Background: Dominant negative STAT3 loss-of-function is the most common genetic cause of hyper-IgE syndrome (HIES). Patients may present with a host of both immune and non-immune manifestations, including connective tissue abnormalities, recurrent infections, malignant predisposition, and biochemical evidence of elevated serum IgE or eosinophilia. Aim: To describe a novel splice-site variant in STAT3 resulting in HIES. Methods: Case report of two family members with HIES. Results: A proband and his son presented with neonatal-onset pustular rash, recurrent skin and sinopulmonary infections and elevated serum IgE and were diagnosed with AD-HIES. They were identified to harbor a novel splice-site variant in the DNA-binding domain (DBD) of STAT3: c.1110-3C>G, predicted to result in defective splicing in exon 12. Interestingly, a number of other patients with AD-HIES with mutations affecting the same splice-site, suggesting this may be a hot-spot for mutagenesis. Conclusion: Splice-site mutations in the DBD of STAT3 are increasingly identified as a cause of AD-HIES. Future work is required to delineate whether patients with splice site mutations have unique clinical characteristics, supporting efforts for genotype-phenotype correlation in this disease.
ABSTRACT
Background: 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 diarrhoea, 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 old, 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, c.2206A>T (p.R736W) and c.5989C>T (p.R1997C).
Conclusion: Compound heterozygous mutations in the LRBA gene caused an atypical presentation of recurrent HLH with CNS manifestations in our patient.
Statement of Novelty: We herein report a 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.
Background: Since the onset of the COVID-19 pandemic, a main challenge for clinicians and public health decision-makers has revolved around risk stratification in vulnerable populations, in particular individuals with inborn errors of immunity (IEI). However, available reports of the clinical course of COVID-19 in patients with IEI show wide variability, from a complete lack of symptoms to severe and complicated disease.
Objective: To present the clinical features and outcomes of SARS-CoV-2 infection in adult patients with IEI.
Methods: A retrospective chart review involving patient characteristics and clinical course of SARS-CoV-2 infection between December 2021-July 2022.
Results: Ten adult patients with IEI followed in our center were diagnosed with COVID-19, as determined by RT-PCR or rapid antigen test. IEI in this cohort included both humoral, combined immunodeficiencies and phagocytic defects, with an underlying lung comorbidity identified in 3 patients. Symptoms were mostly mild and self-limiting. No severe outcomes, complications or mortality were noted in this study.
Conclusions: We suggest that patients affected by a wide range of both humoral and combined IEI may demonstrate resilience, while highlighting the possible protective effects of vaccination and immunoglobulin replacement in this population.
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