Prasad T. Oommen

A novel homozygous Fas ligand mutation leads to early protein truncation, abrogation of death receptor and reverse signaling and a severe form of the autoimmune lymphoproliferative syndrome.

We report a novel type of mutation in the death ligand FasL that was associated with a severe phenotype of the autoimmune lymphoproliferative syndrome in two patients. A frameshift mutation in the intracellular domain led to complete loss of FasL expression. Cell death signaling via its receptor and reverse signaling via its intracellular domain were completely abrogated. In vitro lymphocyte proliferation induced by weak T cell receptor stimulation could be blocked and cell death was induced by engagement of FasL in T cells derived from healthy individuals and a heterozygous carrier, but not in FasL-deficient patient derived cells. Expression of genes implicated in lymphocyte proliferation and activation (CCND1, NFATc1, NF-κB1) was increased in FasL-deficient T cells and could not be downregulated by FasL engagement as in healthy cells. Our data thus suggest, that deficiency in FasL reverse signaling may contribute to the clinical lymphoproliferative phenotype of ALPS.

Specific antibody deficiency and autoinflammatory disease extend the clinical and immunological spectrum of heterozygous NFKB1 loss-of-function mutations in humans

The nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1) is a master regulator of immune and inflammatory responses.[1][1],[2][2] NF-κB1 belongs to the NF-κB/Rel family of transcription factors that consists of five members in humans: NF-κB1 (p105/p50), NF-κB2 (p100/p52

Epidemiology and clinical characteristics of pandemic (H1N1) 2009 influenza infection in pediatric hemato‐oncology and hematopoietic stem cell transplantation patients

For children with hemato‐oncologic diseases, especially after hematopoietic stem cell transplantation (HSCT), the risk for developing complications related to pandemic influenza A (H1N1) 2009 (pH1N1) infection is largely unknown.

Effective treatment of spasticity using dronabinol in pediatric palliative care

BACKGROUNDnCannabis extracts have a wide therapeutic potential but in many countries they have not been approved for treatment in children so far.nnnOBJECTIVEnWe conducted an open, uncontrolled, retrospective study on the administration of dronabinol to determine the value, efficacy, and safety of cannabis-based medicines in the treatment of refractory spasticity in pediatric palliative care.nnnDESIGN AND PARTICIPANTSnSixteen children, adolescents and young adults having complex neurological conditions with spasticity (aged 1.3-26.6 years, median 12.7 years) were treated with dronabinol by our specialized pediatric palliative care team between 01.12.2010 and 30.04.2015 in a home-care setting. Therapeutic efficacy and side effects were closely monitored.nnnRESULTSnDrops of the 2.5% oily tetrahydrocannabinol solution (dronabinol) were administered. A promising therapeutic effect was seen, mostly due to abolishment or marked improvement of severe, treatment resistant spasticity (nxa0=xa012). In two cases the effect could not be determined, two patients did not benefit. The median duration of treatment was 181 days (range 23-1429 days). Dosages to obtain a therapeutic effect varied from 0.08 to 1.0xa0mg/kg/d with a median of 0.33xa0mg/kg/d in patients with a documented therapeutic effect. When administered as an escalating dosage scheme, side effects were rare and only consisted in vomiting and restlessness (one patient each). No serious and enduring side effects occurred even in young children and/or over a longer period of time.nnnCONCLUSIONSnIn the majority of pediatric palliative patients the treatment with dronabinol showed promising effects in treatment resistant spasticity.

Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease.

Autoimmune lymphoproliferative syndrome is frequently caused by mutations in genes involved in the Fas death receptor pathway, but for 20–30% of patients the genetic defect is unknown. We observed that treatment of healthy T cells with interleukin-12 induces upregulation of Fas ligand and Fas ligand-dependent apoptosis. Consistently, interleukin-12 could not induce apoptosis in Fas ligand-deficient T cells from patients with autoimmune lymphoproliferative syndrome. We hypothesized that defects in the interleukin-12 signaling pathway may cause a similar phenotype as that caused by mutations of the Fas ligand gene. To test this, we analyzed 20 patients with autoimmune lymphoproliferative syndrome of unknown cause by whole-exome sequencing. We identified a homozygous nonsense mutation (c.698G>A, p.R212*) in the interleukin-12/interleukin-23 receptor-component IL12RB1 in one of these patients. The mutation led to IL12RB1 protein truncation and loss of cell surface expression. Interleukin-12 and -23 signaling was completely abrogated as demonstrated by deficient STAT4 phosphorylation and interferon γ production. Interleukin-12-mediated expression of membrane-bound and soluble Fas ligand was lacking and basal expression was much lower than in healthy controls. The patient presented with the classical symptoms of autoimmune lymphoproliferative syndrome: chronic non-malignant, non-infectious lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10. Sanger sequencing and whole-exome sequencing excluded the presence of germline or somatic mutations in genes known to be associated with the autoimmune lymphoproliferative syndrome. Our data suggest that deficient regulation of Fas ligand expression by regulators such as the interleukin-12 signaling pathway may be an alternative cause of autoimmune lymphoproliferative syndrome-like disease.

Visceral Leishmaniasis as a Possible Reason for Pancytopenia.

Leishmaniasis is caused by different species of the protozoa, Leishmania, and frequently found in South-Western Asia, Eastern Africa, Brazil, and Mediterranean countries. Leishmania are transmitted to humans by the bite of sandflies. After weeks to months, unspecific symptoms may occur, accompanied by more specific findings like pancytopenia and organomegaly. We report two children with pancytopenia and hepato-/splenomegaly: a 1-year-old boy was first diagnosed with an Adenovirus-infection, accompanied by fever, pancytopenia, and hepatosplenomegaly who had spent his summer vacation in Spain and a 3-year-old boy of Macedonian origin who was first diagnosed with a Parvovirus B19-infection again accompanied by splenomegaly and pancytopenia. In both children, leukemia was excluded by an initial bone marrow puncture. As fever was still persistent weeks after the children’s first hospital stay, both children received antibiotics empirically without sustainable effect. While different autoantibodies were present in both children, an immunosuppressive therapy was initiated in the younger boy without therapeutic success. A second bone marrow puncture was performed and Leishmania were finally detected morphologically and proven serologically. After weight-adjusted treatment with liposomal Amphotericin B for 10u2009days, both children recovered completely without relapse. Aim of this report is to broaden the spectrum of differential diagnoses in children with pancytopenia, splenomegaly, and fever to visceral leishmaniasis particularly when travel history is positive for the Mediterranean area. The infection may mimic more common diseases, such as leukemia, viral infections, or autoimmune diseases, because polyclonal B cell activation and other mechanisms may lead to multiple positive serologic tests. Both cases illustrate typical pitfalls and shall encourage taking Leishmaniasis into diagnostic consideration.

Fluorescence optical imaging and musculoskeletal ultrasonography in juvenile idiopathic polyarticular disease before and during antirheumatic treatment - a multicenter non-interventional diagnostic evaluation

BackgroundValid detection of inflamed joints is essential for correct classification, therapeutic decisions, prognosis and assessment of treatment efficacy in juvenile idiopathic arthritis (JIA). Fluorescence optical imaging (FOI) enables visualization of inflammation in arthritis of finger and hand joints and might be used for monitoring.MethodsA 24-week observational study in polyarticular JIA patients newly starting treatment with methotrexate or an approved biologic was performed in three centers. Patients were evaluated clinically, by gray-scale ultrasonography (GSUS), power-Doppler ultrasonography (PDUS) and FOI at baseline, week 12 and week 24.ResultsOf 37 patients enrolled, 24 patients started methotrexate and 13 patients a biologic for the first time (etanercept nu2009=u200911, adalimumab and tocilizumab nu2009=u20091 each). Mean JADAS 10 decreased significantly from 17.7 at baseline to 12.2 and 7.2 at week 12 and 24 respectively. PedACR 30/50/70/100 response rates at week 24 were 85%/73%/50%/27%. The total number of clinically active joints in hand and fingers at baseline/week 12/week 24 was 262 (23.6%)/162 (16.4%)/162 (9.0%). By GSUS, at baseline/week 12/week 24, 192 (19.4%)/135 (16.1%)/83 (11.5%) joints showed effusions and 186 (18.8%)/107 (12.7%)/69 (9.6%) showed synovial thickening, and by PDUS 68 (6.9%)/15 (1.8%)/36 (5%) joints showed hyperperfusion. Any sign of arthritis was detected by US in a total of 243 joints (24.5%) at baseline, 161 joints (19.2%) at week 12 and 123 joints (17%) at week 24. By FOI at baseline/week 12/week 24, 430 (38.7%)/280 (29.2%)/215 (27.6%) showed a signal enhancement in at least one phase.Summarizing all three points of time, the highest numbers of signals were detected by FOI with 32% of joints, especially in phase 2, while by US 20.7% and by clinical examination 17.5% of joints were active. A high number of joints (21.1%) had FOI signals but were inactive by clinical examination. A total 20.1% of joints with signals in FOI did not show effusion, synovial thickening or hyperperfusion by US.Because of the high number of negative results, specificity of FOI compared with clinical examination/US/PD was high (84–95%), and sensitivity was only moderate.ConclusionFOI and US could detect clinical but also subclinical inflammation. FOI detected subclinical inflammation to a higher extent than US. Improvement upon treatment with either methotrexate or a biologic can be visualized by FOI and US.Trial registrationDeutsches Register Klinischer Studien DRKS00011579. Registered 10 January 2017.

Palliative care for children with a yet undiagnosed syndrome

AbstractThe number of children without a diagnosis in pediatric palliative home care and the process of decision-making in these children are widely unknown. The study was conducted as single-center retrospective cohort study. Between January 2013 and September 2016, 198 children and young adults were cared for; 27 (13.6%) of these were without a clear diagnosis at the start of pediatric palliative home care. A definite diagnosis was ultimately achieved in three children. Median age was 7xa0years (0–25), duration of care 569xa0days (2–2638), and number of home visits 7.5 (2–46). Most patients are still alive (19; 70.4%). Median number of drugs administered was eight (range 2–19); antiepileptics were given most frequently. Despite the lack of a clear diagnosis (and thus prognosis), 13 (48.1%) parents faced with their critically ill and clinically deteriorating children decided in favor of a DNAR order. Comparing this with 15 brain-injured children, signs, symptoms, and supportive needs were similar in both groups.n Conclusion: Children without a clear diagnosis are relatively common in pediatric palliative care and have—like all other patients—the right to receive optimized and symptom-adapted palliative care. Parents are less likely to choose treatment limitation for children who lack a definitive diagnosis.What is Known:• A clear diagnosis is usually considered important for best-practice pediatric palliative care (PPC) including advanced care planning (ACP).• Timely initiation of pediatric palliative care (PPC) is highly recommended in children with life-limiting conditions.What is New:• SWAN (syndrome without a name) children show similar signs and symptoms (mostly neurological) and have similar supportive needs as brain-injured children.• Defining treatment limitations in advance care planning is more difficult for parents of SWAN compared to brain-injured children.

IL-6 blockade in systemic juvenile idiopathic arthritis – achievement of inactive disease and remission (data from the German AID-registry)

BackgroundSystemic juvenile idiopathic arthritis (sJIA) is a complex disease with an autoinflammatory component of unknown etiology related to the innate immune system. A major role in the pathogenesis has been ascribed to proinflammatory cytokines like interleukin-6 (IL-6), and effective drugs inhibiting their signaling are being developed. This study evaluates sJIA patients treated with the IL-6 inhibitor tocilizumab (TCZ) concerning clinical response rate, disease course and adverse effects in a real-life clinical setting.MethodsIn 2009 a clinical and research consortium was established, including an online registry for autoinflammatory diseases (AID) (https://aid-register.de). Data for this retrospective TCZ study were documented by 13 centers.ResultsFrom 7/2009 to 4/2014, 200 patients with sJIA were recorded in the AID-registry. Out of these, 46 (19xa0m, 27 f, age 1–18xa0years) received therapy with TCZ. Long term treatment (median 23xa0months) has been documented in 24/46 patients who were evaluated according to Wallace criteria (active disease 6/24, inactive disease 5/24, remission 13/24 cases). Under observation co-medication were used in 40/46 cases. Adverse events were reported in 11/46 patients. The clinical response rate (no clinical manifestation, no increased inflammation parameters) within the first 12xa0weeks of treatment was calculated to be 35%.ConclusionOut of 200 sJIA children reported in the German AID-registry, 46 were treated with TCZ, showing a clinical response rate of 35% during the first 12xa0weeks, and inactive disease and/or remission under medication in 75% after one year. Adverse events were seen in 24% and severe adverse events in 4%.Trial registrationThe AID-Registry is funded by the BMBF (01GM08104, 01GM1112D, 01GM1512D).

Paraneoplastic limbic encephalitis with SOX1 and PCA2 antibodies and relapsing neurological symptoms in an adolescent with Hodgkin lymphoma

BACKGROUNDnImmune cross-reactivity between malignant and normal tissues causes the rare, so called paraneoplastic syndrome (PS). In approximately 60% of the patients, various onconeural antibodies are detectable in the cerebrospinal fluid (CSF) and are associated with typical tumour entities.nnnMETHODSnWe report an unusual case of paraneoplastic limbic encephalitis (PLE) in a 17-year-old adolescent with classical Hodgkin lymphoma.nnnRESULTSnHe presented with a variety of neurologic and neuropsychiatric symptoms, profound B-symptoms and typical MRI findings including hyperintense lesions with contrast enhancement in the medial temporal lobe and limbic system. Under immunosuppressive therapy and subsequently chemotherapy the neurological situation only temporarily improved and worsened again after interruption of immunosuppression several times. Thus, multiple courses of multidrug immunosuppressive therapy were administered. To date, five years after initial presentation, the young man is able to walk with walking aids and orthoses and is still on oral prednisolone therapy. Analyses of the CSF and serum revealed anti SOX-1 antibodies at initial presentation but PCA-2 antibodies seven months after diagnosis.nnnCONCLUSIONnNeurologic and/or neuropsychiatric symptoms combined with typical MRI findings should raise the suspicion of PS and lead to further diagnostics for an underlying tumour even in children.