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Abstract In this review, we report the developments across pediatric subspecialties that have been published in the Italian Journal of Pediatrics in 2021. We highlight advances in allergy and immunology, critical care, endocrinology, gastroenterology, genetics, hematology, infectious diseases, neonatology, neurology, nutrition, palliative care, respiratory tract illnesses and telemedicine.

Abstract Background Neurofibromatosis type 1 (NF1) is a neurocutaneous syndrome, due to heterozygous pathogenic variants in NF1 gene. The main clinical manifestations are multiple café au lait spots, axillary and inguinal freckling, cutaneous and plexiform neurofibromas, optic glioma, Lisch nodules and osseous lesions, such as sphenoid and tibial dysplasia. Vasculopathy is another feature of NF1; it consists of stenosis, aneurysms, and arteriovenous malformations, frequently involving renal arteries. Case presentation We report on a 9-year-old girl with a novel mutation in NF1 gene and renal artery aneurysm, treated by coil embolization and complicated with hypertension. Conclusion Vasculopathy is a complication of NF1, affecting from 0.4 to 6.4% of patients with NF1. Among the vascular abnormalities, renal artery aneurysm is a rare manifestation, with only a few cases regarding adult patients and no pediatric reports described in current literature. The finding of a vascular abnormality in a specific site requires the evaluation of the entire vascular system because multiple vessels could be involved at the same time.

Abstract In this article, the developments in the field of COVID-19 pandemic published in the Italian Journal of Pediatrics in 2021 are reflected. We describe progresses in SARS-CoV-2 transmission route, clinical presentation, diagnosis, treatment, and access to health care facilities in children. They led to substantial changes in the clinical approach.

Abstract Background Acute pancreatitis is a disorder of reversible inflammation of the pancreas. Only a few cases are related to infections and the most common pathogens are the viruses responsible for mumps, parotitis, and influenza. Epstein-Barr virus (EBV)-associated acute pancreatitis is a rare condition and it may occur in children and adults. Case presentation A 3-year-old female was admitted to the “G. Di Cristina” Children's Hospital in Palermo for vomiting and abdominal pain. Laboratory investigations revealed elevated amylase and lipase, with normal liver function tests. Abdominal ultrasound demonstrated an enlarged pancreas, with hypoechogenic areas; no biliary lithiasis was observed. Infectious disease serology was positive for the presence of EBV VCA IgM and IgG. A diagnosis of EBV-associated acute pancreatitis was made. The patient was treated conservatively and recovered. Conclusions Acute pancreatitis is rarely associated with EBV infection; a review of the English literature revealed only 10 pediatric and 6 adult cases. Patients with pancreatitis should always be evaluated for EBV serology, even in the absence of the typical clinical and hematological features of infectious mononucleosis. For these patients, good prognosis is generally expected.

Abstract 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.

Due to the lipophilic nature of vitamin D, overweight and obese patients have an increased risk of inadequate circulating 25-hydroxy-vitamin D (25(OH)D) concentrations. Vitamin D deficiency has in turn several consequences especially among children and adolescents. Therefore, a few supplementation strategies of vitamin D for pediatric subjects with an excessive body weight have been proposed, but their efficacy remains controversial. The aim of this systematic review and meta-analysis was to evaluate the effect of vitamin D supplementation in overweight and obese children and adolescents. Three databases (PubMed, Embase and Web of Science) were searched to collect trials on the effect of vitamin D supplementation in the pediatric overweight or obese population. Twenty-three studies were included in the systematic review. Results on modification of metabolic or cardiovascular outcomes were controversial. On the other hand, the meta-analysis showed a mean difference by 1.6 ng/ml in subjects supplemented with vitamin D as compared to placebo. In conclusion, vitamin D supplementation slightly increases 25(OH)D levels in pediatric subjects with overweight and obesity. However, the effects on metabolic and cardiovascular outcomes remain controversial. New efforts should be devoted to promoting effective interventions to improve the health of children and adolescents with overweight and obesity.

A copy-number variant (CNV) of 16p11.2 encompassing 30 genes is associated with developmental and psychiatric disorders, head size, and body mass. The genetic mechanisms that underlie these associations are not understood. To determine the influence of 16p11.2 genes on development, we investigated the effects of CNV on craniofacial structure in humans and model organisms. We show that deletion and duplication of 16p11.2 have "mirror" effects on specific craniofacial features that are conserved between human and rodent models of the CNV. By testing dosage effects of individual genes on the shape of the mandible in zebrafish, we identify seven genes with significant effects individually and find evidence for others when genes were tested in combination. The craniofacial phenotypes of 16p11.2 CNVs represent a model for studying the effects of genes on development, and our results suggest that the associated facial gestalts are attributable to the combined effects of multiple genes.

Abstract 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.

Abstract 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.

Abstract Background Quarantine and isolation measures during COVID-19 pandemic may have caused additional stress and challenged the mental health of the youth. Aim of the study is to investigate the COVID-19 pandemic impact on neuropsychological disorders (NPD) of Italian children and adolescents to provide general pediatric recommendations. Material and methods A retrospective multicenter observational study was planned by the Italian Pediatric Society (SIP) to explore the impact of COVID-19 on the access of children to pediatric Emergency Departments (pED) for the evaluation of neuropsychological symptoms, collecting the classification codes of diagnoses between March 1, 2019 and March 2, 2021. The period study was split into two sub-periods: a pre COVID-19 period (from March 1 2019 to March 1, 2020) and a COVID-19 period (from March 2, 2020 to March 2, 2021). As additional information, data on NPD hospitalizations in any pediatric department of the involved centers were recorded. Results During the study period, a total of 533,318 children were admitted to the pED involved in the study. Despite a 48.2% decline of pED admissions, there was a significant increase (83.1%) in patient admissions for NPD. The most frequent NPD conditions which increased during the COVID-19 pandemic were suicidal ideation (+ 147%), depression (+ 115%), eating disorder (+ 78.4%), and psychosis (+ 17.2%). During the pandemic period, a 39.5% increase in NPD hospitalizations was observed as well. The NPD disorders that mostly required hospitalizations were suicidal ideation (+ 134%), depression (+ 41.4%), eating disorder (+ 31.4%), and drug abuse (+ 26.7%). COVID-19 pandemic had a major impact on children's health, mainly on their NPD development. Neuropsychological assessment should be required at the primary level, in the pediatrician's office, to facilitate early capture of the sign of impairment and provide an adequate treatment. Conclusion SIP underlines the psychological consequences of COVID 19 pandemic on the youngest and recommends an early identification of NPD in the pediatric population to avoid other serious consequences for children's physical and mental health.

Abstract 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.

The ketogenic diet is known to be a possible adjuvant treatment in several medical conditions, such as in patients with severe or drug-resistant forms of epilepsy. Its use has recently been increasing among adolescents and young adults due to its supposed weight-loss effect, mediated by lipolysis and lowered insulin levels. However, there are still no precise indications on the possible use of ketogenic diets in pediatric age for weight loss. This approach has also recently been proposed for other types of disorder such as inherited metabolic disorders, Prader-Willi syndrome, and some specific types of cancers. Due to its unbalanced ratio of lipids, carbohydrates and proteins, a clinical evaluation of possible side effects with a strict evaluation of growth and nutritional status is essential in all patients following a long-term restrictive diet such as the ketogenic one. The prophylactic use of micronutrients supplementation should be considered before starting any ketogenic diet. Lastly, while there is sufficient literature on possible short-term side effects of ketogenic diets, their possible long-term impact on growth and nutritional status is not yet fully understood, especially when started in pediatric age.

Intestinal motility disorders represent a frequent problem in children with neurological impairment. These conditions are characterized by abnormal movements of the gut, which can result in symptoms such as constipation, diarrhea, reflux, and vomiting. The underlying mechanisms leading to dysmotility are various, and the clinical manifestations are often nonspecific. Nutritional management is an important aspect of care for children with gut dysmotility, as it can help to improve their quality of life. Oral feeding, when safe and in the absence of risk of ingestion or severe dysphagia, should always be encouraged. When oral nutrition is insufficient or potentially harmful, it is necessary to switch to an enteral by tube or parenteral nutrition before the onset of malnutrition. In most cases, children with severe gut dysmotility may require feeding via a permanent gastrostomy tube to ensure adequate nutrition and hydration. Drugs may be necessary to help manage gut dysmotility, such as laxatives, anticholinergics and prokinetic agents. Nutritional management of patients with neurological impairment often requires an individualized care plan to optimize growth and nutrition and to improve overall health outcomes. This review tries to sum up most significant neurogenetic and neurometabolic disorders associated with gut dysmotility that may require a specific multidisciplinary care, identifying a proposal of nutritional and medical management.

In recent years vitamin D has been in the spotlight of many researchers for its possible role in various disorders, including autoimmune and infectious diseases. Even if vitamin D deficiency remains a major public health problem, its symptomatic manifestations are less and less common in clinical practice, and pediatric age represents a “gray area” where vitamin D supplementation is often administered in the absence of an effective evaluation of its status. Moreover, a poor knowledge about different definitions of “deficiency,” “insufficiency,” and similar terms is spread among clinicians, while guidelines are not univocal, especially after the first year of life. The aim of this brief opinion paper is to sum up recent evidence about vitamin D status and its supplementation in pediatrics, in order to better clarify a common definition of its deficiency. The aim of this opinion article is to raise awareness on this topic among clinicians and encourage a discussion on the real need for routine 25-hydroxycholecalciferol serum evaluation and its supplementation.

Congenital Adrenal Hyperplasia (CAH) is a group of autosomal recessive endocrine disorders characterized by alteration in adrenal hormonal secretions. The most common form is caused by CYP21A2 mutations that result in 21-hydroxylase deficiency. Clinical features can vary, from salt-wasting forms, characterized by a lack of mineralocorticoid activity with a risk of perinatal-onset adrenal crises, to "simple-virilizing" forms with sufficient aldosterone secretion, up to milder "non-classical" forms, with a variable grade of hyperandrogenism but no severe hormonal deficiencies. During pregnancy, CAH 46,XX fetuses are exposed to elevated androgen levels, leading to a variable grade of virilization and potential central nervous system effects if untreated. These patients are usually (but not always) assigned female at birth, but some cases may be misdiagnosed and assigned male, potentially inducing fertility, gender identity, and sexual behavior issues in adulthood. In these patients, the benefits and risks of a late gender transition should be carefully evaluated. In this paper, we reviewed the literature concerning the most interesting peculiarities of these conditions. [ABSTRACT FROM AUTHOR]