Novel hypomorphic mutation in IKBKG impairs NEMO-ubiquitylation causing ectodermal dysplasia, immunodeficiency, incontinentia pigmenti, and immune thrombocytopenic purpura.

NF-κB essential modulator (NEMO) is a component of the IKK complex, which participates in the activation of the NF-κB pathway. Hypomorphic mutations in the IKBKG gene result in different forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males without affecting carrier females. Here, we describe a hypomorphic and missense mutation, designated c.916G>A (p.D306N), which affects our patient, his mother, and his sister. This mutation did not affect NEMO expression; however, an immunoprecipitation assay revealed reduced ubiquitylation upon CD40-stimulation in the patient's cells. Functional studies have demonstrated reduced phosphorylation and degradation of IκBα, affecting NF-κB recruitment into the nucleus. The patient presented with clinical features of ectodermal dysplasia, immunodeficiency, and immune thrombocytopenic purpura, the latter of which has not been previously reported in a patient with NEMO deficiency. His mother and sister displayed incontinentia pigmenti indicating that, in addition to amorphic mutations, hypomorphic mutations in NEMO can affect females.

Fcγ receptor gene polymorphisms in childhood immune thrombocytopenic purpura.

Immune thrombocytopenic purpura (ITP) is a common hematological disorder in the childhood, and it is one of the most common forms of autoimmune disease in pediatric patients. The ITP basis is a primary dysfunction of the immune system. This study aimed to analyze the genetic polymorphisms of the Fcγ receptors IIA and IIIA. The genetic polymorphisms of the Fc receptors γIIA (131H/R) and γRIIIA (158V/F) were analyzed by polymerase chain reaction-restriction fragment length polymorphism technique. Odds ratio and 95% confidence interval were calculated by χ(2) test. Homozygous polymorphic genotype for the FcγRIIIA was significantly more frequent among patients compared with controls (odds ratio = 0.27; 95% confidence interval, 0.09-0.80; P = 0.03). There was no statistical difference between the ITP group and the controls in the analysis of combinations of alleles of the high-affinity Fc receptor, but the ITP individuals with this combination had a lower duration of disease (P = 0.01). Genetic polymorphisms in immune system genes can be important for ITP pathogenesis and disease outcome.

Immune thrombocytopenia with antiphospholipid antibodies in monozygotic twins.

We describe monozygotic twins with immune thrombocytopenia (ITP) associated to antiphospholipid antibodies with a dissimilar clinical expression. The first patient was diagnosed to have ITP at 63 years old and was treated with corticosteroids. She presented ulterior exacerbations of thrombocytopenia requiring intravenous immunoglobulin and subsequent treatment with rituximab. She ultimately had a favorable response without thrombotic events during follow-up. The second patient who had a history of three spontaneous abortions and endometrial adenocarcinoma in complete remission was evaluated for severe thrombocytopenia, ITP was diagnosed at the age of 63. She was treated with steroids and had a favorable response. After few months she developed deep venous thrombosis and pulmonary embolism requiring anticoagulation therapy without hemorrhagic events. Both patients were found to have antiphospholipid antibodies and HLA DR4 (DRB1*04) and HLA DR5 (DRB1*12). The association of those two entities in monozygotic twins could support the presence of common predisposing genes. However, with both patients being genotipically identical, the clinical expression was different. Those cases highlight the possibility that environmental factors may affect the expression of those disorders.

IL1RN VNTR and IL2-330 polymorphic genes are independently associated with chronic immune thrombocytopenia.

Chronic Immune Thrombocytopenia (cITP) is an acquired immune-mediated disease associated with a T-helper cell type 1 (Th1) immune polarization, whose genetic risk factors, however, are largely unknown. We investigated polymorphisms in promoter regions of genes that code molecules involved in proinflammatory immune response [IL1B-31T/C, IL1RN variable number tandem repeats (VNTR), IL2-330T/G, and TNF-307G/A] as well as in genes that code Toll like receptors (TLR) (TLR2 Arg753Gln, TLR4 Asp299Gly and TLR5 Arg(392stop)) in 122 patients with cITP and 541 blood donors. The frequencies of the IL1RN polymorphic allele 2 (P = 0·001) and of the IL2-330 polymorphic allele G (P =0·004) were significantly higher in cITP patients than in blood donors. In logistic analysis adjusting for age and gender, the polymorphisms remained independently associated with cITP. Enhanced serum concentrations of interleukin (IL)-1α and IL-1ß were observed in cITP (P < 10(-3) ) and blood donor (P = 0·04) carriers of the IL1RN*2. Also, the serum levels of IL-2 and γ-interferon (IFN-γ) were increased in cITP patients (P < 10(-3) and P = 0·04 respectively) and blood donors (P < 10(-3) and P = 0·03 respectively) harbouring the IL2-330G allele. Here we demonstrated that IL2-330G and IL1RN*2 are independently associated with cITP and are functional in vivo, which strongly suggests that they contribute to the pathogenesis of cITP.

Predisposition to idiopathic thrombocytopenic purpura maps close to the major histocompatibility complex class I chain-related gene A.

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune condition with poorly known etiology, characterized by platelet destruction. Genetic association studies of this disease are scarce, discrepant, and restricted to major histocompatibility complex (MHC) polymorphisms. Hence, a case-control study was conducted with an aim to map the MHC to IPT susceptibility using HLA-B and nine microsatellite loci encompassing MHC class I, II, and III regions. We compared the allelic frequencies in samples of unrelated healthy controls and ITP patients. After correction for multiple tests, only allele MICA*183, also known as A5.1, demonstrated an association, resulting in the identification of a major predisposing region close to STR-MICA. This result may highlight the putative functional role of MICA in the immune response to ITP.