A case report of a child with pulmonary hypertension associated with SARS-CoV-2 infection.

We encountered a pediatric case of pulmonary hypertension triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A 14-year-old girl was brought to the emergency department of our hospital with fever, respiratory distress, and impaired consciousness. She tested positive for SARS-CoV-2 upon a polymerase chain reaction examination and had prolonged hypoxemia without pneumonia. An echocardiography revealed elevated right ventricular pressure. She was diagnosed with pilocytic astrocytoma at the age of 10 years and underwent a resection of a pituitary tumor. Hormone replacement therapy was administered postoperatively, but her growth hormones were not activated because of concerns about tumor recurrence. Echocardiography at the age of 13 years showed normal right ventricular pressure. On admission, she had an abnormal liver function, elevated liver fibrosis markers, a decreased platelet count, and hepatosplenomegaly, suggesting pulmonary and portal hypertension. The diagnosis was pulmonary hypertension associated with SARS-CoV-2 infection. The mechanism of the pulmonary hypertension was thought to be portal hypertension owing to growth hormone deficiency and SARS-CoV-2 infection. The patient's symptoms improved with oxygenation and bed rest without additional targeted pulmonary hypertension therapy, and her right ventricular pressure decreased. This case demonstrates that a pediatric patient with subclinical pulmonary hypertension may develop pulmonary hypertension triggered by SARS-CoV-2 infection.

Case report: Progressive pulmonary artery hypertension in a case of megalencephaly-capillary malformation syndrome.

Megalencephaly-capillary malformation syndrome (MCAP, OMIM # 602501) is caused by hyperactivity of the thephosphoinositide-3-kinase (PI3K)-Vakt murine thymoma viral oncogene homolog (AKT)-mammalian target of rapamycin (mTOR) pathway, which results in megalencephaly, capillary malformations, asymmetrical overgrowth, and connective tissue dysplasia. Herein, we report the case of a 7-month-old girl with MCAP due to a PIK3CA somatic mosaic variant who presented with atrial tachycardia, finally diagnosed as pulmonary arterial hypertension (PAH). Oxygen therapy and sildenafil decreased pulmonary blood pressure and improved atrial tachycardia. Previous studies reported an association between the PI3K/AKT/mTOR pathway and abnormal pulmonary arterial smooth muscle cell proliferation, which may be associated with PAH. PAH should be considered a potentially lethal complication in MCAP patients, even when no structural cardiac abnormalities are identified in the neonatal period.

Severe neuroglycopenic symptoms due to nonketotic hypoglycemia in children with cardio-facio-cutaneous syndrome.

Cardio-facio-cutaneous syndrome (CFC) (OMIM 115150) is a congenital disease caused by constitutive activation of the Raf/MEK/ERK signaling cascade. Unlike aspects of morphological anomalies, metabolic functions related to the disease have garnered little attention. We present severe neuroglycopenic symptoms due to nonketotic hypoglycemia in two children with CFC (Case 1, a 4-year-old male with c.389A > G heterozygous variant in MAP2K1; Case 2, a 3-year-old male with c.770A > G heterozygous variant in BRAF). Case 1 exhibited a nonketotic hypoglycemic coma and clustered left-hemispheric convulsions despite receiving infusion therapy, leading to severe sequelae with choreoathetosis. Brain magnetic resonance imaging of Case 1 showed T2-elongation with restricted diffusion on the bilateral basal ganglia and thalamus, with the dominance of the right putamen. Case 2 presented a prolonged generalized seizure as an initial clinical symptom but fully recovered. The presence of growth hormone and cortisol deficiency was ruled out in both cases. Blood spots acylcarnitine profiles excluded the co-occurrence of mitochondrial HMG-CoA synthase deficiency and HMG-CoA lyase deficiency. These cases demonstrate the potential vulnerability to nonketotic hypoglycemia, especially during lipid shortages. As children with CFC frequently have difficulties feeding, we suggest great attention should be paid to the potential risk of severe nonketotic hypoglycemia.

Decreased head circumference at birth associated with maternal tobacco smoke exposure during pregnancy on the Japanese prospective birth cohort study.

Maternal tobacco smoke exposure during pregnancy impairs fetal body size, including head circumference (HC) at birth; however, the mechanism still remains unclear. This analysis using a large prospective cohort study evaluated the impact of maternal tobacco exposure on their offspring's HC and the relationship with placental weight ratio (PWR) and placental abnormalities. Parents-children pairs (n = 84,856) were included from the 104,065 records of the Japan Environmental and Children's Study. Maternal perinatal clinical and social information by self-administered questionnaires, offspring's body size, and placental information were collected. Data were analyzed with binominal logistic regression analysis and path analysis. Logistic regression showed significantly elevated adjusted odds ratio (aOR) (1.653, 95% CI 1.387-1.969) for the impact of maternal smoking during pregnancy on their offspring's smaller HC at birth. Maternal exposure to environmental tobacco smoke in the non-smoking group did not increase aOR for the smaller HC. Path analysis showed that maternal smoking during pregnancy decreased the offspring's HC directly, but not indirectly via PWR or placental abnormalities. The quitting smoking during pregnancy group did not increase aOR for the smaller HC than the non-smoking group, suggesting that quitting smoking may reduce their offspring's neurological impairment even after pregnancy.

Specific temperament in patients with nevoid basal cell carcinoma syndrome.

BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS) is a neurocutaneous disease, characterized by tumorigenesis and developmental anomalies due to aberrant sonic hedgehog (Shh) signaling. Patients with NBCCS typically appear calm and carefree, suggesting that a specific personality in these patients may be associated with an enhanced hedgehog pathway. Our study aimed to determine the personality type in these patients. METHODS: We enrolled 14 mentally normal patients with genetically confirmed NBCCS (seven males and seven females; mean age = 25.2 years) and 20 controls (10 males and 10 females; mean age = 27.9 years). The patients were assessed with the Japanese version of the Temperament and Character Inventory, based on the seven-dimensional model of temperament and character, and their clinical symptoms were evaluated. The amygdala volumes of six patients with NBCCS were measured using magnetic resonance imaging with image-processing software. RESULTS: Patients with NBCCS scored significantly lower on harm avoidance (0.89) than controls (1.00; P = 0.0084). Moreover, patients with NBCCS and developmental malformations such as rib anomalies, who may have experienced Shh signaling enhancement from the prenatal period, scored significantly lower on harm avoidance (0.80 [P = 0.0031]). The left amygdala volume was also significantly reduced in patients with NBCCS (P = 0.0426). CONCLUSIONS: Patients with NBCCS who experienced increased Shh signaling from the prenatal period showed significantly lower harm avoidance related to serotonin. The left amygdala volume was significantly reduced in these patients. Our results indicate that Shh signaling may influence the human personality.

Brain morphological analysis in PTEN hamartoma tumor syndrome.

PTEN hamartoma tumor syndrome (PHTS) is a spectrum of hereditary cancer syndromes caused by germline mutations in PTEN. PHTS is of high interest, because of its high rate of neurological comorbidities including macrocephaly, autism spectrum disorder, and intellectual dysfunction. Since detailed brain morphology and connectivity of PHTS remain unclear, we quantitatively evaluated brain magnetic resonance imaging (MRI) in PHTS. Sixteen structural T1-weighted and 9 diffusion-weighted MR images from 12 PHTS patients and neurotypical controls were used for structural and high-angular resolution diffusion MRI (HARDI) tractography analyses. Mega-corpus callosum was observed in 75%, polymicrogyria in 33%, periventricular white matter lesions in 83%, and heterotopia in 17% of the PHTS participants. While gyrification index and hemispheric cortical thickness showed no significant differences between the two groups, significantly increased global and regional brain volumes, and regionally thicker cortices in PHTS participants were observed. HARDI tractography showed increased volume and length of callosal pathways, increased volume of the arcuate fasciculi (AF), and increased length of the bilateral inferior longitudinal fasciculi (ILF), bilateral inferior fronto-occipital fasciculi (IFOF), and bilateral uncinate fasciculus. A decrease in fractional anisotropy and an increased in apparent diffusion coefficient values of the AF, left ILF, and left IFOF in PHTS.

MicroRNAs profiling in fibroblasts derived from patients with Gorlin syndrome.

Gorlin syndrome (GS) is a hereditary disorder with tumorigenicity, caused by constitutive hyperactivity of hedgehog signaling. Smoothened (SMO) antagonists have been effectively used in the clinical treatment of hedgehog signaling-related cancer. However, these treatments have led to problematic side effects, including severe adverse reactions and drug resistance from additional somatic mutations. We profiled microRNAs in GS fibroblasts to explore a novel therapeutic target for controlling hyper-activated hedgehog signaling. To identify GS-related microRNAs, we analyzed dermal fibroblasts from five patients with GS and three normal controls. We used microarray comparative genomic hybridization to screen 632 human microRNAs in GS fibroblasts. We identified 16 down- and 19 upregulated microRNAs with over twofold change in expression. We validated the increased expression of four microRNAs, confirming hsa-miR-196a-5p downregulation and hsa-miR-4485 upregulation using real-time PCR. Moreover, hsa-miR-196a-5p is complementary to sites in the 3' UTR of MAP3K1, which exhibits upregulated expression at mRNA and protein levels in GS fibroblasts. In addition, hedgehog signal induction with exogenous components decreased miR-196a-5p expression and increased map3k1 expression in a mouse mesenchymal cell line. Given that MAP3K1 has been reported to activate hedgehog signaling, hsa-miR-196a-5p may contribute to the positive feedback loop in this pathway.

Facial nerve palsy associated with atomoxetine-induced hypertension.

BACKGROUND: Peripheral facial nerve palsy is characterized by unilateral facial paresis due to ipsilateral facial nerve dysfunction. Most cases are idiopathic; however, some have specific etiologies, such as herpesvirus infection, immunological disorders, and hypertension. Atomoxetine is a norepinephrine reuptake inhibitor that is used in the treatment of attention deficit hyperactivity disorder (ADHD). This drug is known to cause adverse effects, such as nausea, appetite loss, headache, insomnia, and hypertension. CASE DESCRIPTION: We herein describe a case of sudden-onset right peripheral facial palsy in a 9-year-old Japanese boy. The patient's systolic blood pressure was as high as 200 mmHg, and he was therefore admitted to our hospital for investigation. Extensive surveillance including blood examination; endocrinological testing; imaging studies such as computed tomography, magnetic resonance imaging, and renography; and renal biopsy did not reveal any abnormalities. The patient had ADHD and was under treatment with atomoxetine. We discontinued treatment with atomoxetine; the patient showed gradual improvement. His hypertension and facial palsy resolved. We therefore diagnosed the patient with peripheral facial palsy associated with atomoxetine-induced hypertension. CONCLUSION: Although peripheral facial nerve palsy is usually benign and self-limiting, blood pressure should be monitored in children under treatment with atomoxetine and the possibility of drug-induced hypertension should be considered in order to prevent palsy associated with hypertension.

An Acquired Form of Dandy-Walker Malformation with Enveloping Hemosiderin Deposits.

Dandy-Walker malformation (DWM) is a posterior fossa anomaly characterized by hypoplasia and upward rotation of the cerebellar vermis and cystic dilation of the fourth ventricle. The cyst of DWM rarely extends posteriorly to almost completely fill the entire posterior fossa, which mimics primary cerebellar agenesis, a cerebellar porencephalic cyst, and an arachnoid cyst due to the lack of clarity of the thin cystic wall. A 10-month-old female born at 23 weeks' gestation with cerebellar hemorrhage in the neonatal period was admitted to our hospital with dysphagia and side-to-side head bobbing. The detection of hemosiderin deposits enveloping the cyst wall by T2 star-weighted angiography (SWAN) was useful for the differential diagnosis of an acquired form of DWM from primary cerebellar agenesis. Cyst fenestration successfully improved dysphagia and head bobbing. A pathological specimen of the perforated cyst consisted of collagen fibers with hemosiderin deposits but lacked congenital cyst components. In infants with posterior fossa cysts, SWAN will be useful for a differential diagnosis between DWM and primary cerebellar agenesis.

Brain morphology in children with nevoid basal cell carcinoma syndrome.

Brain morphology is tightly regulated by diverse signaling pathways. Hedgehog signaling is a candidate pathway considered responsible for regulating brain morphology. Nevoid basal cell carcinoma syndrome (NBCCS), caused by a PTCH1 mutation in the hedgehog signaling pathway, occasionally exhibits macrocephaly and medulloblastoma. Although cerebellar enlargement occurs in ptch1 heterozygous-deficient mice, its impact on human brain development remains unknown. We investigated the brain morphological characteristics of children with NBCCS. We evaluated brain T1-weighted images from nine children with NBCCS and 15 age-matched normal control (NC) children (mean [standard deviation], 12.2 [2.8] vs. 11.6 [2.3] years old). The diameters of the cerebrum, corpus callosum, and brain stem and the cerebellar volume were compared using two-tailed t-tests with Welch's correction. The transverse diameters (150.4 [9.9] vs. 136.0 [5.5] mm, P = 0.002) and longitudinal diameters (165.4 [8.0] vs. 151.3 [8.7] mm, P = 0.0007) of the cerebrum, cross-sectional area of the cerebellar vermis (18.7 [2.6] vs. 11.8 [1.7] cm2 , P = 0.0001), and total volume of the cerebellar hemispheres (185.1 [13.0] vs. 131.9 [10.4] cm3 , P = 0.0001) were significantly larger in the children with NBCCS than in NC children. Thinning of the corpus callosum and ventricular enlargement were also confirmed in children with NBCCS. We demonstrate that, on examination of the brain morphology, an increase in the size of the cerebrum, cerebellum, and cerebral ventricles is revealed in children with NBCCS compared to NC children. This suggests that constitutively active hedgehog signaling affects human brain morphology and the PI3K/AKT and RAS/MAPK pathways.

Coexistence of neuroblastoma and ganglioneuroma in a girl with a hemizygous deletion of chromosome 11q14.1-23.3.

Constitutional 11q interstitial deletion syndrome presents with congenital anomalies including microcephaly with craniostenosis, minor dysmorphic features, vitreoretinopathy, and renal anomalies. This syndrome is occasionally associated with neuroblastoma (NB) as a life-threatening complication, which is important for clinical care. Although the corresponding locus to NB has been predicted to exist in 11q22-23 by previous deletion studies related to NB, the causative haploinsufficient genes have not yet been identified. We herein reported for the first time the simultaneous coexistence of adrenal NB and abdominal prevertebral ganglioneuroma in a 6-year-old girl with a constitutional hemizygous 11q14.1-23.3 deletion. Of the 11 haploinsufficient genes predicted with an in silico database, we focused on NCAM1 and CADM1 as the genes accountable for NB and ganglioneuroma. The deletion range, especially the 11q22.3 involvement, needs to be determined in 11q deletion cases in order to predict susceptibility to peripheral nerve tumors involving NB and ganglioneuroma.

Hedgehog signaling is synergistically enhanced by nutritional deprivation and ligand stimulation in human fibroblasts of Gorlin syndrome.

Hedgehog signaling is a pivotal developmental pathway that comprises hedgehog, PTCH1, SMO, and GLI proteins. Mutations in PTCH1 are responsible for Gorlin syndrome, which is characterized by developmental defects and tumorigenicity. Although the hedgehog pathway has been investigated extensively in Drosophila and mice, its functional roles have not yet been determined in human cells. In order to elucidate the mechanism by which transduction of the hedgehog signal is regulated in human tissues, we employed human fibroblasts derived from three Gorlin syndrome patients and normal controls. We investigated GLI1 transcription, downstream of hedgehog signaling, to assess native signal transduction, and then treated fibroblasts with a recombinant human hedgehog protein with or without serum deprivation. We also examined the transcriptional levels of hedgehog-related genes under these conditions. The expression of GLI1 mRNA was significantly higher in Gorlin syndrome-derived fibroblasts than in control cells. Hedgehog stimulation and nutritional deprivation synergistically enhanced GLI1 transcription levels, and this was blocked more efficiently by vismodegib, a SMO inhibitor, than by the natural compound, cyclopamine. Messenger RNA profiling revealed the increased expression of Wnt signaling and morphogenetic molecules in these fibroblasts. These results indicated that the hedgehog stimulation and nutritional deprivation synergistically activated the hedgehog signaling pathway in Gorlin syndrome fibroblasts, and this was associated with increments in the transcription levels of hedgehog-related genes such as those involved in Wnt signaling. These fibroblasts may become a significant tool for predicting the efficacies of hedgehog molecular-targeted therapies such as vismodegib.

Coexistence of neuroblastoma detected on staging of Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare proliferative disease accompanied by the accumulation of pathological Langerhans cells, which often spreads into multi-site and multi-organ systems. We here describe a girl with a history of Kawasaki disease and cervical lymphadenopathy who presented with occipital LCH. Adrenal tumor was detected on staging evaluation of LCH and was diagnosed as neuroblastoma on resection using laparoscopic surgery. Neither tumor relapsed following chemotherapy for LCH and resection of neuroblastoma. Although LCH often spreads into multi-organ lesions, invasive biopsy may be needed for tumors with atypical localization for LCH in consideration of the synchronous occurrence of malignancies.

Frameshift mutation in the PTCH2 gene can cause nevoid basal cell carcinoma syndrome.

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental defects and tumorigenesis. The gene responsible for NBCCS is PTCH1, encoding a receptor for the secreted protein, sonic hedgehog. Recently, a Chinese family with NBCCS carrying a missense mutation in PTCH2, a close homolog of PTCH1, was reported. However, the pathological significance of missense mutations should be discussed cautiously. Here, we report a 13-year-old girl diagnosed with NBCCS based on multiple keratocystic odontogenic tumors and rib anomalies carrying a frameshift mutation in the PTCH2 gene (c.1172_1173delCT). Considering the deleterious nature of the frameshift mutation, our study further confirmed a causative role for the PTCH2 mutation in NBCCS. The absence of typical phenotypes in this case such as palmar/plantar pits, macrocephaly, falx calcification, hypertelorism and coarse face, together with previously reported cases, suggested that individuals with NBCCS carrying a PTCH2 mutation may have a milder phenotype than those with a PTCH1 mutation.

Phrenic nerve palsy associated with birth trauma--case reports and a literature review.

Phrenic nerve palsy is a peripheral nerve disorder caused by excessive cervical extension due to birth trauma or cardiac surgery. We describe two new patients with phrenic nerve palsy associated with birth trauma. Both patients exhibited profound dyspnea and general hypotonia immediately after birth. A chest roentgenogram and fluoroscopy revealed elevation of the diaphragm, leading to a diagnosis of phrenic nerve palsy associated with birth trauma. Since they had intermittently exhibited dyspnea and recurrent infection, we performed video-assisted thoracoscopic surgery (VATS) plication in both cases, at an early and a late stage, respectively. Both patients subsequently exhibited a dramatic improvement in dyspnea and recurrent respiratory infection. Interestingly, the late stage operated infant exhibited spontaneous recovery at 7 months with cessation of mechanical ventilation once. However, this recovery was transient and subsequently led to an increased ventilation volume demand, finally resulting in surgical treatment at 15 months. Histological examination of the diaphragm at this time showed grouped muscle atrophy caused by phrenic nerve degeneration. To our knowledge, this is the first pathologically proven report of grouped muscle atrophy of the diaphragm due to phrenic nerve degeneration, suggesting that partial impairment of phrenic nerves resulted in respiratory dysfunction with incomplete recovery. We conclude that recently developed VATS plication is a safe and effective treatment for infants with phrenic nerve palsy, and should be considered as a surgical treatment at an early period.