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Successful Hematopoietic Stem Cell Transplantation in a Patient with LPS-Responsive Beige-Like Anchor (LRBA) Gene Mutation

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Abstract

Purpose

Autosomal recessive mutations in LRBA, encoding for LPS-responsive beige-like anchor protein, were described in patients with a common variable immunodeficiency (CVID)-like disease characterized by hypogammaglobulinemia, autoimmune cytopenias, and enteropathy. Here, we detail the clinical, immunological, and genetic features of a patient with severe autoimmune manifestations.

Methods

Whole exome sequencing was performed to establish a molecular diagnosis. Evaluation of lymphocyte subsets was performed for immunological characterization. Medical files were reviewed to collect clinical and immunological data.

Results

A 7-year-old boy, born to consanguineous parents, presented with autoimmune hemolytic anemia, hepatosplenomegaly, autoimmune thyroiditis, and severe autoimmune gastrointestinal manifestations. Immunological investigations revealed low immunoglobulin levels and low numbers of B and NK cells. Treatment included immunoglobulin replacement and immunosuppressive therapy. Seven years after disease onset, the patient developed severe neurological symptoms resembling acute disseminated encephalomyelitis, prompting allogeneic hematopoietic stem cell transplantation (HSCT) with the HLA-identical mother as donor. Whole exome sequencing of the patient uncovered a homozygous 1 bp deletion in LRBA (c.7162delA:p.T2388Pfs*7). Importantly, during 2 years of follow-up post-HSCT, marked clinical improvement and recovery of immune function was observed.

Conclusions

Our data suggest a beneficial effect of HSCT in patients with LRBA deficiency.

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Acknowledgments

This study was supported by the Swedish Children’s Cancer Foundation, Swedish Research Council, Cancer and Allergy Foundation of Sweden, Swedish Cancer Foundation, and the Stockholm County Council (ALF project), the Frimurare Barnhus Foundation, as well as the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement no. 311335, the Wallenberg Academy Fellows program, and the Swedish Foundation for Strategic Research. B.T. was supported by a PhD student scholarship awarded by the Board of Postgraduate Studies at Karolinska Institute.

Author Contributions

B.T. performed genetic analyses, interpreted results, and wrote the manuscript; P.P. and F.L. cared for the patient and provided clinical data; S.C.C.C. performed immunological analyses and analyzed data; N.K performed radiological investigations and interpreted results; A.L performed genetic analyses and analyzed data; E.L. performed histopathology investigations and interpreted results; J-I.H. analyzed data; J.W cared for the patient and provided clinical data; Y.T.B. designed research, analyzed data, interpreted results, and contributed to drafting the manuscript; M.M. conceived the study, designed research, analyzed data, interpreted results, and wrote the manuscript. All the authors reviewed and approved the final manuscript.

Author information

Author notes

  1. Esther Lörinc

    Present address: Department of Pathology, Skåne University Hospital, Lund, Sweden

Authors and Affiliations

  1. Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden

    Bianca Tesi, Alexandra Löfstedt, Jan-Inge Henter & Marie Meeths

  2. Clinical Genetics Unit, Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden

    Bianca Tesi, Alexandra Löfstedt & Marie Meeths

  3. Astrid Lindgren Children’s Hospital, Karolinska University Hospital Huddinge, Stockholm, Sweden

    Peter Priftakis, Fredrik Lindgren & Jacek Winiarski

  4. Department of Clinical Science Intervention and Technology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden

    Fredrik Lindgren, Nikolaos Kartalis & Jacek Winiarski

  5. Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden

    Samuel C. C. Chiang & Yenan T. Bryceson

  6. Department of Radiology, Karolinska University Hospital Huddinge, Stockholm, Sweden

    Nikolaos Kartalis

  7. Department of Pathology, University Hospital Karolinska Huddinge, Solna, Sweden

    Esther Lörinc

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  1. Bianca Tesi
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Corresponding authors

Correspondence to Bianca Tesi or Marie Meeths.

Additional information

Peter Priftakis and Fredrik Lindgren contributed equally to this work.

Electronic Supplementary Material

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Supplementary Fig. 1

Pancreas imaging pre- and post-HSCT. Ultrasound of the pancreas pre-HSCT (A) and contrast-enhanced pancreatic MRI/MR cholangiopancreatography (MRCP) 15 months post-HSCT therapy (B–F). In (A), the anteroposterior diameter of the parenchyma in the pancreatic body area was 23 mm, which exceeds the upper limit of the normal range in the patient’s age group (11 ± 3 mm). In the coronal maximum intensity projection MRCP image (B), the main pancreatic duct had a diameter of 3 mm and in the pancreatic head area there was one slightly dilated side branch (arrowhead). No parenchymal signal intensity abnormalities were observed in the T2-weighted image (C) or in the dynamic contrast-enhanced series (D–F) (white arrows). Based on (B–F), the findings were considered equivocal of chronic pancreatitis, according to both the Cambridge and the M-ANNHEIM classification. (PDF 2781 kb)

Supplementary Fig. 2

Lung imaging pre- and post-HSCT. Axial (A, D) and coronal (B, E) computer tomography images of the thorax. Pre-HSCT (A, B), multiple nodular-shaped infiltrates (arrows) were visible in both lungs. Sixteen months after HSCT therapy (D, E), all lesions disappeared. Similarly, multiple nodular-shaped infiltrates in the right lung were visible (arrows) pre-HSCT in the chest X-ray (C). The infiltrates disappeared post-HSCT (F). (PDF 2559 kb)

Supplementary Fig. 3

Immunological investigations. (A) Number of lymphocytes subsets measured at five different time points. A vertical dashed line represents the time of HSCT. Normal reference values for each population are shown as vertical bars on the right side of the plot. Empty and filled circles refer to measurement performed by, respectively, a clinical lab (CL) and a research lab (RL). (B) CD8 and NK degranulation assay, measured as percentage of CD107a positive cells after incubation with target cells, in the patient and healthy controls was performed three times pre- and once post-HSCT. (C) NK cytotoxicity, displayed as lytic units at 25 % specific lysis, was assessed in the patient and healthy controls twice pre- and once post-HSCT. (PDF 342 kb)

Supplementary Fig. 4

Additional endoscopic and histological evaluations of the gastrointestinal tract. (A) Colonoscopy at the age of 8 years showed inflammation with cryptitis and ulceration in the rectum resembling ulcerative colitis. Microscopically, lymphocytic colitis was found (B) (×100 H&E stain) and confirmed by CD3 staining (C) (×100 CD3 stain). Post-HSCT, the colonoscopy revealed macroscopically normal colon mucosa (D). Histologically, a reduction in number of lymphocytes was seen post-HSCT, but there is an increased cell proliferation even in the higher sections of the cripts (data not shown). (E) Low-grade esophagitis with macroscopic C. albicans infection (white arrows) was found pre-HSCT, which resolved post-HSCT (F). (PDF 12493 kb)

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Tesi, B., Priftakis, P., Lindgren, F. et al. Successful Hematopoietic Stem Cell Transplantation in a Patient with LPS-Responsive Beige-Like Anchor (LRBA) Gene Mutation. J Clin Immunol 36, 480–489 (2016). https://doi.org/10.1007/s10875-016-0289-y

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