Case Report: Patient with deficiency of ADA2 presenting leukocytoclastic vasculitis and pericarditis during infliximab treatment.

Deficiency of adenosine deaminase 2 (DADA2), first reported in 2014, is a disease with great phenotypic variability, which has been increasingly reported. Therapeutic response depends on the phenotype. We present a case of an adolescent with recurrent fever, oral aphthous ulcers, and lymphadenopathy from 8 to 12 years of age and subsequently presented with symptomatic neutropenia. After the diagnosis of DADA2, therapy with infliximab was started, but after the second dose, she developed leukocytoclastic vasculitis and showed symptoms of myopericarditis. Infliximab was switched to etanercept, with no relapses. Despite the safety of tumor necrosis factor alpha inhibitors (TNFi), paradoxical adverse effects have been increasingly reported. The differential diagnosis between disease new-onset manifestations of DADA2 and side effects of TNFi can be challenging and warrants further clarification.

Recurrent pyogenic infections caused by a novel Gln1420* mutation in the C3 gene.

C3 is a crucial protein of the complement system. Congenital C3 deficiency is extremely rare and manifests through recurrent, severe infections and should always be considered as a differential diagnosis of recurrent pyogenic infections. We report a case of a patient with a novel C3 gene mutation, responsible for complete C3 deficiency with impaired complement system activation and recurrent infections.

Case Report: Wide Spectrum of Manifestations of Ligase IV Deficiency: Report of 3 Cases.

DNA ligase IV deficiency is a rare autosomal recessive disorder associated with impaired DNA repair mechanisms. Most patients with DNA repair defects present with neurologic deficits, combined immunodeficiency, bone marrow failure, and/or hematologic neoplasia. We present 3 unrelated cases of ligase IV deficiency with different clinical presentations. Patient 1 presented at the age of 5 with bone marrow failure, dysmorphic features, and T and B lymphopenia. A compound heterozygous variant L19W/K635fs in the LIG4 gene was identified. Patient 2 presented at the age of 16 with recurrent infections. He had agammaglobulinemia and absent B cells. A homozygous R278H in the LIG4 gene was identified. Patient 3 was referred for vitiligo and B-cell lymphopenia (low class-switched B cells) and hypogammaglobulinemia. Homozygous R278H in LIG4 was also identified. In the last few years, the spectrum of clinical manifestations caused by ligase IV deficiency has widened, making it very difficult to establish an accurate clinical diagnosis. The use of NGS allows a proper diagnosis and provides a better prognosis and adequate family counseling.

Fatal Meningitis in Patient with X-Linked Chronic Granulomatous Disease Caused by Virulent Granulibacter bethesdensis.

Granulibacter bethesdensis is a pathogen reported to cause recurrent lymphadenitis exclusively in persons with chronic granulomatous disease. We report a case of fatal meningitis caused by a highly virulent G. bethesdensis strain in an adolescent in Europe who had chronic granulomatous disease.

[H Factor Deficiency: A Case with an Atypical Presentation]. / Défice de Fator H: Um Caso com Apresentação Atípica.

We report a case of an 18-month-old boy with H factor deficiency with atypical presentation: recurrent acute otitis media and several maternal family members with autoimmune disorders (vitiligo, thyroiditis and immune trombocytopenia). Blood tests revealed low C3 and AH50, as well as low properdin and H factor. I factor was normal. CFH gene molecular test confirmed the H factor deficiency diagnosis. This child had none of the typical manifestations of this disorder, namely Neisseria meningitidis infection or renal disease (glomerulonephritis and atypical haemolytic uremic syndrome). Autoimmune family history and correct interpretation of blood tests' results were crucial for this diagnosis.

Apresenta-se um caso clínico de um rapaz de 18 meses com défice de fator H com apresentação clínica atípica ­ otite média aguda recorrente e história familiar da linhagem materna com doença autoimune (vitiligo, tiroidite e púrpura trombocitopénica imune). Analiticamente apresentava C3 e AH50 diminuídos, assim como properdina e fator H baixos. O fator I era normal. O estudo molecular do gene CFH confirmou o diagnóstico de défice de fator H. Esta criança não teve nenhuma das manifestações típicas, nomeadamente doença invasiva por Neisseria meningitidis ou doença renal (glomerulonefrite e síndrome hemolítica urémica atípica). A história familiar de autoimunidade e a correta interpretação dos achados laboratoriais foram fundamentais para o diagnóstico.

Invasive Meningococcal Disease Unraveling a Novel Mutation in the C5 Gene in a Portuguese Family.

Although bacterial meningitis is a rare presentation of a congenital immunodeficiency, invasive meningococcal disease is classically associated with complement deficiencies. We report a patient from a consanguineous kindred presenting with an invasive meningococcal disease caused by serogroup B meningococcus that revealed an underlying C5 deficiency caused by a novel mutation in the C5 gene.

Novel IL2RG Mutation Causes Leaky TLOWB+NK+ SCID With Nodular Regenerative Hyperplasia and Normal IL-15 STAT5 Phosphorylation.

X-linked severe combined immunodeficiency disease (SCID) is caused by mutations in the interleukin (IL)-2 receptor γ (IL2RG) gene and patients usually present with a TBNK SCID phenotype. Nevertheless, a minority of these patients present with a TBNK phenotype, similar to the IL-7R-deficient patients. We report a patient with a novel missense p.Glu297Gly mutation in the IL2RG gene presenting with a leaky TBNK SCID with delayed onset, moderate susceptibility to infections, and nodular regenerative hyperplasia. He presents with preserved STAT5 tyrosine phosphorylation in response to IL-15 stimulation but not in response to IL-2 and IL-7, resulting in the NK phenotype.

Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa.

Background: The auto-inflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) syndrome is a rare primary immunodeficiency caused by a gain-of-function mutation S707Y in the PLCG2 gene previously described in two patients from one family. The APLAID patients presented with early-onset blistering skin lesions, posterior uveitis, inflammatory bowel disease (IBD) and recurrent sinopulmonary infections caused by a humoral defect, but lacked circulating autoantibodies and had no cold-induced urticaria, contrary to the patients with the related PLAID syndrome. Case: We describe a new APLAID patient who presented with vesiculopustular rash in the 1st weeks of life, followed by IBD, posterior uveitis, recurrent chest infections, interstitial pneumonitis, and also had sensorineural deafness and cutis laxa. Her disease has been refractory to most treatments, including IL1 blockers and a trial with ruxolitinib has been attempted. Results: In this patient, we found a unique de novo heterozygous missense L848P mutation in the PLCG2 gene, predicted to affect the PLCγ2 structure. Similarly to S707Y, the L848P mutation led to the increased basal and EGF-stimulated PLCγ2 activity in vitro. Whole blood assays showed reduced production of IFN-γ and IL-17 in response to polyclonal T-cell stimulation and reduced production of IL-10 and IL-1ß after LPS stimulation. Reduced IL-1ß levels and the lack of clinical response to treatment with IL-1 blockers argue against NLRP3 inflammasome hyperactivation being the main mechanism mediating the APLAID pathogenesis. Conclusion: Our findings indicate that L848P is novel a gain-of-function mutation that leads to PLCγ2 activation and suggest cutis laxa as a possible clinical manifestations of the APLAID syndrome.

Missense mutation of TTC7A mimicking tricho-hepato-enteric (SD/THE) syndrome in a patient with very-early onset inflammatory bowel disease.

Tricho-hepato-enteric syndrome (SD/THE) and Multiple intestinal atresia with combined immune deficiency (MIA-CID) are autosomal recessive disorders that present immunological and gastrointestinal features. There are two different phenotypes of patients with TTC7A mutations: the severe form, caused by null mutations and leading to the classical MIA-CID; and the mild form, caused by missense mutations and leading to predominant features of VEO-IBD, less severe immunological involvement and hair abnormalities. We expand the knowledge about TTC7A deficiency, describing a patient with the mild phenotype of TTC7A deficiency but presenting overlapping features of SD/THE and MIA-CID: intestinal atresia and inflammatory bowel disease evocative of MIA-CID, but also dental abnormalities, huge forehead, liver abnormalities, autoimmune thyroiditis and hypogammaglobulinemia, evocative of SD/THE.

Early home-supported discharge for patients with stroke in Portugal: a randomised controlled trial.

OBJECTIVE: To evaluate an early home-supported discharge service for stroke patients. DESIGN: We carried out a prospective, randomised, open-label, blinded-endpoint trial (allocation ratio of 1:1) with patients assigned to either an early home-supported discharge service or usual care. SETTING: The study was undertaken in Aveiro, Portugal, between April 2009 and April 2013. SUBJECTS: We included stroke patients aged 25-85 years admitted to the stroke unit with an initial Functional Independence Measure of up to 100, who gave informed consent. INTERVENTIONS: Patients in the early home-supported discharge group began their rehabilitation intervention in the stroke unit and the early home-supported discharge team worked with them at home for a maximum of one month. Patients in the control group received usual services. MAIN MEASURES: The primary outcome measure was the Functional Independence Measure at six months after stroke. RESULTS: We randomised 190 patients of whom 34 were lost to follow-up. There were no significant differences (p > 0.5) in the average scores of Functional Independence Measure between the early home-supported discharge (69 ±22; mean ±SD) and the control groups (71 ±17) measured at baseline; and between the early home-supported discharge (107 ±20) and the control groups (107 ±25) measured at six months. The number of individuals with a low Functional Independence Measure score (<60) in the early home-supported discharge group compared with the control group was higher at admission (34/95 vs. 26/95) and lower at follow-up (2/74 vs. 5/78). CONCLUSIONS: It was feasible to implement early home-supported discharge procedures in a Southern European setting, but we have not shown convincing differences in disability at six months.

Hyper-IgD and periodic fever syndrome: a new MVK mutation (p.R277G) associated with a severe phenotype.

Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS; MIM# 260920) is a rare recessively-inherited autoinflammatory condition caused by mutations in the MVK gene, which encodes for mevalonate kinase, an essential enzyme in the isoprenoid pathway. HIDS is clinically characterized by recurrent episodes of fever and inflammation. Here we report on the case of a 2 year-old Portuguese boy with recurrent episodes of fever, malaise, massive cervical lymphadenopathy and hepatosplenomegaly since the age of 12 months. Rash, arthralgia, abdominal pain and diarrhea were also seen occasionally. During attacks a vigorous acute-phase response was detected, including elevated erythrocyte sedimentation rate, C-reactive protein, serum amyloid A and leukocytosis. Clinical and laboratory improvement was seen between attacks. Despite normal serum IgD level, HIDS was clinically suspected. Mutational MVK analysis revealed the homozygous genotype with the novel p.Arg277Gly (p.R277G) mutation, while the healthy non-consanguineous parents were heterozygous. Short nonsteroidal anti-inflammatory drugs and corticosteroid courses were given during attacks with poor benefits, whereas anakinra showed positive responses only at high doses. The p.R277G mutation here described is a novel missense MVK mutation, and it has been detected in this case with a severe HIDS phenotype. Further studies are needed to evaluate a co-relation genotype, enzyme activity and phenotype, and to define the best therapeutic strategies.

Successful Handling of Disseminated BCG Disease in a Child with Severe Combined Immunodeficiency.

In high-burden countries, Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccine is administered in newborn to prevent severe Mycobacterium tuberculosis infection. Because life-threatening disseminated BCG disease may occur in children with primary immunodeficiency, vaccination strategy against tuberculosis should be redefined in non-high-burden countries. We report the case of a patient with X-linked severe combined immunodeficiency (SCID) who developed disseminated BCG disease, highlighting the specific strategies adopted.

[Respiratory infection caused by Chlamydia pneumoniae]. / Infecção respiratória a Chlamydia pneumoniae.

INTRODUCTION: Chlamydia pneumoniae is a pathogen usually associated with respiratory pathology. It has been estimated that this agent causes 5 to 15% of all pneumonias but its incidence among hospitalised children with respiratory infections is unknown. OBJECTIVE: Characterization of the Chlamydia pneumoniae respiratory infections in hospitalised children. PATIENTS AND METHODS: Retrospective longitudinal study of the Chlamydia pneumoniae respiratory infections in children admitted between January 1999 and June 2001 in the Department of Pediatrics in the Fernando Fonseca Hospital-Portugal. Sex, age, race, socio-economic status, number of scholar siblings, frequency of nursery/school, parents smoking habits, familiar atopy, personal history, clinical presentation, diagnosis, treatment and follow-up were analysed for each child. RESULTS: 55 cases were documented, 60% males and 73% whites. The age on admission varied between 17 days and 14 years-old, with a higher incidence below 5 years-old (60%). Twenty-three (42%) of the children were in nursery or in school and 12 (44%) had siblings at school-ages. Parent smoking habits were documented in 21 (38%) and familiar atopy in 21 (38%) children. Respiratory atopy (6 children), gastroesophageal reflux (3), cerebral palsy (1), cleft palate (1) and prematurity (1). Pneumonia was the most frequent clinical presentation (63%), followed by bronchiolitis (20%). The clinical presentation was not specific, with cough (84%), respiratory distress (65%) and fever (58%) being the most frequent signs. The most prevalent radiological pattern was the interstitial (42%). Coinfection by other agents occurred in five cases: S. pneumoniae (2), H. influenzae tipo b (1), P. aeruginosa (1) and tuberculosis (1). Complications were documented in 32 (58%) children: hypoxemia (20), pleural effusion (8), atelectasis (2) e atelectasis and hypoxemia (2). Macrolides were prescribed in 44% cases. DISCUSSION: This study calls the attention to the fact that Chlamydia pneumoniae infection is an etiology to be considered in children with respiratory infection and hospitalisation criteria. This infection can occur in all ages. Because the clinical presentation is not specific and complications can occur, a high level of suspicion is necessary for its diagnosis.

[Echovirus type 13 meningitis: admissions to a paediatric ward at a Lisbon hospital]. / Meningite por echovirus tipo 13.

Infections by echovirus 13 are rare. In our country, it had not been previously reported any infection of this sort until 2000, when eleven echovirus 13 meningitis were observed in the Department of Pediatrics of the Hospital Fernando Fonseca. In England and Spain outbreaks of echovirus 13 meningitis during 2000 was also reported. Based on these facts the authors make an epidemiological analyses of their series.