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Multicenter Study
. 2021 Jan 15:11:612323.
doi: 10.3389/fimmu.2020.612323. eCollection 2020.

Clinical and Genetic Profile of X-Linked Agammaglobulinemia: A Multicenter Experience From India

Amit Rawat  1 , Ankur Kumar Jindal  1 , Deepti Suri  1 , Pandiarajan Vignesh  1 , Anju Gupta  1 , Biman Saikia  2 , Ranjana W Minz  2 , Aaqib Zaffar Banday  1 , Rahul Tyagi  1 , Kanika Arora  1 , Vibhu Joshi  1 , Sanjib Mondal  1 , Jitendra Kumar Shandilya  1 , Madhubala Sharma  1 , Mukesh Desai  3 , Prasad Taur  3 , Ambreen Pandrowala  4 , Vijaya Gowri  3 , Sneha Sawant-Desai  5 , Maya Gupta  5 , Aparna Dhondi Dalvi  5 , Manisha Madkaikar  5 , Amita Aggarwal  6 , Revathi Raj  7 , Ramya Uppuluri  7 , Sagar Bhattad  8 , Ananthvikas Jayaram  9 , Harsha Prasad Lashkari  10 , Liza Rajasekhar  11 , Deenadayalan Munirathnam  12 , Manas Kalra  13 , Anuj Shukla  14 , Ruchi Saka  1 , Rajni Sharma  1 , Ravinder Garg  1 , Kohsuke Imai  15 , Shigeaki Nonoyama  16 , Osamu Ohara  17 , Pamela P Lee  18 , Koon Wing Chan  18 , Yu-Lung Lau  18 , Surjit Singh  1
Affiliations
Multicenter Study

Clinical and Genetic Profile of X-Linked Agammaglobulinemia: A Multicenter Experience From India

Amit Rawat et al. Front Immunol. .

Abstract

Background: There is paucity of literature on XLA from developing countries. Herein we report the clinical and molecular profile and outcome in a multicenter cohort of patients with XLA from India.

Methods: Data on XLA from all regional centers supported by the Foundation for Primary Immunodeficiency Diseases (FPID), USA and other institutions providing care to patients with PIDs were collated. Diagnosis of XLA was based on European Society for Immunodeficiencies (ESID) criteria.

Results: We received clinical details of 195 patients with a provisional diagnosis of XLA from 12 centers. At final analysis, 145 patients were included (137 'definite XLA' and eight 'probable/possible XLA'). Median age at onset of symptoms was 12.0 (6.0, 36.0) months and median age at diagnosis was 60.0 (31.5, 108) months. Pneumonia was the commonest clinical manifestation (82.6%) followed by otitis media (50%) and diarrhea (42%). Arthritis was seen in 26% patients while 23% patients developed meningitis. Bronchiectasis was seen in 10% and encephalitis (likely viral) in 4.8% patients. Pseudomonas aeruginosa was the commonest bacterial pathogen identified followed by Streptococcus pneumoniae, Staphylococcus aureus and Klebsiella pneumoniae. Molecular analysis revealed 86 variants in 105 unrelated cases. Missense variants in BTK gene were the most common (36%) followed by frameshift (22%) and nonsense variants (21%). Most pathogenic gene variants (53%) were clustered in the distal part of gene encompassing exons 14-19 encoding for the tyrosine kinase domain. Follow-up details were available for 108 patients. Of these, 12% had died till the time of this analysis. The 5-year and 10-year survival was 89.9% and 86.9% respectively. Median duration of follow-up was 61 months and total duration of follow-up was 6083.2 patient-months. All patients received intravenous immunoglobulin (IVIg) replacement therapy. However, in many patients IVIg could not be given at recommended doses or intervals due to difficulties in accessing this therapy because of financial reasons and lack of universal health insurance in India. Hematopoietic stem cell transplant was carried out in four (2.8%) patients.

Conclusion: There was a significant delay in the diagnosis and facilities for molecular diagnosis were not available at many centers. Optimal immunoglobulin replacement is still a challenge.

Keywords: BTK gene; X-linked agammaglobulinemia; arthritis; intravenous immunoglobulin; neutropenia.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Shows list and locations of centers that participated in this multicenter study.
Figure 2
Figure 2
Schematic diagram showing inclusion and exclusions of cases in the study. Abbreviations: XLA, X-linked agammaglobulinemia; BTK, Bruton tyrosine kinase.
Figure 3
Figure 3
Clinical profile of patients with X-linked agammaglobulinemia (XLA). (A) Bar chart showing infections that were seen in patients with XLA. (B) Pie chart showing various pathogenic organisms that were isolated from patients with XLA. (C) Pie chart showing various techniques used for isolating the pathogenic organisms.
Figure 4
Figure 4
Clinical photograph of ulcerative skin lesion of a patient with X-linked agammaglobulinemia (XLA) suspected to be related to Helicobacter sp. infection.
Figure 5
Figure 5
Distribution of pathogenic variants on various exons, exon-intron junctions and corresponding domains of BTK gene. cDNA is mentioned in the lower panel while amino acid change is mentioned in the upper panel. Corresponding amino acid changes in the Bruton tyrosine kinase (BTK) protein domains has also been highlighted using various symbols. PH, Pleckstrin homology domain; TH, Tec homology; SH, Src homology; TK, Tyrosine Kinase.
Figure 6
Figure 6
(A) Pie chart showing type of mutations in the BTK gene. (B) Pie chart showing affected domains on the BTK gene. (C) Bar chart showing number of variants located over individual exons of BTK gene. BTK, Bruton tyrosine kinase; TK, tyrosine kinase domain; PH, Pleckstrin homology; TH, Tec homology; SH, Src homology.
Figure 7
Figure 7
Kaplan Meir survival curve of the entire cohort.
Figure 8
Figure 8
Magnetic resonance imaging shows T2-weighted cortical and subcortical hyperintensities in bilateral occipital region.
See this image and copyright information in PMC

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