The RASopathies are a class of developmental disorders caused by germline mutations in the RAS-mitogen-activated protein kinase (MAPK) pathway. Hypertrophic cardiomyopathy (HCM) has been frequently described in children with RASopathy, but only a minority of patients have received formal genotyping. The purpose of this study was to evaluate the genetic basis and clinical outcome of pediatric patients with RASopathy-associated HCM. We retrospectively reviewed the mutation spectrum and clinical outcome of all the patients with RASopathy derived from 168 pediatric HCM cases referred to our institution between January 2012 and July 2018. A heterozygous missense mutation in one of known RASopathy genes was identified in 46 unrelated children with HCM. Mutations in the PTPN11 gene were the most prevalent (19/46); this was followed by mutations in RAF1 (11/46), KRAS (5/46), RIT1 (4/46), BRAF (3/46), SOS1 (2/46), HRAS (1/46), and SHOC2 (1/46). Moreover, two compound heterozygous missense mutations in the LZTR1 gene were identified in one patient with the Noonan syndrome phenotype and HCM. The median age at the diagnosis of HCM was 3.0 months (range 0 months to 8.1 years). Twenty-one of the patients had significant left ventricular outflow tract obstruction and 32 had concomitant congenital heart disease. Three patients with a mutation in exon 13 of the PTPN11 gene died of cardiac failure at the ages of 3.0, 3.5, and 6.0 months. The remaining 44 patients were alive after an average follow-up time of 3.9 years (0.5 to 17.1 years, median 2.9 years) from the initial diagnosis of HCM, including 5 patients with spontaneous regression of their cardiac hypertrophy. RASopathy-associated HCM is a heterogeneous genetic condition characterized by early-onset cardiac hypertrophy and a high prevalence of co-existing congenital heart disease, which is most frequently related to specific mutations in the PTPN11 gene. Rapidly progressive HCM, resulting in an early death, is uncommon in RASopathy patients except those with specific mutations in exon 13 of the PTPN11 gene.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis in children. A delayed or missed diagnosis of pediatric EGPA is common, owing to the atypical clinical manifestation and limited recognition of this disorder. The vasculitis in EGPA typically involves small to medium size vessels. Extensive occlusion of arteries in the extremities was being extremely rare and has never been reported in children. A 10-year and 10-month-old girl with recurrent wheezing and breathlessness during exercise, was initially diagnosed with asthma at the age of five years. Despite unexplained manifestations, including intermittent remarkably increased eosinophilia, uncontrolled allergic rhinitis, and recurrent petechia, from the onset of asthma through to its remission, the consideration of EGPA was completely ignored until the patient presented with aggravated petechia and severe ulceration of the lower extremities, associated with extensive stenosis and/or occlusion of the arteries of the shank and foot. Given her history of asthma, eosinophilia, allergic rhinitis, mononeuropathy, pulmonary infiltrates, and vasculitis confirmed by the skin biopsy, the diagnosis of EGPA was ultimately confirmed. Regrettably, the initial inappropriate and irrational use of corticosteroid failed to relieve the symptoms until more aggressive treatment with intravenous methylprednisolone was started. This was followed by methotrexate treatment, with tapering of prednisone, without relapse over a six-month follow-up. Pediatric rheumatologists should be alert to the possibility of EGPA in children with refractory asthma associated with unexplained manifestations, and should be aware of the thromboembolic complications as vascular sequelae of EGPA.

Background:Cerebral infarction is a rare neurological complication of Kawasaki disease (KD) and occurs in the acute or subacute stage. There have been no reported cases of late-onset fatal cerebral infarction presenting over 1 year after the onset of KD.Case Presentation:A 5-month-old male patient with KD received timely intravenous immunoglobulin therapy; however, extensive coronary artery aneurysms (CAA) and coronary artery thrombosis (CAT) developed 1 month later. Anticoagulation and thrombolytic agents were suggested, but the child's parents refused. Fifteen months after KD onset, an attack of syncope left him with left hemiplegia; brain computerized tomography (CT) scans revealed cerebral infarction of the right basal ganglion without hemorrhage. Magnetic resonance angiography (MRA) revealed severe stenosis of the right middle cerebral artery, and a series of tests were performed to exclude other causes of cerebral infarction. Considering the cerebral infarction and CAT, combination therapy with urokinase and low-molecular-weight heparin (LMWH) was initiated within 24 h of syncope onset, together with oral aspirin and clopidogrel. Five days later, his clinical symptoms partially regressed and he was discharged. Unfortunately, 5 days after discharge, his clinical condition suddenly deteriorated. Repeat brain CT showed hemorrhagic stroke involving the entire left cerebral area, in addition to the previous cerebral infarction in the right basal ganglion, with obvious secondary cerebral swelling and edema, which might have been caused by previous thrombolysis. Severe cerebral hernias developed quickly. Regrettably, the patient's parents abandoned treatment because of economic factors and unfavorable prognosis, and he died soon after.Conclusions:Cerebral infarction and cerebral artery stenosis can develop late, even 1 year after the onset of KD. Pediatricians should be aware of the possibility of cerebrovascular involvement in addition to cardiac complications during long-term follow-up of KD patients. Prompt anticoagulation therapy and regular neuroimaging evaluation are essential for the management of patients with KD with giant CAA and/or CAT.

Background: Cardiovascular involvement is a rare but severe complication of Epstein–Barr virus (EBV) infections. Patients with chronic active EBV (CAEBV) are at increased risk of developing cardiovascular complications and have a poor prognosis. Here, we report the rare case of a pediatric patient with CAEBV and EBV- hemophagocytic lymphohistiocytosis (HLH) complicated with a giant coronary artery aneurysm (CAA) and thrombosis, a giant Valsalva sinus aneurysm, and ascending aorta dilation seven years after the disease onset.Case presentation: A previously healthy 3-year-old girl was initially misdiagnosed as presenting incomplete Kawasaki disease complicated by coronary artery lesions (CALs) for which she received intravenous immunoglobulin and aspirin therapy. Subsequently, she was transferred to our hospital, where we diagnosed her as having a primary EBV infection. After acyclovir therapy, her clinical symptoms resolved with negative EBV-DNA, and she was discharged home with aspirin treatment for the remaining CALs. However, she did not have regular follow-ups after that. Seven years later, the 10-year-old girl developed a prolonged fever and fatigue, and she was diagnosed as presenting CAEBV and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) due to the presence of a high EBV-DNA load, prolonged fever, splenomegaly, bicytopenia, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis, low NK-cell activity, and increased levels of ferritin and soluble CD25. The echocardiography images showed giant left and right coronary artery aneurysms, a giant Valsalva sinus aneurysm, and ascending aorta dilation. Her parents agreed to a therapy with intravenous immunoglobulin, methylprednisolone, antiplatelet, and anticoagulant, but not to the standard therapy of EBV-HLH. However, the cardiovascular complications, including CAAs and thrombosis, Valsalva sinus aneurysm, and aorta lesions, did not resolve. Three weeks later, the patient was finally discharged home asymptomatic. Unfortunately, one month after discharge, the fever recurred the girl. The guardian had refused treatment and took the patient home due to economic difficulties. During our subsequent follow-up visit, the girl subsequently passed away.Conclusions: We reported the case of a pediatric patient with EBV infection who developed rare and fatal cardiovascular complications (CAAs and thrombosis, Valsalva sinus aneurysm, and aortic lesions) seven years after the onset of the infection. Clinicians should be aware of these complications during the long-term follow-up of patients with EBV infection, especially in patients with CAEBV and/or EBV-HLH.

Coronary artery dilation (CAD) had rarely been described as a cardiac complication of febrile disease other than Kawasaki disease (KD). There are rare cases complicated by CAD reported in patients with Mycoplasma pneumoniae (MP) infection. A 6-year-old boy with severe Mycoplasma pneumoniae pneumonia (MPP) was transferred to our hospital due to significant respiratory distress on the 11th day from disease onset. Nadroparin, levofloxacin, and methylprednisolone followed by oral prednisone were aggressively prescribed. His clinical condition gradually achieved remission, and the drugs were withdrawn on the 27th day. Regrettably, the recurrent fever attacked him again in the absence of infection-toxic manifestations. Necrotizing pneumonia (NP) was found on chest CT. And echocardiography revealed right CAD (diameter, 3.40mm; z-score, 3.8), however, his clinical and laboratory findings did not meet the diagnostic criteria of KD. CAD was proposed to result from MP infection, and aspirin was prescribed. Encouragingly, the CAD regressed one week later (diameter, 2.50mm; z-score, 1.4). Additionally, the child defervesced seven days after the initiation of prednisone and Nadroparin treatment. The patient was ultimately discharged home on the 50th day. During follow-up, the child was uneventful with normal echocardiography and fully resolved chest CT lung lesions. CAD can develop in patients with severe MP infection. Pediatricians should be alert to the possibility of CAD in patients with severe MP infection and recognize that CAD might also develop in febrile disease rather than KD.

Background: Cyanosis is a common clinical finding in infants and children. Particularly, central cyanosis can be associated with significant and potentially life-threatening diseases. Acquired methemoglobinemia is a rare but severe or even fatal cause of cyanosis in infants. Due to its rarity, timely diagnosis and appropriate management, particularly in infants, can be challenging in a clinical setting.Case report: We report the case of a previously healthy 49-day-old female infant who presented with central cyanosis. Four hours prior to presentation, her guardian had inappropriately prepared her milk formula using spinach juice. This critical clue hinted to us that this infant might suffer from acquired methemoglobinemia. Upon blood sampling, her blood appeared chocolate brown in color. Furthermore, arterial blood gas analysis revealed abnormal findings, with a significantly elevated percentage of methemoglobinemia at 44.7%. Regarding the history of inappropriate formula preparation using vegetable juice and the abnormal finding of methemoglobinemia, a diagnosis of acquired methemoglobinemia was proposed. Other causes of methemoglobinemia were further excluded. Treatment with methylene blue and vitamin C was immediately initiated. Encouragingly, the cyanosis of this infant resolved 1 h later, with normal results of the repeated blood gas analysis. This infant was discharged home 2 days later and had no abnormal findings during the follow-up.Conclusion: In this study, we reported a rare case of acquired methemoglobinemia in a 49-day-old infant. Inappropriate preparation of the infant milk formula with spinach juice was the potential cause of methemoglobinemia in this case, which presented with central cyanosis. Our findings also suggested that pediatricians should be aware of acquired methemoglobinemia as a potential cause of cyanosis in infants.