Pegvaliase therapy for phenylketonuria: Real-world case series and clinical insights.

OBJECTIVE: The aim of this study is to present a series of case studies on the real-life use of pegvaliase in Italy in managing patients affected by phenylketonuria (PKU) and provide practical insight and support to healthcare professionals currently approaching and facing this novel enzyme substitution therapy. METHODS: A panel of 11 PKU experts from seven leading Italian treatment centers attended online virtual meetings with the aim of reviewing their clinical and practical experiences with pegvaliase based on occurred cases. In selecting the cases, specific consideration was given to the nationwide representation of the centers involved and to the number of patients with PKU managed. Cases were thoroughly reviewed, with comprehensive discussions enabling the identification of key take-home messages regarding pegvaliase therapy. RESULTS: The panel discussed 18 cases, 11 males and 7 females (age range 17-43 years). At the last follow-up (up to 111 weeks after pegvaliase initiation), 11 out of 18 patients (61%) reached Phe levels below 600 µmol/l. Outcomes varied significantly across cases. All cases underscore the potential of pegvaliase in reducing Phe levels, enhancing the quality of life, and promoting social skills and independence. Additionally, the cases highlight the challenges associated with pegvaliase therapy, including managing adverse events and ensuring patient motivation and adherence. CONCLUSION: This is the first report about the Italian experience of managing patients affected by PKU with pegvaliase. Given the limited real-world data on the use of pegvaliase in PKU management, this case series offers valuable insights into the practical implementation and management of pegvaliase therapy in this Country. Continued research and data collection will be crucial to confirm and progress with this treatment. Despite potential challenges, pegvaliase therapy represents a substantial promise in managing PKU in Italy. Patient education, personalized treatment approaches, and careful monitoring are important to ensure optimal patient outcomes.

Lipoprotein(a) in Children and Adolescents: Risk or Causal Factor for Cardiovascular Disease? A Narrative Review.

The evaluation of serum Lp(a) values in childhood and adolescence has been widely debated, and in the last few years, many authors have tried to better define Lp(a) role in atherosclerosis pathogenesis, starting from childhood. In our narrative review, we have evaluated the main historical stages of Lp(a) studies in childhood, trying to focus on pathogenic mechanisms linked to elevated serum Lp(a) values, starting from ischemic stroke and vascular damage, and to its possible direct involvement in premature atherosclerosis from childhood onwards. Historic manuscripts on Lp(a) in pediatric patients have mainly focused on serum Lp(a) values and increased stroke risk. More recently, many studies have evaluated Lp(a) as a coronary vascular disease (CVD) risk factor starting from childhood, especially related to a positive family history of premature CVD. Finally, only a few studies evaluated the role of Lp(a) in premature atherosclerotic processes and endothelial and vascular damage in pediatric patients. Lastly, we have hypothesized a future perspective, with the hope that plasma Lp(a) levels will be treated with a tailored pharmacologic approach, and Lp(a) will become a precocious therapeutic target to control the atherosclerotic pathways from the first years of life.

Possible role of tryptophan metabolism along the microbiota-gut-brain axis on cognitive & behavioral aspects in Phenylketonuria.

Cognitive and psychiatric disorders are well documented across the lifetime of patients with inborn errors of metabolism (IEMs). Gut microbiota impacts behavior and cognitive functions through the gut-brain axis (GBA). According to recent research, a broad spectrum of GBA disorders may be influenced by a perturbed Tryptophan (Trp) metabolism and are associated with alterations in composition or function of the gut microbiota. Furthermore, early-life diets may influence children's neurodevelopment and cognitive deficits in adulthood. In Phenylketonuria (PKU), since the main therapeutic intervention is based on a life-long restrictive diet, important alterations of gut microbiota have been observed. Studies on PKU highlight the impact of alterations of gut microbiota on the central nervous system (CNS), also investigating the involvement of metabolic pathways, such as Trp and kynurenine (KYN) metabolisms, involved in numerous neurodegenerative disorders. An alteration of Trp metabolism with an imbalance of the KYN pathway towards the production of neurotoxic metabolites implicated in numerous neurodegenerative and inflammatory diseases has been observed in PKU patients supplemented with Phe-free amino acid medical foods (AA-MF). The present review investigates the possible link between gut microbiota and the brain in IEMs, focusing on Trp metabolism in PKU. Considering the evidence collected, cognitive and behavioral well-being should always be monitored in routine IEMs clinical management. Further studies are required to evaluate the possible impact of Trp metabolism, through gut microbiota, on cognitive and behavioral functions in IEMs, to identify innovative dietetic strategies and improve quality of life and mental health of these patients.

Prenatal maternal stress during the COVID-19 pandemic and infant regulatory capacity at 3 months: A longitudinal study.

The COVID-19 pandemic is a global traumatic experience for citizens, especially during sensitive time windows of heightened plasticity such as pregnancy and neonatal life. Pandemic-related stress experienced by mothers during pregnancy may act as an early risk factor for infants' regulatory capacity development by altering maternal psychosocial well-being (e.g., increased anxiety, reduced social support) and caregiving environment (e.g., greater parenting stress, impaired mother-infant bonding). The aim of the present longitudinal study was to assess the consequences of pandemic-related prenatal stress on infants' regulatory capacity. A sample of 163 mother-infant dyads was enrolled at eight maternity units in northern Italy. They provided complete data about prenatal stress, perceived social support, postnatal anxiety symptoms, parenting stress, mother-infant bonding, and infants' regulatory capacity at 3 months of age. Women who experienced emotional stress and received partial social support during pregnancy reported higher anxious symptoms. Moreover, maternal postnatal anxiety was indirectly linked to the infants' regulatory capacity at 3 months, mediated by parenting stress and mother-infant bonding. Dedicated preventive interventions should be delivered to mothers and should be focused on protecting the mother-infant dyad from the detrimental effects of pandemic-related stress during the COVID-19 healthcare emergency.

The management of transitional care of patients affected by phenylketonuria in Italy: Review and expert opinion.

Phenylketonuria (PKU) is a metabolic inherited disorder in which transition from infancy to adult care is particularly difficult and not sufficiently regulated. According to the scientific literature, only few medical centers offer healthcare assistance for adult patients with PKU that are therefore still treated in pediatric settings. This generates psychological, emotional, and organizational discomfort among patients, leading them to discontinue the follow-up. European guidelines and national consensus documents underline this unmet need and the lack of practical recommendations for a structured transitional pathway in PKU. The aim of this review and expert opinion is to propose good practices for managing the transition period of PKU patients, based on the literature and the experience of a panel of Italian experts in PKU. The consensus of the experts was obtained through the administration of three rounds of surveys and one structured interview. The result is the first proposal of a pathway for an efficient transition of PKU patients. Key steps of the proposed pathway are the "a priori" planning involving the pediatric and adult teams, the acceptance of the patient and his/her family to the process, the preliminary definition of appropriate spaces in the structure, the organization of meetings with the joint team, and the appointment of a transition coordinator. For the first time, the involvement of decision makers and patient associations is proposed.

Hemiplegic-Migraine-like Attacks as First Manifestation of Diffuse Leptomeningeal Glioneuronal Tumor: A Case Report.

BACKGROUND: Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a low-grade tumor characterized by diffuse leptomeningeal infiltrates. Symptoms are usually secondary to hydrocephalus. Hemiplegic migraine (HM)-like episodes have never been associated with DLGNT, but they have been reported with different inflammatory and tumoral entities involving leptomeninges. OBSERVATIONS: We report the case of a 10-year-old boy with recurrent episodes of right hyposthenia, aphasia, and headache lasting hours to days with complete remission. The electroencephalogram during the attack showed diffuse slower activity on the left hemisphere, which improved together with the symptoms. DLGNT was discovered during a follow-up magnetic resonance imaging and confirmed by biopsy. CONCLUSIONS: This is the first report of HM-like attacks in DLGNT. We discuss the pathogenetic hypotheses of our case and previously reported cases of "symptomatic" HM with leptomeningeal involvement.

Post-partum Women's Anxiety and Parenting Stress: Home-Visiting Protective Effect During the COVID-19 Pandemic.

OBJECTIVES: The COVID-19 pandemic resulted in a particularly adverse and stressful environment for expecting mothers, possibly enhancing feelings of anxiety and parenting stress. The present work assesses mothers' anxiety levels at delivery and parenting stress after 3 months as moderated by home-visiting sessions. METHODS: Women (n = 177) in their second or third trimester of pregnancy during the COVID-19 lockdown were enrolled in northern Italy and split into those who did and did not receive home visits. After 3 months, the association between anxiety at delivery and parenting stress was assessed with bivariate correlations in the whole sample and comparing the two groups. RESULTS: Higher anxiety at birth correlated with greater perceived stress after 3 months. Mothers who received at least one home-visiting session reported lower parenting stress at 3 months than counterparts who did not receive home visits. CONCLUSIONS FOR PRACTICE: The perinatal period is a sensitive time window for mother-infant health, especially during a critical time like the COVID-19 pandemic. We suggest that home-visiting programs could be beneficial during global healthcare emergencies to promote maternal well-being after delivery.

Auditory evaluation of infants born to COVID19 positive mothers.

COVID-19 infection can cause a wide spectrum of symptoms. The audio-vestibular system can also be involved, but there is still debate about this so findings need to be considered carefully. Furthermore, mother to fetus intrauterine transmission of COVID-19 infection in pregnant women is controversial. Few studies are available about the audio-vestibular symptomatology of newborns with intrauterine COVID19 exposure. OBJECTIVES: This study investigates the possible correlation between the COVID19 gestational infection and hearing impairment onset in newborns. The involvement of hearing in COVID19 is verified so the timing and methodology of audiological evaluation of children can be planned. METHODS: Children were subject to newborn hearing screening and audiological evaluation. Newborn hearing screening is carried out prior to hospital discharge using the Automatic Transient Evoked Otoacoustic Emissions test. Audiological evaluation is performed within the child age of 4 months by using maternal, pregnancy, and perinatal case history, COVID19 case history, otoscopy, acoustic immittance test, Distortion Product Otoacoustic Emissions test, and the Auditory Brainstem Response test. RESULTS: 63 children were included in the study. 82.5% of these children were subjects of the newborn hearing screening program. The remaining 11 newborns were not subjected to hearing screening due to isolation measures and their audiological evaluation was carried out directly. Only one of 52 screened neonates showed a bilateral REFER test result but hearing threshold was normal at audiological evaluation. Audiological evaluation showed normal bilateral ABR thresholds in 59/63 children. Four children (6.3% of the total) had ABR threshold alterations but two showed normal threshold at ABR retest performed within 1 month of the first. The other two infants showed monolateral ABR alterations but one of these had a concomitant middle ear effusion. In conclusion, only one child (1.6% of the sample) had an altered ABR. This child had shown one positive SARS-CoV-2 swab in the absence of risk factors for hearing loss. CONCLUSION: This study finds no evidence that maternal COVID19 infection is a risk factor in the development of congenital hearing loss in newborns.

Gut Microbiome Modulation for Preventing and Treating Pediatric Food Allergies.

The increasing prevalence and severity of pediatric food allergies (FA) demands innovative preventive and therapeutic strategies. Emerging evidence suggests a pivotal role for the gut microbiome in modulating susceptibility to FA. Studies have demonstrated that alteration of gut microbiome could precede FA, and that particular microbial community structures early in life could influence also the disease course. The identification of gut microbiome features in pediatric FA patients is driving new prevention and treatment approaches. This review is focused on the potential role of the gut microbiome as a target for FA prevention and treatment.

Rapunzel syndrome: an infrequent cause of severe iron deficiency anemia and abdominal pain presenting to the pediatric emergency department.

BACKGROUND: Iron deficiency anemia (IDA) and abdominal pain are commonly seen in a pediatric emergency department (8 and 18% incidence respectively in our center). They are manifestations of a wide variety of diseases ranging from benign to immediately life-threatening. Trichobezoar is an under-diagnosed entity that has to be considered in children and adolescents, expecially female, suffering from trichotillomania (compulsion to pull hair) and trichophagy (compulsion to swallow hair). When undiagnosed, gastric bezoars may cause gastric ulceration, perforation, haemorrhage and obstruction. CASE PRESENTATION: To underline the importance of including this pathology in the differential diagnosis of IDA and abdominal pain, we present the case of a 14 year-old girl with a huge trichobezoar which completely filled the stomach and extended into the small bowel. Since trichobezoar has an extension to the small bowel, it is classified as Rapunzel syndrome. As the bezoar couldn't be removed by endoscopy, the girl underwent surgical intervention. The patient passed through a gradual re-feeding, with iron and vitamins supplementation, and through a psychiatric counselling. CONCLUSION: The Rapunzel syndrome is a rare entity that may be complicated by life-threatening events. A prompt diagnosis and an appropriate therapy can reduce comorbidities. Gradual re-feeding with supplementation of micronutrients allows adequate catch-up weight with normalization of haematochemical nutritional parameters. Since many of these patients suffer from psychiatric pathology such as PICA with emotional problems and mental retardation, psychological/psychiatric counselling plays an important role in order to prevent bezoar recurrence.

Noonan syndrome-like disorder with loose anagen hair: a second case with neuroblastoma.

Noonan-like syndrome with loose anagen hair (NSLH), also known as Mazzanti syndrome, is a RASopathy characterized by craniofacial features resembling Noonan syndrome, cardiac defects, cognitive deficits and behavioral issues, reduced growth generally associated with GH deficit, darkly pigmented skin, and an unique combination of ectodermal anomalies. Virtually all cases of NSLH are caused by an invariant and functionally unique mutation in SHOC2 (c.4A>G, p.Ser2Gly). Here, we report on a child with molecularly confirmed NSLH who developed a neuroblastoma, first suspected at the age 3 months by abdominal ultrasound examination. Based on this finding, scanning of the SHOC2 coding sequence encompassing the c.4A>G change was performed on selected pediatric cohorts of malignancies documented to occur in RASopathies (i.e., neuroblastoma, brain tumors, rhabdomyosarcoma, acute lymphoblastic, and myeloid leukemia), but failed to identify a functionally relevant cancer-associated variant. While these results do not support a major role of somatic SHOC2 mutations in these pediatric cancers, this second instance of neuroblastoma in NSLAH suggests a possible predisposition to this malignancy in subjects heterozygous for the c.4A>G SHOC2 mutation.

Rickets Types and Treatment with Vitamin D and Analogues.

The definition of "Vitamin D" encompasses a group of fat-soluble steroid compounds of different origins with similar chemical structures and the same biological effects. Vitamin D deficiency and/or a defect in the process of its synthesis or transport predispose individuals to several types of rickets. In addition to cholecalciferol, ergocalciferol, and vitamins D3 and D2, there are also active metabolites for the treatment of this condition which are commercially available. Calcitriol and aphacalcidiol are active metabolites that do not require the renal activation step, which is required with calcifediol, or hepatic activation. The purpose of this review is to summarize current approaches to the treatment of rickets for generalist physicians, focusing on the best vitamin D form to be used in each type, or, in the case of X-linked hypophosphatemic rickets (XLH), on both conventional and innovative monoclonal antibody treatments.

Plant Sterols and Stanols for Pediatric Patients with Increased Cardiovascular Risk.

The atherosclerotic process begins in childhood and progresses throughout adult age. Hypercholesterolemia, especially familial hypercholesterolemia (FH) and metabolic dysfunctions linked to weight excess and obesity, are the main atherosclerosis risk factors in pediatric patients and can be detected and treated starting from childhood. Nutritional intervention and a healthy-heart lifestyle are cornerstones and first-line treatments, with which, if necessary, drug therapy should be associated. For several years, functional foods enriched with plant sterols and stanols have been studied in the treatment of hypercholesterolemia, mainly as nutritional complements that can reduce LDL cholesterol; however, there is a lack of randomized controlled trials defining their long-term efficacy and safety, especially in pediatric age. This review aims to evaluate what the main published studies on sterols and stanols in pediatric subjects with dyslipidemia have taught us, providing an updated picture of the possible use of these dietary supplements in children and adolescents with dyslipidemia and increased cardiovascular risk. Nowadays, we can state that plant sterols and stanols should be considered as a valuable therapy in pediatric patients with hypercholesterolemia, bearing in mind that nutritional and lifestyle counseling and, when necessary, pharmacologic therapy, are the cornerstones of the treatment in developmental age.

Diet and Lipid-Lowering Nutraceuticals in Pediatric Patients with Familial Hypercholesterolemia.

Familial hypercholesterolemia is a genetically determined disease characterized by elevated plasma total and LDL cholesterol levels from the very first years of life, leading to early atherosclerosis. Nutritional intervention is the first-line treatment, complemented with nutraceuticals and drug therapy when necessary. Nutraceuticals with a lipid-lowering effect have been extensively studied in the past few decades, and have been recently included in international guidelines as a complement to nutritional and pharmacological treatment in subjects with dyslipidemia. In this review, we explore current nutritional interventions for dyslipidemia in childhood, with a specific focus on the main nutraceuticals studied for treating severe dyslipidemia in pediatric patients. Additionally, we briefly describe their primary mechanisms of action and highlight the advantages and risks associated with the use of lipid-lowering nutraceuticals in childhood.

Pediatric Gaucher Disease Type 3 Presenting with Oculomotor Apraxia: A Case Report.

We report on a 4-year-old boy affected by Gaucher disease (GD) type 3, who presented with splenomegaly and a history of oculomotor apraxia. GD is a rare lysosomal storage disorder caused by glucocerebrosidase deficiency with multi-organ involvement. Besides common clinical features such as hepatosplenomegaly and skeletal involvement, less frequent neurological symptoms, such as oculomotor apraxia, are indicative of neuronopathic forms of the disease, namely GD type 3, to be confirmed both by enzyme activity and genetic testing. Overall, GD management requires a multidisciplinary approach involving metabolic pediatricians, neurologists, psychologists, and geneticists, and currently relies on early enzyme replacement therapy. Although enzyme replacement therapy has proved to be effective in improving systemic signs and symptoms, it is unable to alleviate neurological complications once these have occurred, as it does not pass across the blood-brain barrier. Neurological improvements may occur through indirect mechanisms. Thus, our case report aims to highlight the importance of considering GD in the differential diagnosis of pediatric patients presenting with splenomegaly associated with neurological manifestations, as early intervention may significantly modify the disease progression and prevent further irreversible complications.

Osteoporosis and Bone Fragility in Children: Diagnostic and Treatment Strategies.

The incidence of osteoporosis in children is increasing because of the increased survival rate of children with chronic diseases and the increased use of bone-damaging drugs. As childhood bone fragility has several etiologies, its management requires a thorough evaluation of all potentially contributing pathogenetic mechanisms. This review focuses on the main causes of primary and secondary osteoporosis and on the benefits and limits of the different radiological methods currently used in clinical practice for the study of bone quality. The therapeutic and preventive strategies currently available and the most novel diagnostic and treatment strategies are also presented. Optimal management of underlying systemic conditions is key for the treatment of bone fragility in childhood. DXA still represents the gold standard for the radiologic evaluation of bone health in children, although other imaging techniques such as computed tomography and ultrasound evaluations, as well as REMS, are increasingly studied and used. Bisphosphonate therapy is the gold standard for pharmacological treatment in both primary and secondary pediatric osteoporosis. Evidence and experience are building up relative to the use of monoclonal antibodies such as denosumab in cases of poor response to bisphosphonates in specific conditions such as osteogenesis imperfecta, juvenile Paget's disease and in some cases of secondary osteoporosis. Lifestyle interventions including adequate nutrition with adequate calcium and vitamin D intake, as well as physical activity, are recommended for prevention.

Probiotics in Infancy and Childhood for Food Allergy Prevention and Treatment.

Food allergy represents a failure of oral tolerance mechanisms to dietary antigens. Over the past few years, food allergies have become a growing public health problem worldwide. Gut microbiota is believed to have a significant impact on oral tolerance to food antigens and in initiation and maintenance of food allergies. Therefore, probiotics have also been proposed in this field as a possible strategy for modulating both the gut microbiota and the immune system. In recent years, results from preclinical and clinical studies suggest a promising role for probiotics in food allergy prevention and treatment. However, future studies are needed to better understand the mechanisms of action of probiotics in food allergies and to design comparable study protocols using specific probiotic strains, defined doses and exposure times, and longer follow-up periods.

Nutrition for Children and Adolescents Who Practice Sport: A Narrative Review.

At a developmental age, adequate physical activity is fundamental to overall health and well-being and preventing obesity. Moreover, establishing active behavior can help children and adolescents meet their growth and neurodevelopmental goals. Nutritional requirements vary according to intensity, frequency, and practiced physical activity or sport; therefore, pediatricians should give children and adolescents and their families adequate counseling, avoiding both nutrient deficiencies and excessive or inadequate supplement intake. The focus should be not only on sports performance but also on the child's well-being, growth, and neurodevelopment. Our narrative review aims to discuss the nutritional needs of children and adolescents who practice physical activity, non-competitive sports activity, and elite sports activity while also analyzing the role of food supplements and the risk of eating disorders within this category of subjects.

Complementary Feeding in the Clinical Practice: An Exploratory Survey among Italian Primary Care Pediatricians.

Introduction: Complementary feeding (CF) is the process of introducing solid or liquid foods (complementary foods, CFs) other than human breast milk (HBM) or infant formula into infants' diet when HBM or infant formula is no longer sufficient to meet infants' nutritional needs. Primary care pediatricians (PCPs) are paramount in guiding and educating infants' families during CF. Materials and Methods: Our exploratory survey aimed to investigate PCPs' current clinical approach to managing CF. From 1 March 2024 to 30 April 2024, a digital questionnaire composed of 32 multiple-choice questions investigating PCPs' attitudes toward CF in healthy, full-term infants was proposed to 1620 PCPs contacted through scientific societies. Results: The questionnaire was completed voluntarily; 707 PCPs (79.5% female, 66.1% aged over 50 years) fully responded to the survey in the proposed timeframe (participation rate 43.6%). Among the responders, 47.5% recommended traditional CF; 42.1% declared to know the baby-led weaning (BLW) approach and on-demand CF (ODCF), but only 32.8% and 12.5% of them recommended these types of CF, respectively. The vast majority (95%) of participants recommended that CF start between 4 to 6 completed months of age. CF routinely based on vegetarian or plant-based diets was supported by 45/707 (6.1%), only if planned by a specialist by 253/707 (35.8%), and only upon request by caregivers by 257/707 (36.3%). Egg and fish introduction was mostly advised in the first year of life, although in case of a positive family history of food allergy, 13.3% of participants recommended the introduction of egg and fish after 12 months. Conclusions: In conclusion, PCPs did not display a homogenous approach to CF; further studies and educational programs are needed to achieve more flexibility and knowledge on this important nutritional issue.