Perceptions and Expectations of Youth Regarding the Respect for Their Rights in the Hospital.

Information obtained from children themselves regarding the characteristics of the ideal hospital that ensure well-being during a hospital stay is scarce. Here, we report the opinions, perceptions, and expectations of 700 children and adolescents about their experiences, assessed through a mixed-method research approach with age-appropriate questionnaires, three open-ended questions, and an analysis of optional pictorial and textual narratives. Most children indicated that, while they acknowledged the expertise of hospital staff, they also noted several shortcomings, e.g., insufficiently understandable medical information as well as emotional and cognitive support. The continuity of schooling and the right to suffer as little as possible were also critical issues. Adolescents valued in particular the quality of care and services provided, the hospital's adherence to equality and non-discrimination rights, and protection systems but negatively perceived several aspects related to play and participation. Significant differences in the co-occurrences of the most frequently used text terms with the keywords "hospital" and "child/adolescent" between age groups highlight variations in the way patients perceive and articulate their experiences within the hospital setting depending on the cognitive processes linked to age. In drawings, prevailing attention was placed on the physical context of the hospital room, with figures expressing mostly negative emotions. Specifically, in this regard, the main emotion in children was sadness, and, in adolescents, it was fear. Overall, these insights are pivotal in the context of our research objectives as they shed light on the nuanced preferences, needs, and perspectives of children and adolescents during their hospital stays. Recognizing the identified shortcomings, we propose recommendations emphasizing the improvement of medical communication clarity, enhancement of emotional and cognitive support, and the improvement of programs to avoid instructional gaps during hospital stays. Addressing these specific needs is critical for a more comprehensive approach to pediatric healthcare provision.

De Novo Mutation in KMT2C Manifesting as Kleefstra Syndrome 2: Case Report and Literature Review.

Diagnosis of pediatric intellectual disability (ID) can be difficult because it is due to a vast number of established and novel causes. Here, we described a full-term female infant affected by Kleefstra syndrome-2 presenting with neurodevelopmental disorder, a history of hypotonia and minor face anomalies. A systematic literature review was also performed. The patient was a 6-year-old Caucasian female. In the family history there was no intellectual disability or genetic conditions. Auxological parameters at birth were adequate for gestational age. Clinical evaluation at 6 months revealed hypotonia and, successively, delay in the acquisition of the stages of psychomotor development. Auditory, visual, somatosensory, and motor-evoked potentials were normal. A brain MRI, performed at 9 months, showed minimal gliotic changes in bilateral occipital periventricular white matter. Neuropsychiatric control, performed at 5 years, established a definitive diagnosis of childhood autism and developmental delay. Molecular analysis of the exome revealed a novel KMT2C missense variant: c.9244C > T (p.Pro3082Ser) at a heterozygous state, giving her a diagnosis of Kleefstra syndrome 2. Parents did not show the variant. Literature review (four retrieved eligible studies, 10 patients) showed that all individuals had mild, moderate, or severe ID; language and motor delay; and autism. Short stature, microcephaly, childhood hypotonia and plagiocephaly were also present. Conclusion. Kleefstra syndrome 2 is a difficult diagnosis of a rare condition with a high clinical phenotypic heterogeneity. This study suggests that it must be taken in account in the work-up of an orphan diagnosis of intellectual disability and/or autism spectrum disorder.

Consumptive Hypothyroidism due to Hepatic Hemangiomas: A Case Series and Review of the Literature.

Consumptive hypothyroidism (CH) is a rare and potentially overlooked complication of hepatic hemangiomas (HH) overexpressing the enzyme deiodinase, which converts thyroxine (T4) to reverse triiodothyronine (rT3). Materials and methods: Here, we report a case series of 3 patients and a systematic review of the literature. Results: Hypothyroidism (mean serum TSH 52.03 mIU/L) was detected at a mean age of 4.6 months (range 3-6) in 3 infants with infantile hepatic hemangiomas, treated with thyroxine (mean dose 12 µg/kg/day). All received treatment with propranolol (1-3 mg/kg/day) from the mean age of 4 months. Hormonal treatment was stopped at a mean age of 20 months (range 12-30). Hypothyroidism reoccurred in a patient concurrently with the increase of liver lesions, requiring liver transplantation (LT) at age 39 months.Literature review retrieved 42 studies (48 patients): HH (n = 43) were isolated in 24 infants and associated with cutaneous hemangiomas in 19. Hemangiomas were only cutaneous in 5.In the first 43 patients, hypothyroidism was detected at a mean age of 1 month; 21 of 43 patients were prescribed propranolol alone (n = 8) or associated with other medicaments (n = 13); 2 of 43 patients underwent LT. Hormonal treatment consisted of T4 in 35 of 43 patients and T3 in 10.CH associated with only cutaneous and extrahepatic visceral hemangiomas (n = 5), detected at a mean age of 7 months (TSH mean levels at diagnosis of 150.3 mIU/L). Three of 5 patients received treatment with propranolol ± other medicaments. All 5 patients were treated with T4. Conclusions: Periodical thyroid function assessment is necessary in patients with hepatic hemangiomas, particularly when lesions' size and number increase rapidly.

Clinical heterogeneity of Kabuki syndrome in a cohort of Italian patients and review of the literature.

Kabuki syndrome (KS) is a well-recognized disorder characterized by postnatal growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability. The syndrome is caused by KMT2D gene mutations or less frequently KDM6A gene mutations or deletions. We report a systematic evaluation of KS patients from Campania region of Italy; data were also compared with literature ones. We collected data of 15 subjects (8 males and 7 females with age range 10-26 years; mean age 16.9 years) with confirmed diagnosis of KS, representing the entire cohort of patients from Campania Region. Each patient performed biochemical testing and instrumental investigation. Neuro-intellectual development, cranio-facial dysmorphisms, and multisystem involvement data were collected retrospectively. For each category, type of defects and frequency of the anomalies were analyzed. Our observation shows that KS patients from Campania region have some particular and previously underscored, neurological and immunological findings. We found high prevalence of EEG's abnormalities (43%) and MRI brain abnormalities (60%). Microcephaly resulted more common in our series (33%), if compared with major cohorts described in literature. Biochemical features of immunodeficiency and autoimmune diseases including thyroid autoimmunity, polyserositis, and vitiligo were observed with high prevalence (54.5%). Low immunoglobulins levels were a frequent finding. Lymphocyte class investigation showed significantly reduced CD8 levels in one patient.Conclusions: These data confirm great heterogeneity of clinical manifestations in KS and suggest to introduce further clinical diagnostic criteria in order to perform a correct and precocious diagnosis. What is Known • Kabuki syndrome is characterized by growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability • Immune dysfunction is a common finding but autoimmune diseases are rarely seen • Neurological features are common What is New • Some particular facial features could help gestalt diagnosis (hypertelorism, broad nasal bridge, micrognathia, tooth agenesis, cutaneous haemangiomas and strabismus) • Higher prevalence of autoimmune disorders than previously reported • Particular neurological features are present in this cohort (EEG and MRI brain abnormalities).

RASopathies and hemostatic abnormalities: key role of platelet dysfunction.

BACKGROUND: Bleeding anomalies have been reported in patients affected by Noonan syndrome. No study has been performed in patients with molecularly confirmed RASopathy. We aimed to characterize the frequency and types of bleeding disorders in patients with RASopathies and evaluate any significant association with laboratory findings. PATIENTS AND METHODS: Forty-nine individuals (PTPN11, n = 27; SOS1, n = 7; RIT1, n = 3; SPRED1, n = 1; LZTR1, N = 3; RAF1, n = 2; BRAF, n = 4; MEK1, n = 1; MEK2, n = 1), and 49 age- and sex-matched controls were enrolled. The "Paediatric Bleeding Questionnaire Scoring Key" was administered to patients and families. Laboratory screening tests including clotting factors dosing, platelet count, Prothrombin Time and Partial Thromboplastin Time, were employed both in patients and controls to characterize the bleeding diathesis. A subgroup of 29/49 patients and 29/49 controls was also tested for platelet function. RESULTS: Regardless of the gene involved, pathological paediatric bleeding scores were recorded in 14/49 (28.5%) patients. Indeed, 7 were mutated in PTPN11, 3 in SOS1, 2 in RIT1, 1 in BRAF, and 1 in MEK1. Compared to patients with normal bleeding scores, those with pathologic bleeding score showed higher prevalence of splenomegaly (p = 0.006), prolonged aPTT (p = 0.04), lower levels of coagulation factor V (FV, p = 0.001), FVII (p = 0.003), FX (p = 0.0008) and FXIII (p = 0.002), higher vWAg (p = 0.04), and lower platelet sensitivity to Ristocetin (p = 0.001), arachidonic acid (AA) (p = 0.009) and collagen (p = 0.01). The presence of hematomas inversely correlated with factor V (p = 0.002), factor VII (p = 0.003), factor X (p = 0.002) and factor XIII (p = 0.004) levels, and directly correlated with platelet response to collagen (p = 0.02) and AA (p = 0.01). The presence of splenomegaly directly correlated with the presence of hematoma (p = 0.006), platelet response to Ristocetin (p = 0.04) and AA (p = 0.04), and inversely correlated with factor V levels (p = 0.03). CONCLUSIONS: Patients with RASopathies and a bleeding tendency exhibit multiple laboratory abnormalities, including platelet-related disorders. Splenomegaly is frequently detected and might be a suggestive sign for qualitative platelet dysfunction. A comprehensive clinical assessment should be carried out at diagnosis, during the follow-up and before any surgical procedures. Since there is currently no consensus on management of bleeding complications, it is important that physicians closely monitor these patients.

Clinical variability of neurofibromatosis 1: A modifying role of cooccurring PTPN11 variants and atypical brain MRI findings.

Neurofibromatosis 1 (NF1) is a disorder characterized by variable expressivity caused by loss-of-function variants in NF1, encoding neurofibromin, a protein negatively controlling RAS signaling. We evaluated whether concurrent variation in proteins functionally linked to neurofibromin contribute to the variable expressivity of NF1. Parallel sequencing of a RASopathy gene panel in 138 individuals with molecularly confirmed clinical diagnosis of NF1 identified missense variants in PTPN11, encoding SHP2, a positive regulator of RAS signaling, in four subjects from three unrelated families. Three subjects were heterozygous for a gain-of-function variant and showed a severe expression of NF1 (developmental delay, multiple cerebral neoplasms and peculiar cortical MRI findings), and features resembling Noonan syndrome (a RASopathy caused by activating variants in PTPN11). Conversely, the fourth subject, who showed an attenuated presentation, carried a previously unreported PTPN11 variant that had a hypomorphic behavior in vitro. Our findings document that functionally relevant PTPN11 variants occur in a small but significant proportion of subjects with NF1 modulating disease presentation, suggesting a model in which the clinical expression of pathogenic NF1 variants is modified by concomitant dysregulation of protein(s) functionally linked to neurofibromin. We also suggest targeting of SHP2 function as an approach to treat evolutive complications of NF1.

Atypically Protracted Course of Liver Involvement in Kawasaki Disease. Case Report and Literature Review.

Hypertransaminasemia in patients with Kawasaki disease (KD) is reported to be transient. Here, we describe a child with an atypically protracted course of liver tests abnormalities and review the inherent literature. The patient was hospitalized at age 7-months for isolated hypertransaminasemia detected during a classical KD diagnosed 3 months before, and persistent since then. KD clinical evolution had been favorable, with rapid response to acetylsalicylic acid and intravenous immunoglobulins. Liver enzymes however remained persistently elevated with a fluctuating pattern (ALT > AST levels; peak of AST 186 IU/L and ALT 240 IU/L). During follow-up, the main causes of liver dysfunction had to be excluded through appropriate and extensive laboratory investigations. Transaminases values become steadily normal only 7 months after the acute presentation of KD. Conclusions: Our report shows that an atypically protracted courses of KD-related hypertransaminasemia above the previously reported temporal limits should be taken into account during the stepwise diagnostic approach to the patient's liver dysfunction. Insidious acetylsalycilic acid-hepatotoxicity warrants consideration in the differential diagnosis.

Hepatic Presentation of Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): Case Report and Systematic Review.

Diagnosis of pediatric steatohepatitis is a challenging issue due to a vast number of established and novel causes. Here, we report a child with Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) presenting with an underrated muscle weakness, exercise intolerance and an atypically severe steatotic liver involvement. A systematic literature review of liver involvement in MADD was performed as well. Our patient is a 11-year-old otherwise healthy, non-obese, male child admitted for some weakness/asthenia, vomiting and recurrent severe hypertransaminasemia (aspartate and alanine aminotransferases up to ×20 times upper limit of normal). Hepatic ultrasound showed a bright liver. MRI detected mild lipid storage of thighs muscles. A liver biopsy showed a micro-macrovacuolar steatohepatitis with minimal fibrosis. Main causes of hypertransaminasemia were ruled out. Serum aminoacids (increased proline), acylcarnitines (increased C4-C18) and a large excretion of urinary glutaric acid, ethylmalonic, butyric, isobutyric, 2-methyl-butyric and isovaleric acids suggested a diagnosis of MADD. Serum acylcarnitines and urinary organic acids fluctuated overtime paralleling serum transaminases during periods of illness/catabolic stress, confirming their recurrent nature. Genetic testing confirmed the diagnosis [homozygous c.1658A > G (p.Tyr553Cys) in exon 12 of the ETFDH gene]. Lipid-restricted diet and riboflavin treatment rapidly ameliorated symptoms, hepatic ultrasonography/enzymes, and metabolic profiles. Literature review (37 retrieved eligible studies, 283 patients) showed that liver is an extramuscular organ rarely involved in late-onset MADD (70 patients), and that amongst 45 patients who had fatty liver only nine had severe presentation. Conclusion: MADD is a disorder with a clinically heterogeneous phenotype. Our study suggests that MADD warrants consideration in the work-up of obesity-unrelated severe steatohepatitis.

A ZFYVE19 gene mutation associated with neonatal cholestasis and cilia dysfunction: case report with a novel pathogenic variant.

BACKGROUND: ZFYVE19 (Zinc Finger FYVE-Type Containing 19) mutations have most recently been associated to a novel type of high gamma-glutamyl transpeptidase (GGT), non-syndromic, neonatal-onset intrahepatic chronic cholestasis possibly associated to cilia dysfunction. Herein, we report a new case with further studies of whole exome sequencing (WES) and immunofluorescence in primary cilia of her cultured fibroblasts which confirm the observation. RESULTS: A now 5-year-old girl born to clinically healthy consanguineous Moroccan parents was assessed at 59 days of life due to severe cholestatic jaundice with increased serum bile acids and GGT, and preserved hepatocellular synthetic function. Despite fibrosis/cirrhosis and biliary ducts proliferation on liver biopsy suggested an extrahepatic biliary obstacle, normal intra-operatory cholangiography excluded biliary atresia. Under choleretic treatment, she maintained a clinically stable anicteric cholestasis but developped hyperlipidemia. After exclusion of the main causes of cholestasis by multiple tests, abnormal concentrations of sterols and WES led to a diagnosis of hereditary sitosterolemia (OMIM #618666), likely unrelated to her cholestasis. Further sequencing investigation revealed a homozygous non-sense mutation (p.Arg223Ter) in ZFYVE19 leading to a 222 aa truncated protein and present in both heterozygous parents. Immunofluorescence analysis of primary cilia on cultured skin fibroblasts showed a ciliary phenotype mainly defined by fragmented cilia and centrioles abnormalities. CONCLUSIONS: Our findings are consistent with and expands the recent evidence linking ZFYVE19 to a novel, likely non-syndromic, high GGT-PFIC phenotype with neonatal onset. Due to the possible role of ZFYVE19 in cilia function and the unprecedented coexistence of a coincidental hereditary sterol disorder in our case, continuous monitoring will be necessary to substantiate type of liver disease progression and/or possible emergence of a multisystemic involvement. What mentioned above confirms that the application of WES in children with undiagnosed cholestasis may lead to the identification of new causative genes, widening the knowledge on the pathophysiology.

Oxidative Stress in Non-alcoholic Fatty Liver Disease. An Updated Mini Review.

Non-alcoholic fatty liver disease (NAFLD) is a challenging disease caused by multiple factors, which may partly explain why it remains still orphan of an adequate therapeutic strategy. Herein we focus on the interplay between oxidative stress (OS) and the other causal pathogenetic factors. Different reactive oxygen species (ROS) generators contribute to NAFLD inflammatory and fibrotic progression, which is quite strictly linked to the lipotoxic liver injury from fatty acids and/or a wide variety of their biologically active metabolites in the context of either a two-hit or a (more recent) multiple parallel hits theory. An antioxidant defense system is usually able to protect hepatic cells from damaging effects caused by ROS, including those produced into the gastrointestinal tract, i.e., by-products generated by usual cellular metabolic processes, normal or dysbiotic microbiota, and/or diet through an enhanced gut-liver axis. Oxidative stress originating from the imbalance between ROS generation and antioxidant defenses is under the influence of individual genetic and epigenetic factors as well. Healthy diet and physical activity have been shown to be effective on NAFLD also with antioxidant mechanisms, but compliance to these lifestyles is very low. Among several considered antioxidants, vitamin E has been particularly studied; however, data are still contradictory. Some studies with natural polyphenols proposed for NAFLD prevention and treatment are encouraging. Probiotics, prebiotics, diet, or fecal microbiota transplantation represent new therapeutic approaches targeting the gut microbiota dysbiosis. In the near future, precision medicine taking into consideration genetic or environmental epigenetic risk factors will likely assist in further selecting the treatment that could work best for a specific patient.

Analgesic effects of breast- and formula feeding during routine childhood immunizations up to 1 year of age.

BACKGROUND: Data on analgesic effects of breast/formula milk sucking while receiving routine childhood immunizations are available only in early infancy, have rarely been compared in the same study, and are not accompanied by information on mothers' satisfaction/acceptance. Here we aimed to compare the analgesic effect of both methods vs. held-only controls up to 1 year of age, and verify mothers' satisfaction. METHODS: Two to 12 months children subjected to vaccine were allocated into three groups: breastfed, formula-fed, and held-only controls. A video recording was performed to analyze pain parameters: crying latency/duration and specific scales [FLACC (Face, Legs, Activity, Cry, and Consolability), NIPS (Neonatal Infant Pain Scale)]. After the procedure, mothers filled in a satisfaction questionnaire. RESULTS: One-hundred and sixty-two children were recruited: 54 breastfed, 35 formula fed, and 73 controls. Breastfed showed the longest crying latency, and together with formula fed, had the shortest duration and lowest pain scores. Most mothers appreciated not only the respective feeding-mediated pain mitigation method used, but also the simply-holding procedure. In all cases, they felt reassured, with an unexpected frequent underestimation of their child's pain during the shot. CONCLUSIONS: The analgesic effect of breastfeeding during vaccination extends also to children >6 months old, and is obtained by formula too. Embracing the child may help to reassure mothers. IMPACT: We confirmed the analgesic effect of breastfeeding during the vaccination procedures in early infancy. We show for the first time that this effect is extended also to children up to 1 year of age, and it may be obtained by formula feeding as well. Most mothers appreciated pain mitigation not only through feeding, but also the simply-holding procedure. In all cases, mothers felt reassured, with an unexpected frequent underestimation of their child' pain during the shot. The promotion of these easily feasible and well-accepted strategies should be further encouraged within health professionals during vaccination procedures.

Humanization interventions in general pediatric wards: a systematic review.

Humanization of care (HOC) interventions have rarely been evaluated and compared. We systematically reviewed the outcomes of published interventions aimed to improve the HOC for hospitalized children. PubMed and Scopus were used as data sources. Studies published between January 1, 2000, and February 28, 2018, were considered eligible if they reported analysis of results vs. either a control group or baseline, or if they measured patient/family/staff satisfaction. Neonatal age, emergency departments, and subspecialty settings were excluded. Data were extracted using a standardized data extraction form including study design, sample size, intervention, outcome/objective, and evaluation of results or pre- post-intervention satisfaction. Twenty-eight of the 12,012 retrieved articles met the inclusion criteria. Most studies were of moderate to low quality. Only six studies were of high quality. Areas of interest dealt with environment (n = 4), provider-patient relationship (n = 6), pet therapy (n = 5), technology (n = 5), family-centered rounds (n = 2), psychological support (n = 3), and staff training (n = 3). The overall trend of the results indicated that interventions were mostly effective and likely to have beneficial effects on several aspects of pediatric hospitalization.Conclusions: Pending further studies of better research quality, the findings of this review may have policy and practice implications for planning HOC interventions by pediatric healthcare professionals. What is Known: • In pediatrics, humanization of care (HOC) provides assistance focused not only on the child as a patient, but on the whole family. • HOC programs have been developed, but information on the overall outcome of local projects aiming to improve in a practical way the hospital taking charge of pediatric patients is still lacking. What is New: • Local HOC interventions are mostly effective and have beneficial effects on several aspects of hospitalization in general pediatrics wards. • The findings of this review may have practice implications for planning HOC interventions by pediatric healthcare professionals.

Humanization of pediatric care in the world: focus and review of existing models and measurement tools.

BACKGROUND: The term "humanization" indicates the process by which people try to make something more human and civilized, more in line with what is believed to be the human nature. The humanization of care is an important and not yet a well-defined issue which includes a wide range of aspects related to the approach to the patient and care modalities. In pediatrics, the humanization concept is even vaguer due to the dual involvement of both the child and his/her family and by the existence of multiple proposed models. OBJECTIVE: The present study aims to analyze the main existing humanization models regarding pediatric care, and the tools for assessing its grade. RESULTS: The main Humanization care programs have been elaborated and developed both in America (Brazil, USA) and Europe. The North American and European models specifically concern pediatric care, while the model developed in Brazil is part of a broader program aimed at all age groups. The first emphasis is on the importance of the family in child care, the second emphasis is on the child's right to be a leader, to be heard and to be able to express its opinion on the program's own care. Several tools have been created and used to evaluate humanization of care programs and related aspects. None, however, had been mutually compared. CONCLUSIONS: The major models of humanization care and the related assessment tools here reviewed highlight the urgent need for a more unifying approach, which may help in realizing health care programs closer to the young patient's and his/her family needs.