Noonan Syndrome-related Myeloproliferative Disorder Occurring in the Neonatal Period: Case Report and Literature Review.

Noonan syndrome-related myeloproliferative disorder (NS/MPD) and juvenile myelomonocytic leukemia (JMML) are rare MPDs that occur in young children. We herein report a case of NS/MPD with neonatal onset. The patient had a characteristic appearance and high monocyte count in the peripheral blood and bone marrow. Genetic testing showed the E139D mutation in PTPN11 ; however, the patient did not meet all the diagnostic criteria for JMML, and we thus diagnosed him with NS/MPD. Eight other cases of NS/MPD with neonatal onset are also summarized. The initial presentation varied, and the prognosis was considered poor compared with previous reports of NS/MPD.

Human RELA dominant-negative mutations underlie type I interferonopathy with autoinflammation and autoimmunity.

Inborn errors of the NF-κB pathways underlie various clinical phenotypes in humans. Heterozygous germline loss-of-expression and loss-of-function mutations in RELA underlie RELA haploinsufficiency, which results in TNF-dependent chronic mucocutaneous ulceration and autoimmune hematological disorders. We here report six patients from five families with additional autoinflammatory and autoimmune manifestations. These patients are heterozygous for RELA mutations, all of which are in the 3' segment of the gene and create a premature stop codon. Truncated and loss-of-function RelA proteins are expressed in the patients' cells and exert a dominant-negative effect. Enhanced expression of TLR7 and MYD88 mRNA in plasmacytoid dendritic cells (pDCs) and non-pDC myeloid cells results in enhanced TLR7-driven secretion of type I/III interferons (IFNs) and interferon-stimulated gene expression in patient-derived leukocytes. Dominant-negative mutations in RELA thus underlie a novel form of type I interferonopathy with systemic autoinflammatory and autoimmune manifestations due to excessive IFN production, probably triggered by otherwise non-pathogenic TLR ligands.

Clinical practice guideline for activated phosphatidyl inositol 3-kinase-delta syndrome in Japan.

Activated phosphatidyl inositol 3-kinase-delta syndrome (APDS) due to gain-of-function variant in the class IA PI3K catalytic subunit p110δ (responsible gene: PIK3CD) was described in 2013. The disease is characterized by recurrent airway infections and bronchiectasis. It is associated with hyper-IgM syndrome due to the defect of immunoglobulin class switch recombination and decreased CD27-positive memory B cells. Patients also suffered from immune dysregulations, such as lymphadenopathy, autoimmune cytopenia or enteropathy. T-cell dysfunction due to increased senescence is associated with a decrease in CD4-positive T lymphocytes and CD45RA-positive naive T lymphocytes, along with increased susceptibility to Epstein-Barr virus/cytomegalovirus infections. In 2014, loss-of-function (LOF) mutation of p85α (responsible gene: PIK3R1), a regulatory subunit of p110δ, was identified as a causative gene, followed in 2016 by the identification of the LOF mutation of PTEN, which dephosphorylates PIP3, leading to the differentiation of APDS1 (PIK3CD-GOF), APDS2 (PIK3R1-LOF) and APDS-L (PTEN-LOF). Since the pathophysiology of patients with APDS varies with a wide range of severity, it is crucial that patients receive appropriate treatment and management. Our research group created a disease outline and a diagnostic flow chart and summarized clinical information such as the severity classification of APDS and treatment options.

Outcomes following induction failure in Japanese children with acute lymphoblastic leukemia.

The characteristics and prognosis of Japanese children with acute lymphoblastic leukemia (ALL) who fail to achieve complete remission after remission induction chemotherapy (i.e., experience induction failure) are poorly understood. Therefore, we retrospectively analyzed data of patients enrolled in Japanese clinical trials for newly diagnosed ALL between 1996 and 2009. Among 4956 participants, 89 (1.8%) experienced induction failure. With a 6.0-year median follow-up, the 5-year overall survival rate of the entire cohort was 43.0% ± 5.5%. Survival rates did not differ between patients with B-cell precursor ALL (BCP-ALL) and T-cell ALL (T-ALL). In multivariate analysis, day 15 M3 marrow (bone marrow blast count ≥ 25%) was significantly correlated with poorer survival in the whole or BCP-ALL cohorts. In T-ALL, age < 6 years was significantly associated with poor survival. However, due to the small sample size, this correlation must be further investigated. Most T-ALL and BCR-ABL-positive BCP-ALL patients underwent allogeneic stem cell transplantation (allo-SCT). Survival rates did not differ between BCR-ABL-negative BCP-ALL patients who did and did not undergo allo-SCT, possibly due to the inclusion of lower-risk patients in the latter group. In conclusion, the induction failure rate and survival after diagnosis of induction failure in our study were comparable to previously reported figures.

Reduced-intensity conditioning is effective for allogeneic hematopoietic stem cell transplantation in infants with MECOM-associated syndrome.

Mutations in the MECOM encoding EVI1 are observed in infants who have radioulnar synostosis with amegakaryocytic thrombocytopenia. MECOM-associated syndrome was proposed based on clinical heterogeneity. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for progressive bone marrow failure. However, data regarding allogeneic HSCT for this rare disease are limited. We retrospectively assessed overall survival, conditioning regimen, regimen-related toxicities and long-term sequelae in six patients treated with allogeneic HSCT. All patients received a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, cyclophosphamide or melphalan, and rabbit anti-thymocyte globulin and/or low-dose total body/thoracic-abdominal/total lymphoid irradiation, followed by allogeneic bone marrow or cord blood transplantation from unrelated donors between 4 and 18 months of age. All patients survived and achieved stable engraftment and complete chimerization with the donor type. Moreover, no patient experienced severe regimen-related toxicities, and only lower grades of acute graft-versus-host disease were observed. Three patients treated with low-dose irradiation had relatively short stature compared to three patients not treated with irradiation. Therefore, allogeneic HSCT with RIC is an effective and feasible treatment for infants with MECOM-associated syndrome. Future studies are needed to evaluate the use of low-dose irradiation to avoid risks of other long-term sequelae.

Stage M Infantile Neuroblastoma With Involvement of Falx Cerebri: Case Report and Literature Review.

Neuroblastoma is the most common extracranial solid tumor in children. When metastasis to the falx cerebri is present, it is classified as stage M; however, its behavior has not been well characterized. Here we present a case of stage M infantile neuroblastoma (NB) with involvement of the falx cerebri, and also summarize the clinical profiles of previously reported cases. Notably, all of the tumors resolved with low-dose chemotherapy alone. Although further study is needed to distinguish NBs presenting at these different intracranial locations, NB with metastasis to the falx cerebri may be categorized as MS when diagnosed at less than 18 months of age.

Novel POLE mutations identified in patients with IMAGE-I syndrome cause aberrant subcellular localisation and protein degradation in the nucleus.

BACKGROUND: DNA replisome is a molecular complex that plays indispensable roles in normal DNA replication. IMAGE-I syndrome is a DNA replisome-associated genetic disease caused by biallelic mutations in the gene encoding DNA polymerase epsilon catalytic subunit 1 (POLE). However, the underlying molecular mechanisms remain largely unresolved. METHODS: The clinical manifestations in two patients with IMAGE-I syndrome were characterised. Whole-exome sequencing was performed and altered mRNA splicing and protein levels of POLE were determined. Subcellular localisation, cell cycle analysis and DNA replication stress were assessed using fibroblasts and peripheral blood from the patients and transfected cell lines to determine the functional significance of POLE mutations. RESULTS: Both patients presented with growth retardation, adrenal insufficiency, immunodeficiency and complicated diffuse large B-cell lymphoma. We identified three novel POLE mutations: namely, a deep intronic mutation, c.1226+234G>A, common in both patients, and missense (c.2593T>G) and in-frame deletion (c.711_713del) mutations in each patient. The unique deep intronic mutation produced aberrantly spliced mRNAs. All mutants showed significantly reduced, but not null, protein levels. Notably, the mutants showed severely diminished nuclear localisation, which was rescued by proteasome inhibitor treatment. Functional analysis revealed impairment of cell cycle progression and increase in the expression of phospho-H2A histone family member X in both patients. CONCLUSION: These findings provide new insights regarding the mechanism via which POLE mutants are highly susceptible to proteasome-dependent degradation in the nucleus, resulting in impaired DNA replication and cell cycle progression, a characteristic of DNA replisome-associated diseases.

A partial form of inherited human USP18 deficiency underlies infection and inflammation.

Human USP18 is an interferon (IFN)-stimulated gene product and a negative regulator of type I IFN (IFN-I) signaling. It also removes covalently linked ISG15 from proteins, in a process called deISGylation. In turn, ISG15 prevents USP18 from being degraded by the proteasome. Autosomal recessive complete USP18 deficiency is life-threatening in infancy owing to uncontrolled IFN-I-mediated autoinflammation. We report three Moroccan siblings with autoinflammation and mycobacterial disease who are homozygous for a new USP18 variant. We demonstrate that the mutant USP18 (p.I60N) is normally stabilized by ISG15 and efficient for deISGylation but interacts poorly with the receptor-anchoring STAT2 and is impaired in negative regulation of IFN-I signaling. We also show that IFN-γ-dependent induction of IL-12 and IL-23 is reduced owing to IFN-I-mediated impairment of myeloid cells to produce both cytokines. Thus, insufficient negative regulation of IFN-I signaling by USP18-I60N underlies a specific type I interferonopathy, which impairs IL-12 and IL-23 production by myeloid cells, thereby explaining predisposition to mycobacterial disease.

The incidence of symptomatic osteonecrosis is similar between Japanese children and children in Western countries with acute lymphoblastic leukaemia treated with a Berlin-Frankfurt-Münster (BFM)95-based protocol.

In this study, we performed a retrospective analysis of a cohort of Japanese paediatric patients with B-cell precursor (BCP)-acute lymphoblastic leukaemia (ALL) treated with a Berlin-Frankfurt-Münster (BFM)95-based protocol, to clarify the incidence, clinical characteristics, and risk factors of osteonecrosis (ON) in comparison to the ALL-02 protocol. We identified a high frequency of ON with the BFM95-based protocol compared to the ALL-02 protocol. The incidence of symptomatic ON with the BFM95-based protocol is comparable to previous studies in Western countries. We believe that the type of treatment regimen has more impact on the incidence of symptomatic ON in paediatric ALL than ethnicity.

Clofarabine monotherapy in two patients with refractory Langerhans cell histiocytosis.

BACKGROUND: Better therapeutic options other than conventional chemotherapy for pediatric patients with refractory Langerhans cell histiocytosis (LCH) remain undetermined. CASE: We successfully treated two patients with refractory and risk organ negative LCH with clofarabine (CLO) monotherapy after recurrence. We administered total 23 courses of CLO monotherapy in patient 1 and 4 courses in patient 2. Both patients had distinct clinical manifestations but achieved a durable complete response with acceptable adverse effects of transient myelosuppression. CLO monotherapy was still effective when he had the second recurrent lesion after first completion of CLO in patient 1. We could discontinue prednisolone to control his refractory inflammation of LCH after completing CLO chemotherapy in patient 2. CONCLUSION: Although large-scale studies are warranted, CLO monotherapy could be a therapeutic option for high efficacy and feasibility besides other intensive combination chemotherapies or allogeneic hematopoietic stem cell transplantation for refractory LCH without risk organ involvement in children.

Case report: Cerebellar swelling and hydrocephalus in familial hemophagocytic lymphohistiocytosis.

Familial hemophagocytic lymphohistiocytosis (FHL) is a severe inborn error of immunity caused by a genetic defect that impairs the function of cytotoxic T and NK cells. There are only a few reported cases of FHL with diffuse swelling of the cerebellum and obstructive hydrocephalus. We report a case of FHL3 with neurological symptoms associated with cerebellar swelling and obstructive hydrocephalus. A male patient was hospitalized several times due to fever and decreased feeding, hepatosplenomegaly, and cytopenia since the first month of life. At 7 months of age, disturbance of consciousness was seen. Brain magnetic resonance imaging revealed signal intensity in the bilateral cerebellar hemispheres, diffusely increased periventricular white matter, and ventriculomegaly. Although he was treated with methylprednisolone pulse therapy, he was unresponsive to the treatment. He was then transferred to a local hospital after tracheotomy but died. Targeted clinical sequencing revealed a homozygous splice-site mutation in UNC13D. Pediatric hemophagocytic lymphohistiocytosis (HLH) includes some cases of central nervous symptom (CNS)-isolated HLH or CNS HLH preceding systemic lesions, which often do not initially meet the diagnostic criteria for FHL. Patients with FHL initiated by cerebellar symptoms may present with an atypical clinical course for HLH, leading to delayed diagnosis and poor outcomes. Despite the usefulness of a combination of a high percentage of lymphocytes in the peripheral leukocytes, a low lactate dehydrogenase level, and a high sIL-2R/ferritin ratio for identifying FHL, the diagnosis may be missed due to the absence of these results. Presymptomatic diagnosis of FHL by screening of newborns and subsequent early treatment of patients with a predicted poor prognosis may contribute to better outcomes.

Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.

We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8+ T cells, memory CD4+ T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4+ T cells. In naive CD4+ T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient's naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.

Refractory T-cell/histiocyte-rich large B-cell lymphoma in a patient with ataxia-telangiectasia caused by novel compound heterozygous variants in ATM.

Ataxia-telangiectasia (A-T) is an autosomal recessive chromosomal breakage syndrome caused by mutation of the ATM (A-T mutated) gene, which encodes a protein kinase that has a major role in the cellular response to DNA damage. Approximately, 10% of A-T patients develop lymphoid malignancies. Deaths caused by extreme sensitivity to chemotherapy for malignancy have been reported, and cancer treatment in A-T is extraordinarily difficult, needing careful monitoring and individualized protocols. We report the case of a 12-year-old girl with A-T diagnosed at the age of 3 in association with IgA deficiency and recurrent pulmonary infections. Sanger sequencing revealed compound heterozygosity of the ATM gene, which bore two novel mutations. At the age of 12, she developed stage IV T-cell/histiocyte-rich large B-cell lymphoma. The tumor was resistant to chemotherapy, and she unfortunately died of cardiac insufficiency and multiple organ failure induced by rapid progression of the disease. The treatment approach for children with A-T and advanced-stage B-non-Hodgkin lymphoma must be refined.

Impaired respiratory burst contributes to infections in PKCδ-deficient patients.

Patients with autosomal recessive protein kinase C δ (PKCδ) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKCδ-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40phox normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients' circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKCδ in activation of the NADPH oxidase complex. Our findings thus show that patients with PKCδ deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype.

Case Report: Infantile-Onset Fulminant Type 1 Diabetes Mellitus Caused by Novel Compound Heterozygous LRBA Variants.

Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency is a subtype of common variable immune deficiency (CVID). Numerous case reports and cohort studies have described a broad spectrum of clinical manifestations and variable disease phenotypes, including immune dysregulation, enteropathy, and recurrent infections. Although LRBA deficiency is an autosomal recessive primary immunodeficiency resulting in a phenotype similar to CVID, it is a monogenic disease and separate from CVID. Recently, in a report of monogenic primary immunodeficiency disorder associated with CVID and autoimmunity, the most common mutated gene was LRBA. We report the case of a girl who presented with fulminant type 1 diabetes at age 7 months. She later experienced recurrent bacterial infections with neutropenia and idiopathic thrombocytopenic purpura. Clinical genome sequencing revealed compound heterozygosity of the LRBA gene, which bore two novel mutations. A genetic basis should be considered in the differential diagnosis for very young patients with fulminant autoimmunity, and the diagnostic work-up should include evaluation of markers of immunodeficiency.