Search

Purpose: MALT1 deficiency is a combined immune deficiency characterized by recurrent infections, eczema, chronic diarrhea, and failure to thrive. Clinical and immunological characterizations of the disease have not been previously reported in large cohorts. We sought to determine the clinical, immunological, genetic features, and the natural history of MALT-1 deficiency. Methods: The clinical findings and treatment outcomes were evaluated in nine new MALT1-deficient patients. Peripheral lymphocyte subset analyses, cytokine secretion, and proliferation assays were performed. We also analyzed ten previously reported patients to comprehensively evaluate genotype/phenotype correlation. Results: The mean age of patients and disease onset were 33 ± 17 and 1.6 ± 0.7months, respectively. The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%). Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively. The majority of patients had normal T and NK cells, while eight (89%) exhibited reduced B cells. Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications. One patient received hematopoietic stem cell transplantation (HSCT) and five patients died as a complication of life-threatening infections. Analyzing this cohort with reported patients revealed overall survival in 58% (11/19), which was higher in patients who underwent HSCT (P = 0.03). Conclusion: This cohort provides the largest analysis for clinical and immunological features of MALT1 deficiency. HSCT should be offered as a curative therapeutic option for all patients at the early stage of life.

PURPOSE To assess clinical characteristics of torpedo maculopathy (TM) lesions in an infant population with age ≤1.5 years and to investigate the role of NEXMIF mutation in the development of TM. METHODS Retrospective analysis of medical records of 17 consecutive infants with the diagnosis of TM between 2016 January and 2019 December were done. Fundus images and a hand-held spectral-domain optical coherence tomography (Envisu 2300, Bioptigen, Morrisville, NC, USA) were used to identify clinical characteristics of TM lesions. Additional molecular testing for mutation screening for NEXMIF gene was also carried out. RESULTS Totally 55334 infants were screened during the study period and 17 (0.03%) were identified as having TM. The mean age at the time of diagnosis was 3.94±5.08 months. All TM lesions showed variable degrees of hypopigmentation. Satellite lesion in one infant was nasally located to the main TM lesion. Absence, disruption, loss, degeneration and/or irregularity of the ellipsoid zone were common findings on OCT examination. No pathogenic or likely pathogenic variant of NEXMIF gene was detected. CONCLUSION Fundoscopic appearance and OCT findings of lesions show similarities to those already reported previously. Contrary to popular belief, a nasally located satellite lesion was observed in one of our case.

To the Editor: FCH And Mu Domain Containing Endocytic Adaptor 1 (FCHO1) gene encodes a protein that plays a critical role in clathrin-mediated endocytosis, a biological process that maintains cellular functions in signaling, nutrient- and growth factor- uptake, and diferentiation [1–3]. Recently, biallelic mutations in FCHO1 were linked to a combined immunodefciency that is characterized by recurrent infections caused by bacteria, viruses, mycobacteria, fungi, T cell lymphopenia, and hypogammaglobulinemia [4, 5]. Sidra Precision Medicine Program

Systemic autoinflammatory diseases (SAIDs) may not always present with typical clinical findings of a monogenic disease. We aimed to genetically screen and diagnose these clinically unclassified patients by next-generation sequencing (NGS) analysis.A total of 64 patients who had clinical findings of a periodic fever syndrome but did not meet the clinical diagnostic criteria for any SAID or had clinical findings for more than one monogenic SAID were identified as "clinically unclassified SAIDs." NGS panel analysis, including 16 genes, was performed in these patients. Patients, who could not be classified as one of the defined SAID after the result of the NGS gene analysis, were identified as "undefined SAID."The most common autoinflammatory symptoms in unclassified SAID patients were abdominal pain (60.9%), arthralgia (48.4%), urticarial rash (43.8%), myalgia (40.6%), oral aphthae (28.1%), and conjunctivitis (20.3%), respectively. In the result of the NGS gene panel screening, pathogenic, likely pathogenic variants, or VUS (variants of uncertain significance) were detected in 36 of 64 patients in at least one gene in the NGS panel. A total of 15 patients were diagnosed with a monogenic SAID according to both phenotypic and genotypic data; 12 patients as FMF, two patients as FCAS, and one patient as TRAPS, respectively. A total of 49 patients who did not meet the classification criteria including genetic results for a monogenic SAID were followed as undefined SAID.The classification criteria described for SAIDs so far unfortunately do not cover all patients with signs of periodic fevers. The NGS gene panel appears to be a useful diagnostic tool for some of the patients with clinically unclassified SAID findings. Key Points • The classification criteria described for SAIDs do not cover all patients with signs of periodic fevers • The use of the undefined SAID nomenclature will benefit clinicians for diagnosis and initiating early treatment • The NGS panel appears to be a useful diagnostic tool in patients with clinically unclassified SAIDs.

Marshall-Stickler syndrome represents a spectrum of inherited connective tissue disorders affecting the ocular, auditory, and skeletal systems. The syndrome is caused by mutations in the COL2A1, COL11A1, COL11A2, COL9A1, and COL9A2 genes. In this study, we examined four Turkish families with Marshall-Stickler syndrome using whole-exome sequencing and identified one COL2A1 mutation and three COL11A1 mutations. Two of the COL11A1 mutations were novel. Our findings expand our knowledge of the COL11A1 mutational spectrum that causes Marshall-Stickler syndrome.