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[Paper Type: Novel mutation and VUS] AND [Author: Merico, Daniele] (3) | 21 May 2024 |
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- Background: The prevalence of atopic disease, which consists of conditions such as atopic dermatitis, allergies, and asthma, has been on the rise in recent decades. In children, atopic dermatitis often acts as an initial manifestation of atopic disease and frequently precedes the development of food allergies, asthma, and allergic rhinitis. Mutations in the FLG gene, encoding the fillagrin precursor profillagrin, serve as a genetic risk factor for these diseases. Approximately 25%–50% of individuals with atopic dermatitis carry FLG mutations. It has been proposed that FLG mutations exhibit variations specific to different populations, indicating distinct patterns within each population.Severe allergic symptoms could indicate the presence of an underlying immunodeficiency or immune dysregulation and in patients with severe, early-onset, or simultaneous allergic conditions, these could be suggestive of an underlying Primary Atopic Disorder. Specifically, the allergic triad characterized by elevated IgE levels, eosinophilia, and eczema is a common feature in various inborn errors of immunity that could be mistakenly diagnosed as severe allergic conditions.Method: Our patient’s medical record was analyzed retrospectively, including her medical history, as well as results from immune laboratory tests and genetic analyses.Results: We present a 9-year-old female of mixed ethnicity with a history severe eczematous rash diagnosed with atopic dermatitis. Whole exome sequencing analysis revealed an initially novel heterozygous variant in the FLG gene (NM_002016: EXON3:c.C2218T: p.R740X).Conclusion: Healthcare providers caring for patients with atopic dermatitis and recurrent staphlococcus infections should be aware of the significant link between filaggrin gene mutations and the development of severe, persistent atopic dermatitis that begins in childhood, as well as its association with recurring staphlococcus infections. Additionally, they should keep in mind that certain inborn errors of immunity may predominantly manifest as severe and treatment-resistant atopic disorders.Statement of novelty: We have identified a rare variant in the FLG gene associated with severe atopic dermatitis and allergies.
- FREE ACCESSBackground: Lipopolysaccharide-responsive beige-like anchor (LRBA) is an intracellular protein that regulates the recycling of cytotoxic T lymphocyte-associated protein 4 (CTLA4), an immune checkpoint molecule which prevents ongoing activation of T cells. Deficiency of LRBA results in increased trafficking and degradation of CTLA4, and consequently, uncontrolled T cell responses. The phenotypic spectrum of LRBA deficiency arising from biallelic loss-of-function typically includes recurrent infections, autoimmunity, lymphoproliferation, chronic diarrhea, hypogammaglobulinemia, and cytopenia.Aim: To report an atypical presentation of LRBA deficiency arising from a set of compound heterozygous LRBA variants, encompassing recurrent hemophagocytic lymphocytosis (HLH) and neurological manifestations.Methods: Clinical data was gathered through retrospective chart review. Expanded genetic analysis including whole exome sequencing was performed.Results: Our patient initially presented at age 15 months with fever, seizures, and encephalopathy. HLH-work-up showed bicytopenia, elevated ferritin and triglyceride, and low fibrinogen, however, he did not yet meet the diagnostic criteria for HLH. MRI brain and EEG at diagnosis was suggestive of acute necrotizing encephalopathy of childhood. He responded to pulsed IV methylprednisolone treatment with minimal residual neurological deficit on follow-up. At 36 months of age, he had a repeat presentation and rapidly deteriorated. He developed severe encephalopathy with fixed dilated pupils. Whole exome sequencing revealed a set of compound heterozygous missense variants in the LRBA gene, a novel c.2206A>T (p.R736W) and c.5989C>T (p.R1997C) variant.Conclusion: Compound heterozygous mutations in the LRBA gene caused an atypical presentation of recurrent HLH with central nervous system (CNS) manifestations in our patient.Statement of Novelty: We herein report a novel set of compound heterozygous mutations in LRBA with atypical presentation of recurrent HLH with CNS manifestations, thus expanding the known phenotypic spectrum of LRBA deficiency.
- OPEN ACCESSBackground: DNA ligase IV deficiency is a rare autosomal recessive condition resulting from mutations in LIG4, an essential component of the non-homologous end-joining pathway that prevents mutagenesis and apoptosis. Patients with LIG4 deficiency present with varying degrees of combined immunodeficiency, or less commonly, severe combined immunodeficiency (SCID). Assessment of thymus pathology has been instrumental in defining a growing number of T cell deficiencies. In this case report, we present thymic histopathology of a LIG4 deficient patient who presented with SCID.Methods: Whole exome sequencing and Sanger confirmation were used to identify a novel mutation in LIG4. Standard immune work up and histopathology were completed to characterize deficits in immune function and dysplastic thymic architecture in our patient.Results: Next generation sequencing techniques identified a homozygous c.1102G>T, resulting in amino acid change D368Y in the adenylation domain of LIG4. Histopathology revealed a distinct absence of Hassall’s corpuscles, lack of cortico-medullary demarcation, as well as lack of T cells and Langerhans histiocytes in the thymic medulla.Conclusion: We have identified a novel mutation in LIG4 resulting in a SCID phenotype. Underdevelopment of the thymus, characterized by a lack of Hassall’s corpuscles and competent thymocytes, likely contributes to the immune defects observed in patients with mutations in LIG4.Statement of novelty: We report here a novel mutation in LIG4 as well as the first description of detailed thymus pathology in this condition.