiting. Renal bicarbonate loss masked hypochloremic and hypokalemic metabolic alkalosis classically present in IHPS and delayed its diagnosis. Antropyloric ultrasound examination and cystourethrography were diagnostic. After Fredet-Ramstedt extramucosal pyloromyotomy feeding and growing was regular and he was discharged home. Comparative whole-genome hybridization detected a maternal inherited interstitial deletion of 1.56 Mb on Xp22.31(6,552,712_8,115,153) × 0 involving the STS gene, but not the KAL1 gene. CONCLUSIONS: Aberrant cholesterol sulfate storage due to STS deletion as the underlying pathomechanism is not limited to oculocutaneous phenotypes but could also lead to co-occurrence of both IHPS and kidney abnormalities, as we report. Thus, although these two latter pathologies have a high incidence in the neonatal age, their simultaneous association in our patient is resembling not a chance but a real correlation expanding the clinical spectrum associated with Xp22.31 deletions.

The social role of pediatrics in the past and present times.

Pediatrics and society are closely related. This link is as old as the history of Pediatrics, and dates to the second half of the eighteenth century. The vocation of the first European pediatric schools, indeed, was clinical and scientific, as well as social. The founding fathers of Pediatrics were scientists of great talent, and many of them benefactors and philanthropists. They spent their lives assisting the suffering childhood, and became promoters and organizers of social securities for the poorest and most vulnerable categories. The attention to the problems of abandonment was closely linked to study, prevention, and treatment of pathologies (especially infectious, deficiency and neurological ones). The profile and activity of pediatricians grew in the following decades after the birth of the first pediatric schools. The University institutions contributed to provide a further impulse to childcare as well as cultural authority, also thanks to the foundation of the first chairs and scientific journals of Pediatrics. The relevance and prestige of the studies performed rapidly spread throughout Europe, and also reached our country, contributing to a progressive and relevant improvement in the quality of children's care, and in the meantime to the decrease of neonatal and infant mortality rates.Today's pediatricians, as in the past, must spend his efforts to face the needs of children and their families, be their social receptor, interpreter if necessary, and credible and authoritative interlocutor beside institutions. The current coronavirus pandemic dramatically exposed social inequalities and inequities. In this new scenario, the pediatrician's role of defender of all children becomes even more necessary and indispensable. Here we trace the historical steps which led to the birth and development of pediatrics, as independent medical discipline with ethical and social vocation. Its rise within the University institutions is analyzed, as well as the contribution of the greatest European and Italian masters. Finally, the role of today's pediatrician is described, his responsibilities also in dealing with new health critical issues, related to the biological, cultural, and psychological changes of the patients of present days. He must have holistic competences, to effectively take care of all children. In addition, he must socially act to guarantee the best possible context for the well-being of the child.

Necrotizing enterocolitis in the preterm: newborns medical and nutritional Management in a Single-Center Study.

Necrotizing enterocolitis (NEC) is a typical disorder of preterm newborns, with a high mortality and morbidity rate. The therapeutic and nutritional management of disease depends on several factors. Its prognosis is linked, in addition to the severity of the disease and the need for surgery, to a correct enteral feeding in these patients. This study aims to identify the clinical characteristics of 18 patients with NEC, evaluating the different therapeutic paths undertaken, the type of formula used and the survival rate of this population. Average time of enteral nutrition before the NEC onset was 11,3 ± 11,6 days, with an average fasting period since the onset of 24 ± 18.9 days. 77.8% of patients received surgery and resumed enteral nutrition 17.7 ± 17.9 days after the intervention. The overall survival rate of our cohort was 55.5%. More prospective studies are needed to evaluate the long-term outcomes of survived children with NEC.