Clinical expression in Pfeiffer syndrome type 2 and 3: surveillance in Japan.

Pfeiffer syndrome (PS) is a classic type of craniosynostosis syndrome. Severe cases usually require emergency care at birth. However, early diagnosis is often precluded by the rarity and consequent low awareness of this disease. This study aimed to clarify phenotypic expressions useful for the diagnosis of PS. We reviewed all cases of PS type 2 or 3 according to Cohen's classification that were reported between 1980 and 2011 in Japan. Clinical and genetic information were extracted from the patients' medical records. A total of 23 patients with PS type 2 or 3 were identified. All 23 patients presented with craniosynostosis, midface hypoplasia, proptosis, broad thumbs, and wide great toes. FGFR2 mutations were confirmed in all 8 patients in whom genetic analyses were performed. In addition to classic symptoms, elbow ankylosis and sacrococcygeal defects were present in 70% and 30% of the patients, respectively. During an average follow-up of 22 months, 22% of patients died before 1 year of age. Elbow ankylosis and sacrococcygeal defects were the phenotypic features recognizable at a glance. These defects strongly suggest the presence of PS in newborns with craniosynostosis.

Improving circulatory disturbance in transient abnormal myelopoiesis.

Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome (DS) is characterized by circulating blast cells in the blood. TAM usually resolves spontaneously, but several studies have associated this condition with early death, focusing on the development of effective treatments. We report the case of a neonate with DS who had TAM and novel GATA1 mutation. Although the patient eventually died of hepatic failure, exchange blood transfusion and low-dose cytarabine treatment dramatically improved pulmonary hypertension and acute renal failure refractory to conventional therapy. Such a blast-reducing approach might be useful for improving circulatory disturbances in neonates with DS and TAM.

Age-related clinical characteristics of isolated congenital unilateral absence of a pulmonary artery.

Unilateral absence of a pulmonary artery (UAPA) is a rare anomaly. Although UAPA has been reported previously, its age-related pathogenesis and symptoms remain unclear. This retrospective cohort study included cases of UAPA reported in Japan at medical meetings or in the literature from 1990 through 2009. Patients with other congenital cardiac defects were excluded from the study. Clinical status was assessed according to age, and the clinical course of patients with isolated UAPA was compared with that of patients who had UAPA with a patent ductus arteriosus (PDA). Of the 92 patients with UAPA identified, 78 had isolated UAPA (14 with PDA). Hemoptysis and collateral arteries were observed in 0 and 13% of patients with isolated UAPA who were younger than 1 year, as compared with 24 and 50% of those 20 years of age or older, respectively. Pulmonary hypertension was present in 5% of the patients aged 1 to 19 years. Among patients 20 years or older, however, 32% had pulmonary hypertension, and 8% died. Compared with isolated UAPA, UAPA with PDA was associated with an earlier diagnosis (median age, 20 vs. 0 years; p = 0.002), a higher prevalence of pulmonary hypertension (22% vs. 86%; p < 0.0001), and a higher mortality rate (4% vs. 21%; p = 0.046). Collateral artery formation and pulmonary hypertension progress with age in patients with UAPA. Early diagnosis and revascularization may prevent the age-related progression of UAPA.

Effective VCR/DEX pulse maintenance therapy in the KYCCSG ALL-02 protocol for pediatric acute lymphoblastic leukemia.

In a previous study of childhood acute lymphoblastic leukemia (ALL) by the Kyushu-Yamaguchi Children's Cancer Study Group, ALL-96, we achieved a 72.1 % 5-year event-free survival (EFS) and an 84.8 % 5-year overall survival (OS). In a subsequent study, ALL-02, we adopted a vincristine dexamethasone (VCR/DEX) pulse regimen as maintenance therapy in the context of the ALL-96 study using the same risk classification and treatment schedule. A total of 156 pediatric cases of ALL were treated with ALL-02. All of the patients were classified as standard-risk or high-risk. Risk stratification was based on white cell counts, immunophenotype, the presence of central nervous system (CNS) disease at diagnosis, organomegaly, and early treatment response (day 14 bone marrow status). The 7-year EFS and OS rates were 77.7 % (95 % CI 70.6-84.8 %) and 89.5 % (95 % CI 84.6-94.4 %), respectively. CNS 3 status [hazard ratio (HR) = 5.0, p = 0.009] and high white blood cell count at diagnosis (HR = 2.6, p = 0.047) were risk factors for poor EFS in multivariate analysis. Our strategies to categorize patients into two risk groups, and to treat with a VCR/DEX pulse were feasible and reasonably effective treatments for pediatric ALL.

Successful unrelated cord blood transplantation for Epstein-Barr virus-associated lymphoproliferative disease with hemophagocytic syndrome.

We report a case of successful umbilical cord blood transplantation (CBT) for Epstein-Barr virus (EBV)-associated lymphoproliferative disease (LPD) in a 6-year-old girl. The patient had hemophagocytic syndrome with excessive circulating levels of EBV DNA that was refractory to immunochemotherapy. Multiple hepatosplenic lesions favored the diagnosis of EBV-associated LPD, although the aggressive course precluded the histopathologic diagnosis. Unrelated CB cells mismatched at 1 HLA locus were infused after patient conditioning with 900 mg/m2 etoposide, 2 g/m2 cytarabine, 16 mg/kg busulfan, and 200 mg/kg cyclophosphamide. Complete chimeric status was obtained on day 19 posttransplantation. Drug fever and acute graft-versus-host disease of the skin (grade II) were the major complications. A transient increase of EBV DNA 1 year after CBT indicated a primary EBV infection of the donor cells. The patient is alive with no evidence of disease 27 months after CBT. There has been no previous report of successful CBT for EBV-related LPD/lymphoma. CBT can be a curative treatment for the disease, even if no viral memory has been set in the stem cell source.

Quantification of circulating varicella zoster virus-DNA for the early diagnosis of visceral varicella.

Varicella zoster virus (VZV)-DNA was quantified in peripheral blood of 2 patients with visceral varicella due to endogenous reactivation. An 18-year-old male contracted varicella following the courses of chemotherapy for T cell lymphoma. Another 18-year-old male suffered from varicella 16 months after the complete engraftment of hematopoietic stem cell transplantation. Both patients had past VZV infection, but no recent contact with the disease. Paralytic ileus and ascites preceded the skin lesions. Quantitative real-time polymerase chain reaction revealed >200 copies of VZV per 1 ml of whole blood before or at the time when cropping vesicles emerged. The viral load reflected their prolonged clinical courses. Similar levels of VZV-DNA were detected in primary varicella patients, but not in herpes zoster patients or immunocompromised children without varicella or zoster. Quantitative monitoring of circulating VZV-DNA may be useful for the diagnosis and assessing the treatment response of visceral varicella in immunocompromized hosts.

Predisposition to subdural hemorrhage in X-linked myotubular myopathy.

X-linked myotubular myopathy is a severe congenital myopathy that can involve multiple organs. We report on a 10-month-old boy who manifested X-linked myotubular myopathy with subdural hemorrhage. The diagnosis of X-linked myotubular myopathy was based on typical muscle pathology and MTM1 missense mutation. The patient had undergone no traumatic episodes or bleeding diathesis. Axial growth acceleration is known to occur in X-linked myotubular myopathy, potentially leading to dolichocephaly. In our patient, an enlarged subdural space apparently stretched the bridging veins, increasing susceptibility to subdural hemorrhage. Patients who manifest X-linked myotubular myopathy with typical dolichocephaly are at increased risk for subdural hemorrhage.

Nephrolithiasis as an extra-intestinal presentation of pediatric inflammatory bowel disease unclassified.

Urolithiasis is quite rare in pediatric inflammatory bowel disease (IBD) compared with the incidence at 9-18% in adult cases. The diagnosis and treatment of pediatric IBD is challenging. Indeterminate colitis (IC), originally proposed as a subgroup of fulminant IBD, has also been used for patients when the diagnosis of either UC or CD cannot be made with certainty. Such patients should be diagnosed as having "IBD unclassified" based on evidence including mucosal biopsy samples. We report herewith a 9-year-old boy with isolated colitis that reached a diagnosis of IBD unclassified. Infliximab therapy led to a successful remission after the refractory course. However, urolithiases were impacted in the urethral valves and vesico-ureteral junction. Microhematuria was noticed from the onset of colitis. Renal calculi were detected on the X-ray films during the first line treatment. Transurethrally crushed stones consisted of calcium oxalate. Renal calculi are more closely associated with CD than ulcerative colitis in adult patients for the ileal involvement. The oxalate stones and treatment response indicated a CD-like pathophysiology. Nephrolithiasis might be a rare but noticeable extra-intestinal presentation of pediatric IBD. Infliximab therapy could be an option in pediatric refractory colitis to change the critical steroid dependency.

Successful self-infusion of activated prothrombin complex concentrate for prophylaxis in a child with a factor VIII inhibitor.

Regular self-infusion of an activated prothrombin complex concentrate (APCC) has been successfully introduced to a 14-year-old boy with hemophilia A. The child was diagnosed as a neonate, and at age 7 years, developed a high titer (127 BU/mL) factor VIII inhibitor coincident with a protracted ankle joint bleeding. From age 7-10 years, he received on-demand therapy using a prothrombin complex concentrate (PCC), PROPLEX-ST. From age 10-14 years, he received prophylaxis with PROPLEX-ST, initiated after an intracranial hemorrhage and coincident anamnestic inhibitor response. Throughout 7-year period of PCC treatment, he experienced recurrent bleeding episodes. Self-prophylaxis with APCC, FEIBA VH [Anti-inhibitor Coagulant Complex] (50 U/kg/dose three times per week) using infusion pump was initiated at 14 years of age and has continued for 2 years. There were no bleeding, thrombotic events or other adverse events after initiation of this prophylaxis, and inhibitor levels decreased to 1 BU/mL. His quality of life was improved, particularly with respect to school. Our long observation proposes a well-disciplined home-based FEIBA prophylaxis in inhibitor-positive hemophiliacs.

Rheumatic fever-mimicking carditis as a first presentation of chronic active Epstein-Barr virus infection.

UNLABELLED: A 7-y-old girl presented with prolonged fever, arrhythmia and cardiomegaly during the treatment course of group A beta-haemolytic streptococcal pharyngitis. The isolated rheumatogenic strain M1 suggested the diagnosis of rheumatic fever. However, serous pericardial effusion contained high levels of Epstein-Barr virus (EBV) DNA. Clonally proliferating EBV+ T cells were determined in the circulation. The atypical carditis without valvitis was then complicated by coronary artery dilatations. Four months after the start of prednisolone plus antiviral/bacterial therapy, EBV+ T-cell lymphoma developed in the thigh. CONCLUSION: Atypical carditis may be a notable and life-threatening presentation of chronic active EBV infection to be differentiated from rheumatic fever.

Perforin defects of primary haemophagocytic lymphohistiocytosis in Japan.

The perforin gene was analysed in 15 Japanese patients with primary haemophagocytic lymphohistiocytosis (HLH). Perforin gene defects were found in two out of eight patients with familial HLH (FHL), and one out of seven without affected siblings. Four novel mutations were identified. Compound heterozygous mutations (one FHL and one sporadic HLH) and only one allele mutation (one FHL) were defined. Flow cytometry revealed no perforin expression in CD8+ or CD56+ cells from a surviving patient with a mutation. The frequency of mutation was at least 20% of FHL in Japan. Flow cytometry for intracellular perforin may be useful for the screening of FHL2.

Cytokine imbalance in hyper-IgE syndrome: reduced expression of transforming growth factor beta and interferon gamma genes in circulating activated T cells.

Hyper-IgE syndrome (HIES) is a primary immunodeficiency disease characterized by recurrent infections and marked immunoglobulin (Ig)E elevation. To assess the proper T-cell defects of HIES, the cytokine profile of naturally activated T cells was compared between HIES, atopic dermatitis and chronic granulomatous disease (CGD). Intracellular flow cytometric analysis after in vitro stimulation showed no difference in the proportion of interferon (IFN)gamma- or interleukin 4 (IL-4)-producing T cells among these diseases. Quantitative polymerase chain reaction (PCR) for the cytokine genes was performed using circulating highly fractionated HLA-DR+ and HLA-DR- T cells. The IFNgamma/IL-4 or IFNgamma/IL-10 ratios were lower in HLA-DR+ T cells of HIES than in CGD (P = 0.0106, 0.0445), but did not differ between HIES and atopy. The transforming growth factor-beta (TGFbeta)/IL-4 ratio in HLA-DR+ T cells of HIES was lower than that of atopy (0.0106) or CGD (0.0062). The TGFbeta/IL-4 ratio in HLA-DR- T cells of HIES was also lower than that of atopy (0.0285). Stepwise logistic regression analysis identified TGFbeta/IL-4 ratios in HLA-DR+ (0.0001) or HLA-DR- (0.0086) T cells as the most powerful parameters to distinguish HIES from atopy and/or CGD. Serum IgE levels negatively correlated with IFNgamma/IL-4 (0.0108), IFNgamma/IL-10 (0.0254), or TGFbeta/IL-4 (0.0163) ratios in HLA-DR+, but not HLA-DR-, T cells. These results suggested that the in vivo activated T cells of HIES did not sufficiently express the IFNgamma and TGFbeta genes, which could affect IL-4-dependent IgE production. The reduced TGFbeta expression may involve the indigenous T-cell defects of HIES.

Essential roles of perforin in antigen-specific cytotoxicity mediated by human CD4+ T lymphocytes: analysis using the combination of hereditary perforin-deficient effector cells and Fas-deficient target cells.

Although the cytotoxic mechanisms of murine CTLs have been investigated extensively using various mutant and knockout mice, those of human CTLs, especially CD4+ CTLs, are still obscure. To clarify the roles of perforin in Ag-specific cytotoxicity mediated by human CD4+ CTLs, alloantigen-specific and HSV-specific human CD4+ T lymphocyte bulk lines and clones were established from a patient with hereditary perforin deficiency and her healthy father, and their cytotoxic activities were investigated. Alloantigen-specific CD4+ T lymphocytes expressing perforin exerted cytotoxicity against Fas-negative as well as Fas-positive allogeneic B lymphoblastoid cell lines established from members of a family with hereditary Fas deficiency. Perforin-deficient, but not perforin-expressing, CD4+ T lymphocytes failed to show strong cytotoxicity against HSV-infected autologous B lymphoblastoid cells. Perforin-deficient CD4+ T lymphocytes could exert relatively low level cytotoxicity against allogeneic IFN-gamma-treated keratinocytes. Although cytotoxicity mediated by perforin-expressing CD4+ CTLs was almost completely inhibited by concanamycin A, a potent inhibitor of the perforin-mediated cytotoxic pathway, cytotoxicity against IFN-gamma-treated keratinocytes mediated by perforin-deficient CD4+ T lymphocytes was inhibited only partially by concanamycin A, but was inhibited significantly by antagonistic anti-Fas Ab and anti-Fas ligand Ab. The combination of perforin-deficient effector T lymphocytes and Fas-negative target cells used in the present study provides a novel experimental system for studying the detailed mechanisms of human CTL-mediated cytotoxicity. The present data demonstrate that perforin-negative CD4+ CTLs can exert cytotoxicity against Fas-sensitive target cells; however, perforin plays essential roles in Ag-specific cytotoxicity mediated by human CD4+ as well as CD8+ CTLs.