Marfan syndrome is caused by pathogenic variants in FBN1. We identified a novel heterozygous frameshift variant in FBN1 (NM_000138.5: c.6784_6787del, NP_000129.3:p.(Gln2262TrpfsTer28)) in an adult male with severe cardiovascular manifestations. The variant was absent from population databases and fulfilled PVS1 and PM2 criteria. This finding expands the mutational and phenotypic spectrum of FBN1 and highlights the clinical utility of genetic testing in family-based clinical management of Marfan syndrome.

Mutations in TSC1 or TSC2 in axons induce tuberous sclerosis complex. Neurological manifestations mainly include epilepsy and autism spectrum disorder (ASD). ASD is the presenting symptom (25–50% of patients). ASD was observed at significantly higher frequencies in participants with TSC2 than those with TSC1 mutations. The occurrence of TSC2 mutations is about 50% larger than TSC1. Therefore, ASD may develop due to TSC2 deficiency. TSC2 regulates microRNA biogenesis and Microprocessor activity via GSK3β. Of reference, everolimus has the best treatment target because of the higher potency of interactions with mTORC2 rather than rapamycin. Mutations in the TSC1 and TSC2 genes result in the constitutive hyperactivation of the mammalian target of the rapamycin (mTOR) pathway, contributing to the growth of benign tumors or hamartomas in various organs. TSC2 mutations were associated with a more severe phenotypic spectrum than TSC1 mutations because of the inhibition of the mTOR cascade. There are few studies on the peptide analysis of this disorder in relation to everolimus. Only one study reported that, in ten plasma samples, pre-melanosome protein (PMEL) and S-adenosylmethionine (SAM) were significantly changed as diagnostic prognostic effects. Our study on peptide analysis in Protosera Inc (Osaka, Japan) revealed that three peptides that were related to inflammation in two patients with tuberous sclerosis, who showed a 30% decrease in ASD symptoms following everolimus treatment. TSC2 mutations were associated with a more severe phenotypic spectrum due to the inhibition of the mTOR cascade. PMEL and SAM were significantly changed as diagnostic effects.

We aimed to assess the efficacy, safety, and pharmacokinetics of an oral risperidone solution and two types of supplementations with PUFAs. We assigned 39 participants with mild ASD (mean age ± standard deviation = 14.6 ± 6.0 years) to three treatment groups (each n = 13): RIS-OS; equal doses of 240 mg of omega-3 PUFA docosahexaenoic acid and omega-6 PUFA arachidonic acid (1:1) (aravita); and omega-6 precursor linoleic acid (480 mg) and omega-3 precursor alpha-linolenic acid (120 mg) (4:1) (awake). The primary outcome was the Autism Diagnostic Interview—Revised score. The secondary outcomes were the Social Responsiveness Scale (SRS) and Aberrant Behavior Check scores. The results of the linear mixed-effects model revealed that the RIS-OS group exhibited significant improvement in the SRS subscale scores of social motivation at weeks 8, 12, and 16 compared with the aravita and awake groups, as well as in the SRS subscale score of social mannerisms at weeks 12 and 16 compared with the aravita group. Moreover, the RIS-OS group showed a trend towards significantly lower plasma ceruloplasmin (Cp) levels. Their plasma insulin-like growth factor (IGF) levels were significantly higher at week 8 than in the subsequent weeks. The high Cp and IGF levels may be attributed to reduced neuroinflammation. These findings demonstrate, firstly, that reduced inflammation through increased anti-inflammatory proteins such as Cp and IGF has clinical effects on the motivation–reward system and mannerisms in patients with ASD through the amelioration of dopamine D2, 5-HT2a, and 5-HT2b dysfunction.

Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by a wide range of clinical manifestations, including café-au-lait macules, cutaneous neurofibromas, and an increased risk of certain malignancies. Historically, there has been no approved medical therapy specifically aimed at achieving tumor shrinkage or regression. Surgical intervention is often limited by factors such as the inaccessibility of the tumor location, involvement of critical tissues, suboptimal timing, or the inability to achieve complete resection. Recent advancements in targeted therapies, particularly MEK inhibitors, have introduced promising treatment options for patients with severe manifestations of NF1. This review highlights the pathophysiology of NF1 and the therapeutic role of MEK inhibitors and presents a detailed case study of a patient treated with selumetinib, a novel MEK inhibitor. While the therapeutic potential of selumetinib has been demonstrated in preclinical and clinical studies, including those involving Japanese patients, this review aims to evaluate its application in real-world clinical practice. A comprehensive discussion of the case study provides insights into the efficacy, safety, and clinical challenges associated with selumetinib treatment, offering valuable perspectives for its use in managing NF1.

Protein-losing enteropathy (PLE) is characterized by hypoproteinemia caused by the leakage of plasma proteins from the gastrointestinal tract wall into the lumen. We report a case of PLE occurring during low-dose adrenocorticotropic hormone (ACTH) therapy for West syndrome. A 6-month-old boy diagnosed with West syndrome was initially treated with sodium valproate and vitamin B6. Although the frequency of seizures decreased, electroencephalography findings did not improve. Consequently, low-dose ACTH therapy and a ketogenic diet were introduced. On day 5 (X + 5 days) after initiating ACTH therapy, scrotal edema and hypoalbuminemia were observed. Scintigraphy revealed leakage of radionuclides into the gastrointestinal tract, leading to a diagnosis of PLE. ACTH therapy was discontinued on X + 6 days, while valproate, vitamin B6, and the ketogenic diet were continued. Following the cessation of ACTH therapy, the patient showed improvement. We identified ACTH therapy as the likely cause of PLE in this case. This represents the first report of PLE diagnosed during ACTH therapy.

Rett syndrome is a rare neurodevelopmental disorder caused by mutations in the MECP2 gene on the X chromosome, primarily affecting females. It is characterized by developmental regression, stereotypic hand movements, seizures, and microcephaly due to decelerated head growth. However, atypical presentations, such as macrocephaly and hyperostosis frontalis interna (HFI), are rarely reported. HFI, defined as abnormal thickening of the frontal bone, is uncommon in pediatric populations and is often linked to metabolic disturbances, hormonal imbalances, or prolonged anti-seizure medication (ASM) use. We report the case of a 16-year-old girl with genetically confirmed Rett syndrome who presented with macrocephaly (+2.5 SD) and HFI. Genetic testing identified a pathogenic MECP2 mutation (c.882C>T, Arg270Stop), confirming the diagnosis. The patient’s early development was normal until 18 months, when developmental regression occurred, including loss of speech, impaired social interactions, and stereotypic hand movements. She was also diagnosed with central precocious puberty at age 9, treated with leuprorelin acetate for three years, during which her growth in height ceased. By age 16, her height was -2.6 SD. Brain MRI revealed thickening of the frontal bone and enlarged frontal sinuses, consistent with HFI. She experienced intractable epilepsy managed with multiple ASMs. Reduction in ASM doses improved dystonia but led to seizure recurrence. Additional evaluations revealed mild osteopenia and altered hormonal profiles, suggesting systemic effects of MECP2 dysfunction. This case highlights the expanded phenotypic spectrum of Rett syndrome, emphasizing the impact of MECP2 mutations on cranial growth and bone metabolism. Hormonal dysregulation and ASM use may contribute to these anomalies. Comprehensive evaluation and genetic testing are critical for differentiating Rett syndrome from overlapping conditions. A multidisciplinary approach is essential to manage rare manifestations and improve personalized care strategies.

Esterified ARA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is further metabolized by COXs and lipoxygenases (LOXs) and cytochrome P450 (CYP) enzymes. PGs produce detrimental effects due to their proinflammatory properties. The generation of prostaglandin (PG)G2 and PGH2 is triggered by cyclooxygenase (COX) isozymes such as COX-1 and COX-2. Prostaglandin E2 (PGE2) is significantly elevated in ASD. Considerable data indicate that COX enzymes and their metabolites of ARA play important roles in the initiation and development of human neurodevelopmental diseases. The involvement of disrupted COX2/PGE2 signaling in ASD pathology in changing neuronal cell behavior and the expression of ASD-related genes and proteins is due to disrupted COX2/PGE2 signaling. Prostacyclin (PGI2) is synthesized from arachidonic acid by metabolic-pathway-dependent cyclooxygenase (COX) and synthesized in a primary step of ARA transformation (PGG2, PGH2), by degradation of the abovementioned prostaglandins.

Primary angiitis of the central nervous system (PACNS) is a rare inflammatory vasculitis localised to the central nervous system. Treatment of severe PACNS often includes glucocorticoids and cyclophosphamide; however, some cases exhibit resistance to glucocorticoids, leading to severe neurological sequelae. In this case report, a 14-year-old female patient presented with fever, headache, and short-term memory loss. Her blood test results showed no significant abnormalities. HLA-B51 and A26 were both positive. Cerebrospinal fluid examination showed no elevated interleukin-6. Brain magnetic resonance imaging with fluid-attenuated inversion recovery sequences demonstrated hyperintense signals in the bilateral basal ganglia, left thalamus, and insula. Contrast-enhanced T1-weighted imaging showed peripheral enhancement of the lesions. Given the possibility of a demyelinating disorder, glucocorticoids were administered. However, the patient remained febrile, and magnetic resonance imaging (MRI) revealed disease progression. To differentiate infectious and malignant diseases, a biopsy of the left thalamic lesion was performed. Histopathological examination revealed coexisting lymphocytic and granulocytic vasculitis affecting small arteries and arterioles. Based on the clinical course and laboratory results, the patient was diagnosed with PACNS. Despite intravenous immunoglobulin, intravenous cyclophosphamide, and rituximab, the patient became comatose, and the brain MRI worsened. Following infliximab, clinical symptoms and brain MRI improved. The clinical course suggests that infliximab was effective for this patient with glucocorticoid-resistant PACNS. As potential associations have been previously reported between HLA-B51/A26 and vasculitis in Behçet disease, our case may suggest a pathophysiological link between vascular-BD and a subset of PACNS, which may also explain the good clinical response to infliximab. Further research is warranted to address this hypothesis.

Pseudohypoparathyroidism (PHP) is a rare disorder characterized by convulsions, tetany, and sensory abnormalities caused by hypocalcemia due to parathyroid hormone (PTH) resistance. Only few patients present with involuntary movements. We report the case of a 7-yr-old girl with PHP and involuntary movements triggered by running. Initially, she was suspected of having paroxysmal kinesigenic dyskinesia and was treated with carbamazepine (CBZ). Involuntary movements were reduced. However, 2 months post-treatment, she experienced convulsions during a fever. Blood tests and brain computed tomography revealed hypocalcemia, hyperphosphatemia, elevated intact PTH, and calcifications in the frontal cortex and basal ganglia. The patient showed no features of Albright's hereditary osteodystrophy. The involuntary movements disappeared after the discontinuation of CBZ and initiation of calcium and active vitamin D preparations. Methylation-specific multiplex ligation-dependent probe amplification for the GNAS region and microsatellite analysis of chromosome 20 led to the diagnosis of PHP1B caused by epimutation. In 15 reported cases, with or without intracranial calcification, PHP-associated involuntary movements disappeared or became less severe with treatment for hypocalcemia; in eight of 11 cases, they were triggered by exercise or movement. PHP-associated hypocalcemia can trigger exercise-induced involuntary movements owing to lowered serum ionized calcium levels. In such patients, early blood tests are vital for the differential diagnosis of PHP.

Background: Acute disseminated encephalomyelitis (ADEM) is a rare, immune-mediated inflammatory disorder of the central nervous system (CNS), typically characterized by the acute onset of multifocal demyelination. The pathogenesis of ADEM remains unclear, but it is believed to be triggered by an autoimmune response, often following viral infections or vaccinations. Case report: This case report describes a 3-year-old child who developed ADEM after receiving two concurrent influenza vaccines: one for seasonal influenza and one for the 2009 H1N1 pandemic. The patient presented with motor regression, mild pleocytosis in cerebrospinal fluid (CSF), and typical MRI findings of ADEM. Steroid pulse therapy resulted in rapid improvement, and the patient recovered fully without sequelae. Results: Although the influenza vaccine has been linked to ADEM in some studies, it remains uncertain whether the simultaneous administration of both vaccines contributed to the onset of ADEM. While influenza vaccines are considered safe and effective by health organizations such as the CDC, data suggest that the incidence of ADEM and other neurological complications is significantly higher after natural influenza infections compared to vaccination. This highlights the importance of vaccination in preventing severe outcomes. Conclusions: This case underscores the importance of monitoring and reporting adverse events following vaccination to refine our understanding of rare complications like ADEM. While simultaneous vaccine administration warrants further research, the benefits of vaccination in preventing severe complications from natural infections far outweigh the risks. Continued vigilance and improved surveillance systems are essential for maintaining public confidence in vaccination programs.

In this study, we report two cases of siblings diagnosed with primary ciliary dyskinesia (PCD) sharing an identical genotype yet exhibiting distinct phenotypes. A 13-year-old girl with acute pneumonia was admitted to our hospital. Chest and sinus radiography revealed situs inversus and bilateral maxillary sinusitis. Chest computed tomography revealed bronchiectasis. Her 6-year-old brother with acute bronchitis was admitted and was diagnosed with bronchial asthma due to recurrent wheezing. Unlike his sister, he did not have situs inversus. Both patients had a chronic wet cough and were diagnosed with bronchial asthma by their family doctor. The mean PCD rule (PICADAR) scores were 9 and 7, respectively. Genetic analysis confirmed the presence of the same homozygous mutation (c.546C > A,pTyr182Ter) in DNAI2. To date, there have been four reports of the same pathogenic variants but different PCD phenotypes. Pathological variants of DNAI2 cause the loss of the outer dynein arm, the absence of which results in a lack of primary ciliary movement involved in the left-right axis formation during the embryonic period. A lack of functional cilia results in randomized visceral asymmetry; hence, the same pathogenic variant may exhibit different phenotypes. PCD is often overlooked and is sometimes managed as bronchial asthma, as in these siblings. In our case, the PICADAR score was useful in predicting the clinical diagnosis of PCD.

The number of people immersed in excessive gaming has increased in this age of rapid digitalization. The World Health Organization and American Psychiatric Association Organization recognize a gaming disorder as a condition that results in significant problems in daily life as a result of excessive gaming. Both organizations emphasize the similarities to behavioral addictions such as gambling. We examined the appropriate usage of video games from the perspectives of health and management in this study. For the general population, video games provide positive impacts such as stress alleviation and memory improvement. Game playing leads to a loss of time and money for the individual. It also has a negative impact on the individual’s family and social life, evolving into a social problem. Gaming addiction is often accompanied by psychological disorders and other addictions, and long-term medical treatment, including approaches to the individual’s psychological background and cognitive-behavioral therapy, is necessary. Therefore, the prevention of gaming disorder is essential. From a societal standpoint, action is required in three contexts: the government, game developers, and within the household as a whole. Simultaneously, the public needs to understand the positive potential of gaming, such as e-sports.

Background: We report a rare case highlighting the progression of liver disease in a male patient with idiopathic childhood-onset growth hormone (GH) deficiency. Case presentation: The patient was diagnosed with hypopituitarism at six years old and was treated with thyroxine therapy and GH for his short stature, with testosterone added at the age of 15. GH therapy was discontinued when the patient was 18 years old, but thyroid and testosterone treatments continued. The patient had been taking medication for hyperlipidemia until the age of 30 and was noted to have impaired glucose tolerance at the age of 40, but HbA1c levels remained normal. At the age of 47, esophageal varices were incidentally discovered via endoscopy, revealing liver cirrhosis. Laboratory tests showed liver dysfunction and abnormal lipid levels, and hepatitis viral markers were absent. The patient had no history of drinking alcohol or smoking, and no family history of diabetes. Results: Ultimately, this case demonstrates that metabolic dysfunction-associated steatotic liver disease (MASLD/metabolic dysfunction-associated steatohepatitis (MASH)) is under-recognized in GH deficiency cases and can progress to liver cirrhosis. Conclusions: Therefore, careful evaluation of MASLD/MASH in childhood-onset GH deficiency is necessary, and GH replacement therapy should continue into adulthood, if possible.

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by mutations in the TSC1 and TSC2 genes, leading to the dysregulation of the mammalian target of rapamycin (mTOR) pathway. This dysregulation results in the development of benign tumors across multiple organ systems and poses significant neurodevelopmental challenges. The clinical manifestations of TSC vary widely and include subependymal giant cell astrocytomas (SEGAs), renal angiomyolipomas (AMLs), facial angiofibromas (FAs), and neuropsychiatric conditions such as autism spectrum disorder (ASD). mTOR inhibitors, notably everolimus, have become central to TSC management, with documented efficacy in reducing the sizes of SEGAs and AMLs and showing promise in addressing additional TSC-related symptoms. Case Presentation: We report the case of an 11-year-old male diagnosed with TSC, presenting with hallmark features including hypopigmented macules, early-onset infantile spasms, SEGA, and AMLs. Initial interventions included adrenocorticotropic hormone (ACTH) therapy and sodium valproate for seizure management and a minimally invasive keyhole craniotomy for SEGA reduction. At age 12, oral everolimus therapy was introduced to address both SEGA recurrence risk and ASD-related social deficits. Over the course of 24 weeks, a reduction in the size and erythema of the patient’s FAs was observed, alongside improvements in social engagement, suggesting potential added benefits of systemic mTOR inhibition beyond tumor control. Results: Treatment with everolimus over a 24-month period led to significant reductions in both FA and AML size, as well as measurable improvements in ASD-associated behaviors. Therapeutic drug monitoring maintained serum levels within the effective range, minimizing adverse effects and underscoring the tolerability and feasibility of long-term everolimus administration. Conclusions: This case underscores the efficacy of oral everolimus in reducing FA size in a pediatric TSC patient, with broader therapeutic benefits that support the potential of mTOR inhibition as a multi-targeted strategy for TSC management. Further studies are needed to explore the full range of applications and long-term impact of mTOR inhibitors in TSC care.

D EAR E DITOR , A 5-year-old girl developed difficulty in walking owing to muscle weakness and erythema of the face after coro-navirus disease 2019. The patient had severe autism spectrum disorder, psychomotor retardation and an unbalanced diet. Erythematous eruptions were observed on the eyelids and mid-face, suggestive of heliotrope eruptions and malar rashes, respectively. No generalized oedema was observed upon physical examination. The following blood test results were obtained: creatinine kinase, 725IU/l; aldolase, 17.3mg/dl; C3, 76.9mg/dl; C4, 38.9mg/dl; and CH50, 44.1 U/ml. These cutaneous findings were suggestive of JDM. Short tau inversion recovery (STIR) MRI revealed high signal intensities for muscle and s.c. lesions in both thighs, consistent with myositis with s.

In adult intensive care, brain hypothermia therapy (BHT) was reported to be effective in neuroprotection after resuscitation and cardiac arrest. By contrast, in neonatal intensive care, the pathophysiology of brain damage caused by hypoxic–ischemic encephalopathy (HIE) is attributed to circulatory disturbances resulting from ischemia/reperfusion, for which neonatal brain cryotherapy is used. The International Liaison Committee on Resuscitation, 2010, recommends cerebral cryotherapy for HIE associated with severe neonatal pseudoparenchyma death. The usefulness of BHT for neuroprotection in infants and children, especially in pediatric acute encephalopathy, is expected. Theoretically, BHT could be useful in basic medical science and animal experiments. However, there are limitations in clinical planning for treating pediatric acute encephalopathy. No international collaborative study has been conducted, and no clinical evidence exists for neuroprotection using BHT. In this review, we will discuss the pathogenesis of neuronal damage in hypoxic and hypoperfused brains; the history of BHT, its effects, and mechanisms of action; the success of BHT; cooling and monitoring methods of BHT; adverse reactions to BHT; literature on BHT. We will review the latest literature on targeted temperature management, which is used for maintaining and controlling body temperature in adults in intensive care. Finally, we will discuss the development of BHT and targeted temperature management as treatments for pediatric acute encephalopathy.

Polyunsaturated fatty acids (PUFAs) undergo lipid peroxidation and conversion into malondialdehyde (MDA). MDA reacts with acetaldehyde to form malondialdehyde-modified low-density lipoprotein (MDA-LDL). We studied unsettled issues in the association between MDA-LDL and the pathophysiology of ASD in 18 individuals with autism spectrum disorders (ASD) and eight age-matched controls. Social behaviors were assessed using the social responsiveness scale (SRS). To overcome the problem of using small samples, adaptive Lasso was used to enhance the interpretability accuracy, and a coefficient of variation was used for variable selections. Plasma levels of the MDA-LDL levels (91.00 ± 16.70 vs. 74.50 ± 18.88) and the DHA/arachidonic acid (ARA) ratio (0.57 ± 0.16 vs. 0.37 ± 0.07) were significantly higher and the superoxide dismutase levels were significantly lower in the ASD group than those in the control group. Total SRS scores in the ASD group were significantly higher than those in the control group. The unbeneficial DHA/ARA ratio induced ferroptosis via lipid peroxidation. Multiple linear regression analysis and adaptive Lasso revealed an association of the DHA/ARA ratio with total SRS scores and increased MDA-LDL levels in plasma, resulting in neuronal deficiencies. This unbeneficial DHA/ARA-ratio-induced ferroptosis contributes to autistic social behaviors and is available for therapy.

The association between the lipid peroxidation product malondialdehyde (MDA)-modified low-density lipoprotein (MDA-LDL) and the pathophysiology of autism spectrum disorder (ASD) is unclear. This association was studied in 17 children with ASD and seven age-matched controls regarding autistic behaviors. Behavioral symptoms were assessed using the Aberrant Behavior Checklist (ABC). To compensate for the small sample size, adaptive Lasso was used to increase the likelihood of accurate prediction, and a coefficient of variation was calculated for suitable variable selection. Plasma MDA-LDL levels were significantly increased, and plasma SOD levels were significantly decreased in addition to significantly increased plasma docosahexaenoic acid (DHA) levels and significantly decreased plasma arachidonic acid (ARA) levels in the 17 subjects with ASD as compared with those of the seven healthy controls. The total ABC scores were significantly higher in the ASD group than in the control group. The results of multiple linear regression and adaptive Lasso analyses revealed an association between increased plasma DHA levels and decreased plasma ARA levels, which were significantly associated with total ABC score and increased plasma MDA-LDL levels. Therefore, an imbalance between plasma DHA and ARA levels induces ferroptosis via lipid peroxidation. Decreased levels of α-linolenic acid and γ-linolenic acid may be connected to the total ABC scores with regard to lipid peroxidation.