Castleman disease in a child with short stature

We report a 14‐year‐old boy with Castleman disease in this article. He complained of short stature, and his body height was 133.8 cm (<3rd percentile; z score ?4.5). There was marked delay in the appearance of secondary sexual characteristics. He was found to have a remittent fever and a lower mid‐abdominal tumor. Blood test revealed microcytic hypochromic anemia, thrombocytosis, polyclonal hypergammaglobulinemia, hyperfibrinogenemia, and elevated erythrocyte sedimentation rate. The serum IL‐6 and C‐reactive protein levels were increased. The mass was found to be mixed hyaline vascular and plasma cell type of Castleman disease through a pathological examination. Lymph nodes affected by Castleman disease cause overproduction of IL‐6. It decreases IGF‐1, IGFBP‐3 and serum testosterone levels. As a result of tumorectomy, his short stature and delay in the development of secondary sexual characteristics were improved.     

Paraneoplastic syndrome and intrathoracic Castleman disease

We report two cases of intrathoracic Castleman disease presenting with paraneoplastic syndrome. Patient 1 was a 10-year-old girl with short stature. She was found to have delayed bone age, slow growth velocity, and iron-deficiency anemia, which was refractory to treatment. Thrombocytosis and hypergammaglobulinemia were later detected. Chest X-ray revealed a hilar mass. Patient 2 was a 14-year-old boy who had severe cough, progressive mucocutaneous erosion, and dermatitis. Chest X-ray showed a mediastinal mass. Sections of skin biopsy showed findings consistent with pemphigus disease. In each case, the histological diagnosis of Castleman disease was made.     

Iron-deficiency anemia in Castleman disease: implication of the interleukin 6/hepcidin pathway

In addition to occasional autoimmune hemolytic anemia, unexplained iron-deficiency anemia has been reported in childhood Castleman disease (CD). The recent discovery of hepcidin has regenerated the research on iron metabolism. This hormone is a key regulator of iron homeostasis, mainly by inhibiting intestinal iron absorption. Liver expression of hepcidin increases in response to interleukin 6 (IL-6). With chronic overproduction of IL-6 as a hallmark, CD could be an interesting human model for studying the contribution of the IL-6/hepcidin pathway in the pathogenesis of anemia of chronic disease. We report here the case of a 16-year-old boy with chronic iron-deficiency anemia (plasma ferritin: 19 μg/L; plasma iron: 2.2 μmol/L; negative bone marrow Perls' Prussian blue stain), inflammatory syndrome (C-reactive protein: 108 mg/L), and growth retardation for the previous 2 years. Diagnostic workup revealed a large mesenteric mass corresponding to localized CD of mixed histologic type. Resection of the tumor resulted in complete resolution of iron-deficiency anemia and inflammatory syndrome. Parallel variations of plasma IL-6, C-reactive protein, and hepcidin concentrations, together with tumor immunohistochemistry, strongly suggested that IL-6 synthesized by the tumor caused both the inflammation and iron deficiency through enhancement of hepcidin production by the liver. The results of this unique case study (1) explain the mechanism of iron deficiency observed in some children with CD, (2) confirm in vivo the regulatory effect of IL-6 in human hepcidin production, and (3) suggest that iron deficiency is a causal link between IL-6 and anemia of chronic disease.     

Localized abdominal Castleman disease masquerading as malabsorption syndrome

Castleman disease is a rare lymphoproliferative disorder of unclear etiology. It usually presents as localized enlarged lymph nodes in children. Surgical excision is curative in localized form. Clinical findings of malabsorption are rarely reported in the literature. Herein, we describe a 14-year-old girl who presented with anemia, failure to thrive, osteoporosis, zinc, and vitamin deficiency. She was diagnosed as localized mesenteric mixed type of Castleman disease. Her clinical findings improved after surgical excision of the mass.     

Chronic active EBV infection with features of granulomatosis with polyangiitis

Herein, we report the case of a 13‐year‐old boy with multiple recurrent ulcers on his legs. He developed severe sinusitis at 10 years of age and had significant weight loss (6 kg) in the 2 months prior to admission. Histology of tissue biopsied from the ulcer indicated small vessel vasculitis and granulomatous inflammation. Given that these findings met the diagnostic criteria for granulomatosis with polyangiitis (GPA), he was treated with immunosuppressive agents. Further pathology, however, indicated Epstein–Barr virus (EBV)‐encoded RNA (EBER) in most lymphocytes in the same sample. The EBER‐positive lymphocytes were mainly CD4‐positive T cells. The EBV‐DNA load in the peripheral blood was also abnormally increased (1.0 × 10⁴ copies/μg DNA). Thus, the diagnosis was established as chronic active EBV infection (CAEBV). This case illustrates the necessity of careful differential diagnosis of CAEBV owing to its clinical resemblance and pathological overlap with GPA.     

Expression of and responses to CD2 and CD3 in 18‐month‐old children with and without atopic dermatitis

We hypothesize that atopy is associated with a reduced T‐cell function early in life and an imbalance in cytokine production. The purpose of this study was to investigate the expression of and responses to CD2 and CD3 in children who did or did not develop atopic dermatitis early in life. The expression of CD2 and CD3 was analyzed by flow cytometry, and proliferation of CD2 and CD3 was studied by ³H‐thymidine incorporation in phytohaemagglutinin (PHA)‐ and anti‐CD3‐stimulated peripheral blood mononuclear cells (PBMC) of 18‐month‐old children, 25 with and 29 without atopic dermatitis. Exogenous interleukin (IL)‐2 was added to compensate for possible functional differences in accessory cells. Anti‐CD3‐induced secretion of IL‐4, IL‐5, IL‐6, IL‐10, IL‐13, and interferon‐γ (IFN‐γ) was analyzed by enzyme‐linked immunosorbent assay (ELISA). Atopy was associated with a low proportion of CD2⁺ lymphocytes. Responsiveness to PHA, which activates lymphocytes partly via the sheep erythrocyte receptor, CD2, was reduced in the allergic children. The anti‐CD3‐induced proliferation declined more rapidly with antibody dilution in the allergic than in the non‐allergic children. Atopic dermatitis was associated with high levels of anti‐CD3‐stimulated IL‐5 secretion. The IL‐4/IL‐10 and IL‐4/IFN‐γ ratios were higher in children with elevated total immunoglobulin E (IgE) levels. Skin prick test‐negative children with eczema produced higher levels of IL‐10 than skin prick test‐positive children. In conclusion, atopic children have a reduced T‐cell function. Atopic dermatitis is associated with increased IL‐5 production, while high total IgE levels are associated with high IL‐4/IFN‐γ and IL‐4/IL‐10 ratios.     

Chronic urticaria of neonatal onset: A potential sign of autoinflammation

We present a 6 year old boy with chronic urticaria of neonatal onset associated in childhood with features of neurological and joint inflammation. Genetic analysis confirmed the diagnosis of neonatal onset multi‐inflammatory disorder (NOMID). Daily subcutaneous anti‐IL‐1 receptor antagonist therapy resulted in a dramatic and sustained amelioration of systemic inflammation. NOMID must be considered in any child with chronic urticaria of neonatal/infantile onset, particularly if associated with joint and/or neurological inflammation.     

新生儿MN血型不合溶血病3例报道暨文献复习

目的总结新生儿MN血型不合溶血病的临床特点、诊治经验及发病机理。方法报告我科近年诊治的3例新生儿MN血型不合溶血病,复习我科曾报道的另外2例,并通过中国知网、万方数据库和维普中文期刊数据库,检索国内近24年来报告的所有病例报告,对患儿的临床表现和实验室检查进行总结分析。结果包括本文报道的3例,国内共报道31例新生儿MN血型不合溶血病,MN型25例,M型6例;直接抗人球蛋白试验阳性13例,抗体释放试验阳性17例,患儿血型抗体IgG抗M型阳性28例;母亲血型抗体IgG抗M型阳性30例,IgM抗M阳性16例。31例患儿中6例（19．4％）为第1胎发病,贫血发生率67．7％,其中重度贫血发生率29．0％,重度高胆红素血症发生率22．6％;较多患儿需要换血（29．0％）和输血（45．2％）;病死率9．7％。结论新生儿MN血型不合溶血病容易出现黄疸、贫血,可导致患儿急性死亡。光疗、输注丙种球蛋白、白蛋白等治疗效果良好,严重病例需要换血、输血治疗。为了提高MN溶血病的诊断率,应检测孕妇MN血型及抗M抗体效价。     

Toxocara canis infection: Unusual trigger of systemic lupus erythematosus

Infection by Toxocara canis can cause systemic vasculitis. We report here a unique case of systemic lupus erythematosus (SLE) triggered by T. canis infection. An 8‐year‐old girl was treated with albendazole therapy for common toxocariasis, but she developed two weeks later, asthenia, fever, infiltrated maculopapular eruption of the face, peripheral vascular disease with necrosis of the fingers and inflammatory anemia with proteinuria. Anti‐nuclear, anti‐DNA and anti‐Sm antibodies positivity, together with minimal change nephritis with mesangial exclusive IgM deposit on renal biopsy and clinical relapse after initially successful steroid therapy, led to the diagnosis of SLE. T. canis infection can trigger systemic lupus but must also be ruled out of the differential diagnosis given its association with autoimmunity.     

Case of cytomegalovirus‐associated direct anti‐globulin test‐negative autoimmune hemolytic anemia

A 1‐year‐old boy developed autoimmune hemolytic anemia after a negative direct anti‐globulin test. The concentration of erythrocyte membrane‐associated immunoglobulin G, determined using an immunoradiometric assay, correlated with disease activity. He was positive for cytomegalovirus (CMV) both serologically and by quantitative real‐time polymerase chain reaction, indicating that his autoimmune hemolytic anemia was directly caused by CMV infection. Since anti‐CMV immunoglobulin G was not absorbed by the patient's erythrocytes, cross‐reaction between erythrocyte antigens and CMV was not likely a causative factor for hemolysis.     

Novel mutation in the TMPRSS6 gene with iron‐refractory iron deficiency anemia

Iron‐refractory iron deficiency anemia (IRIDA) is a rare autosomal recessive disease characterized by congenital hypochromic microcytic anemia, low transferrin saturation, low serum iron, normal–high serum ferritin, and increased hepcidin. This disease is caused by loss‐of‐function mutations in TMPRSS6 that lead to high hepcidin and result in severe anemia. We report our experience with an 11‐year‐old Japanese girl with hypochromic microcytic anemia, low serum iron, and high serum ferritin, with anemia that was refractory to the oral iron that was prescribed frequently from early childhood. Presence of high hepcidin suggested a diagnosis of IRIDA, which was eventually confirmed by identification of a novel homozygous mutation, p.Pro354Leu, in the TMPRSS6 gene. This case suggests that serum hepcidin should be routinely measured for differential diagnosis when patients with IDA are unresponsive to oral iron or have unusual clinical features.     

Castleman disease in a pediatric liver transplant recipient: a case report and literature review

Castleman disease is a rare hematologic disorder, closely linked to the HHV-8, and most commonly observed in immunocompromised individuals. Thirteen months following a liver transplant for CPS-1 defect, a 15-month-old boy presented with fevers, anemia, and growth retardation. Abdominal CT scan showed splenomegaly and generalized lymphadenopathy. Histology of chest wall lymph nodes revealed a mixed CD3+ T-cell and CD20+ B-cell population with atretic germinal centers consistent with multicentric Castleman disease. Qualitative DNA PCR detected HHV-8 in the resected lymph node and in the blood, supporting the diagnosis. Immunosuppression was tapered, and he was transitioned from tacrolimus to sirolimus. His graft function remained stable, and repeat imaging showed regression of the lymphadenopathy. The child is living one yr after Castleman disease diagnosis with a well-functioning graft. Castleman disease is a potential complication of solid organ transplant and HHV-8 infection. Reduction in immunosuppression and switch to sirolimus may be an effective strategy to treat this condition.     

Giant cell hepatitis with autoimmune hemolytic anemia in a Korean infant

Giant cell hepatitis (GCH) with autoimmune hemolytic anemia (AHA) is a very rare disease characterized by early onset and severe clinical manifestations, including immune hemolytic anemia and hepatitis with cholestasis. The prognosis is poor despite aggressive immunosuppressive therapy. We report here the first case of GCH with AHA in East Asia. A 2‐month‐old boy was admitted with jaundice. Blood test indicated abnormal liver function and low hemoglobin. Direct Coombs test and several autoantibodies associated with liver disease were positive, and liver biopsy was consistent with GCH. He was treated with prednisolone and ursodeoxycholic acid, and at the time of writing was in clinical and biochemical remission after prednisolone was stopped.     

FDG‐PET in macrophage activation syndrome associated with systemic juvenile idiopathic arthritis

We herein describe a case of systemic juvenile idiopathic arthritis (s‐JIA)‐associated macrophage activation syndrome (MAS) in which the ^18Ffluorodeoxyglucose positron emission tomography (^18FFDG‐PET) findings were characteristic. The pattern of greater ^18FFDG accumulation into the spleen compared with the liver was more remarkable in this patient compared with s‐JIA. This pattern, however, was also observed in cases of acute leukemia. In the present patient, serum interleukin (IL)‐18 was extremely elevated (255 000 pg/mL), whereas in leukemia patients it is mildly elevated (360–1480 pg/mL). ^18FFDG‐PET might be a useful indicator of s‐JIA and MAS in patients with fever of unknown origin. The pattern of ^18FFDG accumulation, however, can also be observed in acute leukemia. The combination of ^18FFDG‐PET and serum IL‐18 might be useful for the diagnosis of s‐JIA and MAS.     

The use of a Berlin Heart EXCOR LVAD in a child receiving chemotherapy for Castleman's disease

We present the unique case of a pediatric patient who received chemotherapy for a diagnosis of CD, while mechanically supported with a Berlin EXCOR LVAD secondary to restrictive cardiomyopathy. A four‐yr‐old previously healthy male with restrictive cardiomyopathy required MCS after cardiac arrest but was diagnosed with multicentric CD, a non‐malignant lymphoproliferative disorder fueled by excessive IL‐6 production. Treatment with IL‐6 blockade (tocilizumab) every two wk and methylprednisolone had no effect on his lymph nodes or cardiac function while on temporary RotaFlow. A Berlin LVAD was placed for treatment with rituximab, COP, vincristine, and methylprednisolone. After three courses of chemotherapy, his inflammatory markers normalized and his lymphadenopathy decreased but cardiac function remained severely depressed. He tolerated chemotherapy on the Berlin but required frequent titrations of his anti‐coagulation regimen and he did suffer a hemorrhagic stroke. His clinical status improved significantly with rehabilitation, and he tolerated heart transplantation without further complications. MCS is a feasible option as a bridge to recovery or heart transplant eligibility for patients with hemodynamic collapse requiring chemotherapy but it does necessitate close titration of the anti‐coagulation regimen to coincide with changes in the inflammatory state.     

Microscopic polyangiitis in a girl with severe anemia and no respiratory symptoms

ANCA‐positive microscopic polyangiitis is a rare in children. We reported an 11‐year‐old girl without respiratory symptoms with sever anemia which shows signs of hemolytic anemia in test data. Chest X‐ray and computed tomography scans suggested alveolar hemorrhage. The patent developed night hypoxia and moderate proteinuria. Serum MPO‐antibody was highly positive and renal biopsy demonstrated segmental necrosis or crescent formation. A diagnosis of microscopic polyangiitis was made. She responded to pulsed methylprednisolon and pulsed Endoxan therapy. Microscopic polyangitiis should be considered early in the differential diagnosis of patients presenting with anemia of an unknown origin.     

氨茶碱抗哮喘气道炎症的机制研究

目的探讨氨茶碱抗哮喘气道炎症的机制。方法采用卵蛋白(OVA)致敏的过敏性哮喘豚鼠为模型，诱发哮喘后24h利用放射免疫法测定肺组织白细胞介素2(IL-2)、IL-6含量，免疫组织化学方法检测肺组织细胞间黏附分子1(ICAM-1)蛋白表达。结果哮喘组肺组织IL-2、IL-6含量及ICAM-1阳性表达均显著高于正常对照组，氨茶碱组IL-2、IL-6及ICAM-1阳性表达较哮喘组明显降低。结论氨茶碱抗哮喘气道炎症机制可能与降低IL-2、IL-6合成或释放，降低肺组织ICAM-1阳性表达，从而抑制炎症细胞在气道浸润有关。     

Child‐onset systemic sclerosis positive for anticentromere antibodies: Two Japanese cases

Systemic sclerosis (SSc) is an uncommon connective tissue disease of childhood. Moreover, pediatric SSc positive for anticentromere antibodies (ACA) is extremely rare. We describe two cases of ACA‐positive SSc in Japanese girls with clinical findings. Case 1 is a 15‐year‐old female. From disease onset at 7 years, she developed limited cutaneous (no internal involvement) SSc positive for ACA and anti‐U1RNP antibodies, but negative for antitopoisomerase I antibodies (ATA). She also showed calcinosis, sclerodactyly, and telangiectasia, but not Raynaud's phenomenon. Case 2 is also a 15‐year‐old female with onset at the same age. Her diagnosis was limited cutaneous SSc positive for ACA, anti‐SSA/Ro antibodies, and anti‐thyroid antibodies, but not ATA. She showed sclerodactyly, telangiectasia, and Raynaud phenomenon, as well as complicated Sjögren's syndrome and chronic thyroiditis with euthyroidism. We reported that two Japanese girls with SSc were positive for ACA and other antibodies with the exception of ATA.     

BK virus encephalitis and end‐stage renal disease in a child with hematopoietic stem cell transplantation

BK virus encephalitis after HSCT is uncommon. Several reports of native kidney BKVN in patients with HSCT, hematologic malignancies, human immunodeficiency virus infection, and non‐renal solid organ transplantation have been described. However, an uncommon combination of BK encephalitis and ESRD of native kidneys secondary to BK virus in a child with HSCT has not been described. We report a 10‐year‐old boy who presented with a gradually rising serum creatinine during treatment for severe autoimmune hemolytic anemia, which he developed 9 months after receiving an allogeneic HSCT for aplastic anemia. There was no proteinuria or hematuria present. Serum BK virus load was 5 × 10⁶ copies/mL. A renal biopsy showed evidence of BKVN. He developed fever, seizures, and confusion, and the (CSF) showed significant presence of the BK virus (1 × 10⁶ copies/mL) along with biochemical evidence of viral encephalitis. Cerebrospinal fluid cultures were negative. Despite significant clinical symptoms and presence of BK virus in CSF, the magnetic resonance brain imaging findings were minimal. With reduction of immunosuppression, there was resolution of BK encephalitis but BKVN remained resistant to multiple anti‐BK virus agents, including leflunomide and cidofovir. He eventually became dialysis‐dependent and, 6 years later, received a renal transplant from his mother. This case illustrates that BK virus in severely immunocompromised HSCT recipient may lead to BK encephalitis and BKVN of native kidneys, even without hemorrhagic cystitis, leading to ESRD. Knowledge of such is important for appropriate timely evaluation and management.