NF-κB plays critical roles in the development and function of the immune system , skeletal system, and epithelium, including intestinal epithelium. NFκB has important roles in vasculogenesis, angiogenesis, and development of the lymphatic system too. Dysregulation of NF-κB function is known to underlie numerous pathological processes, including immune deficiency, autoimmune diseases, cancer, cardiovascular disease, and a variety of other inflammatory-mediated diseases.
We report a patient with mutation in NF-κB2 gene.
We report a 11-year-old boy from non-consanguineous parents who presented to our clinic with history of chronic cough since 4 months old. he also had history of alopecia, oral aphtus lesions and recurrent sinusitis too. he was healthy otherwise until 9-year-old.
At nine years old his clinical picture complicated with left hemiparesis due to brain stroke. All of coagulation and rheumatologic tests were normal.
His immunological study shows decreased level of IgM, IgA levels and antibody response and increased CD3 and CD4 based on age reference values. Other immunologic tests were normal .
Due to recurrent sinusitis and poor antibiotic response we planned to treat him with IVIG and prophylactic antibiotics.
Unfortunately, before beginning of IVIG treatment he admitted to another hospital with fever, vomiting, diarrhea and seizure and expired.
His whole exome sequencing detected pathogenic heterozygous nonsense variant in NF-κB2 gene at Exon 22.
Clinical Presentation of our patient shows that primary immune deficiency patients may have wide spectrum of clinical signs and symptoms.
Activated phosphoinositide 3-kinase delta (PI3K) syndrome (APDS) is characterized by variable humoral and cellular defects, recurrent infections, lymphoma, autoimmune features, and growth and developmental delay.
Sweet syndrome, or acute febrile neutrophilic dermatosis, is a rare inflammatory skin condition. About half of cases have an underlying systemic disorder, mainly malignancies and autoinflammatory conditions. It has only been sporadically reported in patients with immunodeficiency.
We report a boy with APDS presenting as a combined immunodeficiency and Sweet syndrome.
Immunological tests, skin biopsies and PID gene panel analysis were performed.
A boy, currently 16 years old, suffered from recurrent bacterial infections since the age of 3 years. He also developed bronchiectasis, lymphadenopathies and splenomegaly. Immunological work-up revealed low IgG2, reduced polysaccharide antibody responses, monocytopenia and T, B and NK lymphopenia. Recently, we identified a PIK3CD mutation causing APDS.
Remarkably, since 5 years of age, he had recurrent painful erythematous nodules and plaques on his limbs and abdomen, accompanied by fever and elevated inflammatory markers. Biopsies showed a dense neutrophilic infiltrate confirming the diagnosis of Sweet syndrome. Acute episodes responded well to systemic corticosteroids. Up till now, he requires dapsone maintenance therapy to prevent relapse.
To our knowledge, this is the first report of an APDS patient with Sweet syndrome. The pathophysiology of Sweet syndrome is unclear but involves activation of innate inflammatory signaling. Previous studies have demonstrated a role for PI3K/Akt signaling in NLRP3-inflammasome activation. Together, this suggests dysregulation of inflammasome activation in APDS patients, implying potentially therapeutic effects of IL-1 inhibition.
We report a 5 year old boy initially evaluated for acute temporary vision disorder – blurred vision and diplopia, afebrile. MRI scan showed oval lesion 6x7x7mm in parasagittal mesencephalic region, slightly increased signal in T2W, with restricted diffusion in DWI, no signs of hemorrhage. Clinical immunologist consultation was requested for suspicion of autoimmune encephalomyelitis. Hypogammaglobulinemia IgG, IgA, IgM with low B cells and low post-vaccination antibodies have been detected. Patient was classified under CVID follow-up group and placed on regular IG replacement. Within next months he remained asymptomatic, with low inflammatory markers.
Targeted NGS for genes associated with PID was performed on MiSeq (Illumina) in the patient. Mutations were confirmed by Sanger sequencing.
NGS analysis revealed 2 missense variants in ADA2 gene in trans configuration. 1) c.506G>A (p.R169Q) was previously described as disease causing mutation, in association with antibody deficiency and inconstantly with vascular manifestation; 2) c.505C>T (p.R169W) novel variant was revealed in a neighboring DNA position, affecting the same amino acid; prediction tools evaluated it as damaging and a change of the same amino acid has already been described as disease causing mutation, indicating that this variant can be considered pathogenic as well.
We describe a patient carrying compound heterozygous loss-of-function mutations in ADA2 gene presenting under an overlapping phenotype of unspecific focal neurologic symptomatology associated with an ischemic stroke and immunodeficiency of B cell compartment. NGS methods are the best choice for detecting molecular defects in preschool age hypogammaglobulinemia patients.
Ataxia telangiectasia (A-T) is a devastating multi-system disorder characterized by progressive cerebellar ataxia, immunodeficiency, chronic pulmonary disease and chromosomal instability. Cutaneous granulomas are a known phenomenon in A-T but extra-dermal manifestation of granulomas at lymphoreticular system and lung has not been reported so far.
The clinical presentation, immunological findings, the course and discussion of potential treatment options of one patient will be reported.
Here we report an A-T (c.6573-9G>A; c.8319ˍ8323dup) patient 6 years old with lymphadenopathy, splenomegaly, hepatomegaly, increasing pulmonary nodules ( from few millimeters to 1 centimeter in 6 months) (images 1-4) without respiratory symptoms. Immunoglobulin serum levels were: IgG 811 mg/dl (replacement on going: 600 mg/kg s.c.), IgA 32 mg/dl, IgM 1750 mg/dl, low CD4, absent CD4CD45RA ad low CD8. The biopsy of laterocervical lymph node showed a non-necrotizing follicle hyperplastic and granulomatous lymphadenopathy. No infection agents (mycobacteria, pneumocistys, fungi, CMV, EBV and HHV8) in the lymph node and in the bronchoalveolar lavage (BAL). We decided to perform an MRI of the lung after 3 months. A lung biopsy and all potential treatments are under discussion (steroids and monoclonal antibodies).
Little is known about the clinical presentation, course and treatment of granulomas in A-T; this is the ﬁrst report of extra-dermal manifestation of granulomas lymphoreticular system and lung. In recent years new insight have been generated into granulomatous inflammation, this have made possible the increasing numbers of therapeutic agents targeting immune pathways, but actually there is no standard treatment
In addition to recurrent infections, the majority of common variable immunodeficiency (CVID) patients have inflammatory and autoimmune manifestations of unknown etiology. We have previously shown that gut microbial dysbiosis, including increased levels of Gammaproteobacteria, is associated with systemic inflammation in CVID. The gut microbial dependent systemic metabolite trimethylamine N-oxide (TMAO) has been related to systemic inflammation in other diseases. We hypothesized that TMAO through the gut-microbial axis could contribute to systemic inflammation in CVID.
We measured plasma levels of TMAO and inflammatory markers in 104 CVID patients and 30 healthy controls. In addition, we related TMAO levels to our previous data on gut microbial composition and obtained a dietary questionnaire from 40 CVID patients.
CVID patients had higher plasma levels of TMAO than controls (p=0.021). TMAO correlated positively with the prototypic inflammatory cytokines TNF (p=0.008, rho=0.259) and IL-12 (p=0.012, rho=0.245) known to be involved in the pathogenesis of CVID-related autoimmune complications. Furthermore, gut microbial abundance of Gammaproteobacteria in CVID patients correlated positively with TMAO levels (p=0.021, rho=0.363). Finally, the use of table sugar was associated with elevated TMAO levels (p=0.006, rho=0.437), whereas wine consumption correlated negatively with TMAO levels (p=0.023, rho=-0.369).
CVID patients have increased plasma levels of the gut microbiota-dependent metabolite TMAO associated with increased inflammatory markers and an abundance of the TMA producing Gammaproteobacteria in the gut. TMAO appears linked to systemic inflammation in CVID through the gut microbial axis, which could potentially be modified by diet.
STAT1 gain of function (STAT1 GOF) is a congenital disorder characterized by a broad clinical spectrum, with chronic mucocutaneous candidiasis as the more common phenotype. We report a patient diagnosed with STAT1 GOF.
The immunophenotype and functional assays were analyzed by flow cytometry, the genetic study was performed by a NGS customized panel containing all the immunodeficiency diseases-related genes and the result was confirmed by Sanger sequencing.
The patient a 31-year-old woman, who at 18 months, suffered persistent candida infections refractory to the antifungal treatment. During her childhood presented pneumonia, herpes-zoster infection and several sinusitis as the main infectious processes. Moreover, severe osteopenia was detected. The patient needed GH treatment due to a failure to thrive associated with malabsorption syndrome and chronic hepatitis. At 15 years old, premature menopause and ovary failure were detected. In 2017 the genetic study showed a heterozygous variant, c.1885C>T (p.H629Y), in STAT1 gene. Functional assays showed a dephosphorylation defect in STAT1p, and elevated Th1/Th17 ratio was found, therefore the patient was diagnosed with STAT1 GOF. Currently, her recurrent respiratory infections have improved, however, autoimmune processes became a serious problem. A few years ago she developed a vasculopathy and hidradenitis suppurativa with an infectious and autoinflammatory component.
Given the complexity of clinical manifestation in these patients, treatments are widely varied: prophylaxis of infections, antifungals, immunosupressive drugs, and immunoglobulins. Recently, ruxolitinib has been proposed as a new option with encouraging results.
Background: Familiar Mediterranean Fever (FMF) is an autoinflammatory disease inherited with an autosomal recessive pattern and characterized by recurrent episodes of fever with polyserositis or/and arthritis. Colchicine is the first-line drug in treating the disease and preventing the occurrence of secondary amyloidosis. However, 5-10% of patients do not respond to colchicine and are candidates for biologics.
AIm: The purpose of this study was to determine the factors that affect the response to colchicine in pediatric patients with FMF.
Methods: Articles from the PubMed database were searched without time limitation in the literature. Only studies of English language with pediatric patients were included.
Results: Non-response to treatment has been associated with higher disease activity associated with specific mutations in the MEFV gene (eg M694V / M694V). Environmental factors and co-inflammatory diseases (eg, arthritis) also contribute to the severity of the disease. Other factors are related to the bioavailability of colchicine with emphasis on genetic polymorphisms in the ABCB1 transporter gene (MDR1) and interactions with drugs that inhibit the cytochrome P450 protein as well as the Pgp transporter protein (ABCB1). Finally, non-compliance to treatment should be considered in all patients with poor response.
Conclusions: Given the undesirable effects and the high cost of biological factors, it is crucial to accurately identify those patients who are high risk of not responding to colchicine and to determine the causes of ineffectiveness of treatment in this patient group.
Autoinflammatory diseases are a heterogeneous group of disorders caused by dysregulation in the innate immune system. The protein A20, encoded by TNFAIP3, is involved in the negative regulation of nuclear factor-κB signaling. In 2016, heterozygous mutations in the TNFAIP3 gene have been found to cause A20 haploinsufficiency, presented as an early-onset systemic inflammation that resembles Behçet’s disease.
We presented an 8-year-old boy referred to our hospital at the age of 4 with history of recurrent pain in lower limbs. He developed recurrent oral and genital aphthae, conjunctivitis and headache. He also suffered self-limited fever, abdominal pain, diarrhea and arthralgia. The patient responded poorly to colchicine requiring methotrexate. Laboratory analysis revealed high serum level of IgE (800 UI/mL) and normal IgG, IgA and IgM levels. Tests for autoantibodies and HLA-B51 were negative. The family history showed 3 patients with recurrent oral ulcer and similar symptoms, members over 3 generations in the same family (his sister, mother and grandmother).
Mutation analysis of TNFAIP3 revealed the novel monoallelic (p.W356R) variant and in silico studies predicted a deleterious effect on protein function. No mutations were found in MEFV, MVK and TNFRSF1A genes. The variant is segregated in the family members with the autoinflammatory disease. After genetic diagnosis he began treatment with adalimumab with considerable clinical improvement.
Discovery of new monogenetic autoinflamatory diseases such as A20 haploinsufficiency helps to advance our understanding of disease pathogenesis and to develop targeted therapies for them.
Hyperimmunoglobulinaemia D syndrome is an autoinflammatory disease usually representing recurrent episodes of fever, arthralgia/arthritis, cervical lymphadenopathy, vomiting, diarrhoea, abdominal pain and skin rashes lasting 3-7 days every 4-8 weeks since their infancy.
Herein, we report an 18-month-old patient with recurrent attacks of fever and pharyngitis lasting 2-3 days every 10-15 days since the first two weeks of life. Inflammatory attacks were accompanied by diarrhoea, oral aphthous ulcers, cervical lymphadenopathy, maculopapular rash, severe leukocytosis and perianal fistulae/abscess.
After the initiation of canakinumab, the patient was clinically improved with complete healing of perianal fistulas/abscesses.
In conclusion, hyperimmunoglobulinaemia D syndrome should be considered in differential diagnosis of inflammatory bowel disease and recurrent perianal abscess/fistula in a patient with inflammatory attacks.