Childhood gratification syndrome: Demystifying the clinical conundrum with a narrative literature review of the past 5 decades.

Background: Childhood gratification syndrome (CGS) refers to self-stimulatory or masturbatory behaviors in children, which may have an onset as early as in infancy (IGS). Aim: The aim of this review is to understand the various clinical manifestations of CGS/IGS and their clinical differentiation from commonly misdiagnosed neurological and physical illnesses and to formulate a preliminary approach to their diagnosis and management. Methods: This narrative review is based on a search of literature over the past 50 years (1972-2022) in three online databases (PubMed/Medline, Embase, and Google Scholar). Results: The behaviors are episodic, occurring for brief periods, involving posturing, stereotypical limb movements, pubic pressure with autonomic hyperactivity, and postepisodic lethargy. They mimic seizures, movement disorders, abdominal pain, and tics. The paper also highlights the gap in the current knowledge to guide future research in the area. CGS usually represents nonpathological "pleasure-seeking" habits of childhood, but at times, it may become problematic for the child and his family. A careful history and videotape analysis of the events confirms the diagnosis and behavioral therapy with parental reassurance as the mainstay of treatment. Conclusion: A better understanding and clinical awareness of the CGS are necessary to prevent misdiagnosis and delay in appropriate intervention.

The impact of meteorological factors on the incidence of infantile atopic dermatitis.

BACKGROUND: The role of the climate regarding atopic dermatitis (AD) in infants is still unclear. This study aimed to determine the relationship between meteorological conditions and the incidence of early AD. METHODS: The study was conducted using a retrospective design. We analyzed children aged 0-24 months with clinically diagnosed AD (n = 603), including infantile eczema (IE, n = 292), in relation to the mean monthly meteorological data in Minsk. The Mantel-Haenszel method was used to study the association between an AD outcome and meteorological variables, stratifying by potential confounders. Seasons of birth were analyzed in children diagnosed with AD before 6 months of age (n = 567) and at 12 months of age (n = 350) from 2005 to 2019. RESULTS: The incidence rate of IE was negatively associated with air temperature (adjusted incidence rate ratio = 0.75; 95% confidence interval (CI) 0.59-0.94), precipitation (0.74; 95% CI 0.58-0.93), and positively associated with atmospheric pressure (1.31; 95% CI 1.04-1.66). The highest incidence rate of IE was during spring, and the lowest was during summer. Incidences of AD were less frequent among infants born in the spring (18.1% vs. 29.4%, P < 0.001) than among older children. The principal component analysis identified three meteorological combinations where the first one (warm, low humidity) was negatively associated with the incidence rate of AD among children aged 0-24 months (0.77; 95% CI 0.65-0.92), and the third one (rainy, low atmospheric pressure) with IE (0.70; 95% CI 0.54-0.90). CONCLUSION: Continental seasonal cold-humid weather may influence early AD incidence. Moreover, short-term meteorological factors may play an important role in the onset of IE.

Maternal history of angioma is associated with infantile hemangioma and port-wine stain in children: a population-based, cohort study of mother-child pairs from the United Kingdom.

The two most prevalent childhood vascular abnormalities are infantile hemangioma (IH) and port-wine stain (PWS). They become apparent shortly after birth but have distinct pathophysiology and clinical manifestations. The goal of this study was to determine if mother's history of angioma or PWS is associated with these vascular abnormalities. We evaluated an UK anonymized electronic medical records database with medical records that were linked between children and their mothers. Cox proportional hazards models were used to evaluate the association between maternal factors and the time of onset of either IH or PWS in children. Between 2004 and 2021, 639,085 children were linked to their mom's medical data with a total of 4,270,773 person-years of follow up. Children born to mothers with an angioma as compared to a mother without an angioma were more than 60% more likely to have an IH (HR: 1.64 [1.07, 2.52]). Children born to mothers with a PWS as compared to children born to mothers without a PWS were nearly 20 times more likely to have a PWS (18.95 [4.71,76.26]). Mothers with angiomas were not more likely to have children with PWS and mothers with PWS were not more likely to have children with IH. The effect estimates were minimally changed after adjustment. We demonstrated that children born to mothers with angiomas or PWS were at increased risk of IH or PWS, respectively.

Genotypic and phenotypic analysis of Korean patients with tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder caused by mutations in the TSC1 or TSC2 gene. The aim of this study was to analyze the genotypes and phenotypes of Korean patients diagnosed with TSC and expand our understanding of this disorder. This retrospective observational study included 331 patients clinically diagnosed with TSC between November 1990 and April 2023 at Severance Children's Hospital, Seoul, South Korea. The demographic and clinical characteristics of the patients were investigated. Thirty novel variants were identified. Of the 331 patients, 188 underwent genetic testing, and genotype-phenotype variation was analyzed according to the type of gene mutation and functional domain. Fourty-nine patients (49/188, 26%) were had TSC1 mutations, 103 (55%) had TSC2 mutations, and 36 (19%) had no mutation identified (NMI). Hotspots were identified in exons 8 of TSC1 and exons 35 and 41 of TSC2. Patients with TSC2 mutations exhibited a significantly younger age at the time of seizure onset and had refractory epilepsy. Infantile epileptic spasms syndrome (IESS) was more common in the middle mutation domain of TSC2 than in the hamartin domain. Additionally, retinal hamartoma, cardiac rhabdomyoma, and renal abnormalities were significantly associated with TSC2 compared with other gene types. This study contributes to our understanding of TSC by expanding the genotypic spectrum with novel variants and providing insights into the clinical spectrum of patients with TSC in Korea.

Portal vein hypoplasia is present in patients with biliary atresia at the time of diagnosis.

BACKGROUND: In patients with biliary atresia (BA), severe portal hypertension (HTN) develops even with successful bile flow restoration, suggesting an intrinsic factor driving portal HTN independent from bile obstruction. We hypothesize that patients with BA have abnormal portal vein (PV) development, leading to PV hypoplasia. METHODS: In this observational cohort study, we enrolled patients who were referred to a tertiary center from 2017 to 2021 to rule out BA. Newborns who underwent computed tomography (CT) angiogram as a clinical routine before intraoperative cholangiogram, and laparoscopic Kasai hepatoportoenterostomy. The diameter of the PV and hepatic artery (HA) were compared to the degree of liver fibrosis in the wedge biopsies. The jaundice clearance, native liver survival, and clinical portal hypertensive events, including ascites development and intestinal bleeding, were assessed. RESULTS: 47 newborns with cholestasis were included in the cohort; 35 were diagnosed with BA. The patients with BA had a smaller median PV diameter (4.3 vs. 5.1 mm; p < 0.001) and larger median HA diameter (1.4 vs. 1.2 mm; p < 0.05) compared to the patients with other forms of cholestasis. The median PV and HA diameter did not correlate with the degree of liver fibrosis. Among 35 patients with BA, 29 patients (82.9%) achieved jaundice clearance, and 23 patients (65.7%) were alive with their native liver at two years of age. Seven patients (20%) developed intestinal bleeding, and seven patients (20%) developed ascites, with one overlapping patient. CONCLUSION: PV hypoplasia is present in patients with BA independent of liver fibrosis at the time of diagnosis.

The treatment of infantile giant café au lait spot using golden parameter therapy with a high fluence 1064-nm Q-switched Nd: YAG laser.

BACKGROUND: Infantile café au lait spot is a brown macule with various sizes (diameter: 0.5 cm-30 cm). Infantile giant café au lait spot (IGCALS) is a huge (diameter >20cm) irregular-shaped benign hyperpigmented skin disorder that arises in infants. There has been no clearly established laser treatment consensus for the treatment of IGCALS because infants are too fragile to receive laser treatment with long hours and broad areas along with the possibility of undesirable cosmetic results. OBJECTIVES: This study investigated the safety and efficacy of Golden Parameter Therapy (GPT) using a high fluence 1064-nm Q-switched Nd:YAG laser (QSNL) for IGCALS treatment. METHODS: This study included 24 Korean patients with IGCALS. Twenty-one patients who were treated with a 1064-nm QSNL weekly for 30-50 treatment sessions with GPT. The parameters included a spot size of 7 mm, a fluence of 2.2 J/cm2 and a pulse rate of 10 Hz with one pass using a sliding-stacking technique over the IGCALS. In control group, three patients were treated with a 532-nm picosecond laser monthly for three treatment sessions with a spot size of 3 mm, a fluence of 1 J/cm2 and a pulse rate of 2 Hz. RESULTS: After the last treatment, 21 patients with IGCALS reached the complete removal of pigmented lesions, which can be considered optimal cosmetic results without any side effects such as purpura, crust, post-inflammatory hyperpigmentation, iatrogenic punctate leukoderma, and scarring. There are no recurrences in any patients after 6-21 months' follow-up, but treatment failure occurred in three patients who were treated with 532 nm picosecond laser. CONCLUSIONS: Convincingly, we argue that early intervention before 12 months of age with GPT using a high fluence 1064 nm QSNL is a safe, applicable and effective treatment for IGCALS, minimizing side effects without any recurrences.

Impact of neonatal sepsis on neurocognitive outcomes: a systematic review and meta-analysis.

INTRODUCTION: Sepsis is associated with neurocognitive impairment among preterm neonates but less is known about term neonates with sepsis. This systematic review and meta-analysis aims to provide an update of neurocognitive outcomes including cognitive delay, visual impairment, auditory impairment, and cerebral palsy, among neonates with sepsis. METHODS: We performed a systematic review of PubMed, Embase, CENTRAL and Web of Science for eligible studies published between January 2011 and March 2023. We included case-control, cohort studies and cross-sectional studies. Case reports and articles not in English language were excluded. Using the adjusted estimates, we performed random effects model meta-analysis to evaluate the risk of developing neurocognitive impairment among neonates with sepsis. RESULTS: Of 7,909 studies, 24 studies (n = 121,645) were included. Majority of studies were conducted in the United States (n = 7, 29.2%), and all studies were performed among neonates. 17 (70.8%) studies provided follow-up till 30 months. Sepsis was associated with increased risk of cognitive delay [adjusted odds ratio, aOR 1.14 (95% CI: 1.01-1.28)], visual impairment [aOR 2.57 (95%CI: 1.14- 5.82)], hearing impairment [aOR 1.70 (95% CI: 1.02-2.81)] and cerebral palsy [aOR 2.48 (95% CI: 1.03-5.99)]. CONCLUSION: Neonates surviving sepsis are at a higher risk of poorer neurodevelopment. Current evidence is limited by significant heterogeneity across studies, lack of data related to long-term neurodevelopmental outcomes and term infants.

Facial Segmental Infantile Haemangioma: A Cutaneous Mosaicism Quandary.

Mosaicism has long been considered the underlying mechanism of segmental infantile hemangiomas (SIH). This was a prospective pilot case-control study conducted with the objective to quantify the percentage overlap of silhouettes of facial SIH with those of Blaschko lines (the most well studied archetypical pattern of mosaicism on face) as compared to other mosaic disorders on face. Lesional silhouettes of 8 patients with SIH (Group A) and 6 patients with other facial dermatosis known to have blaschkoidal distribution (Group B), were overlapped on a standardized template with Blaschkoidal lines on the frontal view of face. The alignment was done via the auto align tool of Photoshop and the percentage of overlap was calculated with an online image comparison software (IMGonline.com.ua). There was a significant difference in mean overlap in Group A (72.92 ± 15.6 %) as compared to Group B (90.1 ± 4.3%; P=0.018). Hence, we concluded that facial SIH do not follow lines of Blaschko.

Pleomorphic xanthoastrocytoma with NTRK fusion presenting as spontaneous intracranial hemorrhage-case report and literature review.

Background: Pleomorphic xanthoastrocytoma (PXA) is a rare brain tumor that accounts for <1% of all gliomas. An in-depth understanding of PXA's molecular makeup remains a work in progress due to its limited numbers globally. Separately, spontaneous intracranial hemorrhage (pICH) is an uncommon but potentially devastating emergency in young children, often caused by vascular malformations or underlying hematological conditions. We describe an interesting case of a toddler who presented with pICH, later found to have a PXA as the underlying cause of hemorrhage. Further molecular interrogation of the tumor revealed a neurotrophic tyrosine receptor kinase (NTRK) gene fusion and CDKN2A deletion more commonly seen in infantile high-grade gliomas. The unusual clinicopathological features of this case are discussed in corroboration with published literature. Case presentation: A previously well 2-year-old male presented with acute drowsiness and symptoms of increased intracranial pressure secondary to a large right frontoparietal intracerebral hematoma. He underwent an emergency craniotomy and partial evacuation of the hematoma for lifesaving measures. Follow-up neuroimaging reported a likely right intra-axial tumor with hemorrhagic components. Histology confirmed the tumor to be a PXA (WHO 2). Additional molecular investigations showed it was negative for BRAFV600E mutation but was positive for CDKN2A homozygous deletion and a unique neurotrophic tyrosine receptor kinase (NTRK) gene fusion. The patient subsequently underwent second-stage surgery to proceed with maximal safe resection of the remnant tumor, followed by the commencement of adjuvant chemotherapy. Conclusion: To date, there are very few pediatric cases of PXA that present with spontaneous pICH and whose tumors have undergone thorough molecular testing. Our patient's journey highlights the role of a dedicated multidisciplinary neuro-oncology team to guide optimal treatment.

Desmoplastic infantile astrocytoma/ ganglioglioma in a pediatric onset multiple sclerosis patient: A case report.

Here we present a co-occurrence of a non-typical presentation of DIG/DIA and multiple sclerosis in a 13-year-old female. Our case highlights how a thorough investigation prior to treatment is needed in patients with such condition to choose proper management for better prognosis.

The effect of therapeutic touch on colic symptoms in infantile colic infants: A randomised controlled study.

AIM: This study aimed to examine the effects of therapeutic touch (TT) on infantile colic symptoms (Infant Colic Scale (ICS) score, crying time and sleep time). METHODS: This randomised controlled trial included infants aged 4-12 weeks diagnosed with infantile colic in a pediatric unit of a hospital. Infants were assigned to intervention or control groups using a stratified randomisation method. The intervention group received TT sessions six times, 3 days a week, in addition to usual care for 2 weeks. The control group received the usual care. Data were collected using Mother-Infant Information Form, ICS, Crying and Sleep Time Follow-Up Forms. The infants were followed up for two weeks. RESULTS: A total of 64 infants who met the criteria were included in the study, including intervention (n = 32) and control (n = 32) groups. There was a statistically significant difference between the groups (intervention and control) in terms of ICS scores (U = 4.5; P < 0.001; d = 3.252; 95% confidence interval (CI) = 2.505-3.999), crying time (F = 57.097; ŋp 2 = 0.461; P < 0.001) and sleep time (F = 17.884; ŋp 2 = 0.211; P < 0.001). When the intervention group was compared with the control group at all time points, the size of the effect (group × time interaction) was found to be high. CONCLUSIONS: TT effectively relieved symptoms, decreased crying time and increased sleep time in infants with infantile colic. TT is recommended to relieve colic in infants.

Advantages of Early Surgical Management of Periorbital Infantile Hemangiomas.

Background: Early evaluation and treatment of periorbital infantile hemangiomas (POIH) were associated with lower rates of ophthalmological complications. Objective: To evaluate age and characteristics associated with improved anisometropic astigmatism (anisoastigmatism) and eye symmetry measured by diopters and a 5-point scale, respectively, in patients with POIH treated with surgical excision. Methods: A retrospective study was performed on patients with POIH. Patient characteristics and eye symmetry were analyzed between patients with resolved and unresolved anisoastigmatism after surgery. Statistical analyses included the Mann-Whitney U tests, chi-square tests, and linear regression models. Results: In total, 54 patients were included (male: 20, female: 34). Upper medial eyelid was the most commonly affected site (resolved: 45%, unresolved: 43%), followed by upper lateral and upper central. Fifty-six percent (31/55) had postoperative resolution of anisoastigmatism, whereas 44% (24/55) did not. Earlier surgical evaluation (median: 4.5 vs. 6.0 months, p = 0.047) and excision (median: 5.0 vs. 12.0 months, p = 0.005) were associated with reversible anisoastigmatism. Good and suboptimal eye symmetry were not associated with earlier surgical excision (median: 6 vs. 6.5 months, p = 0.87). Follow-up ranged from 1 month to 12 years. Conclusion: Earlier surgical excision was associated with reversing anisoastigmatism but was not significant for improving eye symmetry.

Are SCN2A-related BFNISs also responsible for seizures in adulthood? A case report opens new scenarios.

Large cohort studies and variant-specific electrophysiology have enabled the delineation of different SCN2A-epilepsy phenotypes, phenotype-genotype correlations, prediction of pharmacosensitivity to sodium channel blockers, and long-term prognostication for clinicians and families. One of the most common clinical presentations of SCN2A pathological variants is benign familial neonatal-infantile seizures (BFNIS), which are characterized by seizure onset between the first day of life and 23 months of age and typically resolve, either spontaneously or with the aid of sodium channel blockers, within the first 2 years of life. In 2004, Berkovic et al. reported the case of a young boy affected by SCN2A-related BFNIS whose mother, who carried the same pathological variant, had also presented with BFNIS in infancy. Our case report focuses on the aforementioned woman who, more than 40 years later, presented two additional seizures, therefore opening the possibility of a role for SCN2A-related seizures in adulthood.

Pediatric dilated cardiomyopathy: a review of current clinical approaches and pathogenesis.

Pediatric dilated cardiomyopathy (DCM) is a rare, yet life-threatening cardiovascular condition characterized by systolic dysfunction with biventricular dilatation and reduced myocardial contractility. Therapeutic options are limited with nearly 40% of children undergoing heart transplant or death within 2 years of diagnosis. Pediatric patients are currently diagnosed based on correlating the clinical picture with echocardiographic findings. Patient age, etiology of disease, and parameters of cardiac function significantly impact prognosis. Treatments for pediatric DCM aim to ameliorate symptoms, reduce progression of disease, and prevent life-threatening arrhythmias. Many therapeutic agents with known efficacy in adults lack the same evidence in children. Unlike adult DCM, the pathogenesis of pediatric DCM is not well understood as approximately two thirds of cases are classified as idiopathic disease. Children experience unique gene expression changes and molecular pathway activation in response to DCM. Studies have pointed to a significant genetic component in pediatric DCM, with variants in genes related to sarcomere and cytoskeleton structure implicated. In this regard, pediatric DCM can be considered pediatric manifestations of inherited cardiomyopathy syndromes. Yet exciting recent studies in infantile DCM suggest that this subset has a distinct etiology involving defective postnatal cardiac maturation, such as the failure of programmed centrosome breakdown in cardiomyocytes. Improved knowledge of pathogenesis is central to developing child-specific treatment approaches. This review aims to discuss the established biological pathogenesis of pediatric DCM, current clinical guidelines, and promising therapeutic avenues, highlighting differences from adult disease. The overarching goal is to unravel the complexities surrounding this condition to facilitate the advancement of novel therapeutic interventions and improve prognosis and overall quality of life for pediatric patients affected by DCM.

Clinical features and genotype-phenotype correlations in epilepsy patients with de novo DYNC1H1 variants.

OBJECTIVE: DYNC1H1 variants are involved on a disease spectrum from neuromuscular disorders to neurodevelopmental disorders. DYNC1H1-related epilepsy has been reported in small cohorts. We dissect the electroclinical features of 34 patients harboring de novo DYNC1H1 pathogenic variants, identify subphenotypes on the DYNC1H1-related epilepsy spectrum, and compare the genotype-phenotype correlations observed in our cohort with the literature. METHODS: Patients harboring de novo DYNC1H1 pathogenic variants were recruited through international collaborations. Clinical data were retrospectively collected. Latent class analysis was performed to identify subphenotypes. Multivariable binary logistic regression analysis was applied to investigate the association with DYNC1H1 protein domains. RESULTS: DYNC1H1-related epilepsy presented with infantile epileptic spasms syndrome (IESS) in 17 subjects (50%), and in 25% of these individuals the epileptic phenotype evolved into Lennox-Gastaut syndrome (LGS). In 12 patients (35%), focal onset epilepsy was defined. In two patients, the epileptic phenotype consisted of generalized myoclonic epilepsy, with a progressive phenotype in one individual harboring a frameshift variant. In approximately 60% of our cohort, seizures were drug-resistant. Malformations of cortical development were noticed in 79% of our patients, mostly on the lissencephaly-pachygyria spectrum, particularly with posterior predominance in a half of them. Midline and infratentorial abnormalities were additionally reported in 45% and 27% of subjects. We have identified three main classes of subphenotypes on the DYNC1H1-related epilepsy spectrum. SIGNIFICANCE: We propose a classification in which pathogenic de novo DYNC1H1 variants feature drug-resistant IESS in half of cases with potential evolution to LGS (Class 1), developmental and epileptic encephalopathy other than IESS and LGS (Class 2), or less severe focal or genetic generalized epilepsy including a progressive phenotype (Class 3). We observed an association between stalk domain variants and Class 1 phenotypes. The variants p.Arg309His and p.Arg1962His were common and associated with Class 1 subphenotype in our cohort. These findings may aid genetic counseling of patients with DYNC1H1-related epilepsy.

Analysis of gut microecological characteristics and differences between children with biliary atresia and non-biliary atresia in infantile cholestasis.

Introduction: In infants with cholestasis, variations in the enterohepatic circulation of bile acids and the gut microbiota (GM) characteristics differ between those with biliary atresia (BA) and non-BA, prompting a differential analysis of their respective GM profiles. Methods: Using 16S rDNA gene sequencing to analyse the variance in GM composition among three groups: infants with BA (BA group, n=26), non-BA cholestasis (IC group, n=37), and healthy infants (control group, n=50). Additionally, correlation analysis was conducted between GM and liver function-related indicators. Results: Principal component analysis using Bray-Curtis distance measurement revealed a significant distinction between microbial samples in the IC group compared to the two other groups. IC-accumulated co-abundance groups exhibited positive correlations with aspartate aminotransferase, alanine aminotransferase, total bilirubin, direct bilirubin, and total bile acid serum levels. These correlations were notably reinforced upon the exclusion of microbial samples from children with BA. Conclusion: The varying "enterohepatic circulation" status of bile acids in children with BA and non-BA cholestasis contributes to distinct GM structures and functions. This divergence underscores the potential for targeted GM interventions tailored to the specific aetiologies of cholestasis.

Expanded phenotypic spectrum of UDP-glucose-6-dehydrogenase recessive neurodevelopmental disorder: Two novel descriptions with or without epileptic encephalopathy.

Recent advances in the understanding of infantile developmental epileptic encephalopathies (IDEE) have revealed the association of biallelic pathogenic variants in UGDH. In this study, we report two novel combinations identified by exome sequencing: p.(Arg135Trp) with p.(Arg65*) and p.(Arg102Trp) with p.(Arg65*). Both combinations share a common pathogenic nonsense variant, with the missense variants strategically located in the NAD-binding domain of the UGDH protein, predicted in structural models to create new interactions with the central domain. The first patient exhibited the typical UGDH-related disease phenotype and progressive microcephaly, a rarely reported feature. In contrast, the second patient presented an atypical phenotype, including absence of seizure, severe intellectual disability, ataxic gait, and abnormal eye movements. This comprehensive analysis extends the phenotypic spectrum of UGDH syndrome beyond early infantile intractable encephalopathy to include intellectual disability without epilepsy.