Aleinikova, Olga V.

Gamez-Diaz, Laura

Grimbacher, Bodo

Guryanova, Irina E.

Haapaniemi, Emma

Mareika, Yuliya E.

Migas, Alexandr A.

Mikhaleuskaya, Taisiya M.

Rojas, Jessica

Sakovich, Inga S.

Sharapova, Svetlana O.

Journal of Clinical Immunology

English

Svetlana O. Sharapova

Emma Haapaniemi

Inga S. Sakovich

Jessica Rojas

Laura Gámez-Díaz

Yuliya E. Mareika

Irina E. Guryanova

Alexandr A. Migas

Taisiya M. Mikhaleuskaya

Bodo Grimbacher

Olga V. Aleinikova

Crossref

Novel LRBA Mutation and Possible Germinal Mosaicism in a Slavic Family

Helsingin yliopiston digitaalinen arkisto

LETTER TO EDITORNovel LRBA Mutation and Possible Germinal Mosaicismin a Slavic FamilySvetlana O. Sharapova1 & Emma Haapaniemi2,3 & Inga S. Sakovich1 & Jessica Rojas4 & Laura Gámez-Díaz4 &Yuliya E. Mareika1 & Irina E. Guryanova1 & Alexandr A. Migas1 & Taisiya M. Mikhaleuskaya1 & Bodo Grimbacher4 &Olga V. Aleinikova1Received: 10 October 2017 /Accepted: 17 May 2018 /Published online: 26 May 2018# Springer Science+Business Media, LLC, part of Springer Nature 2018Keywords LRBAhomozygousmutation . multiple autoimmunity . germlinemosaicism . Slavic familyTo the Editor,Lipopolysaccharide-responsive beige-like anchor protein(LRBA) deficiency was first described in 2012 [1].Currently, the data more than 100 patients around the worldhas been published, presenting with a broad range of clinical,immunologic, and genetic manifestations [1–22]. This immu-nodeficiency can manifest as common variable immunodefi-ciency (CVID), autoimmune lymphoproliferative-like syn-d r om e (AL P S ) - l i k e , i mmu n e d y s r e g u l a t i o npolyendocrinopathy enteropathy X-linked (IPEX)-like, auto-immune polyendocrinopathy candidiasis ectodermal dystro-phy (APECED)-like, isolated diabetes mellitus, arthritis, andcombined immunodeficiency (CID) with multiple autoim-mune diseases [1–22].Here, we report the clinical, genetic, and immunologicaldata from two siblings in a Belarusian family with a homozy-gous, truncating LRBAmutation (c.2762G>C, p.Ser921Stop).Patient 1 (P1), male, was born at term to non-consanguineousparents (Fig. 1a). At his first year of life, he had several non-complicated respiratory tract infections. At the age of 4 years,he contracted infectious mononucleosis. He recovered butsubsequently developed pneumonia, pancytopenia, and gen-eralized lymphadenopathy and hepatosplenomegaly. A lymphnode biopsy showed reactive changes and predominant follic-ular hyperplasia. Within a year, the condition progressed toautoimmune hemolytic anemia (AIHA) and hemolytic crisiswhich required intensive care. The patient responded to highdoses of steroids, but attempts to taper medication led to re-lapses. He received two courses of rituximab (375 mg/m2),which stopped the hemolysis and improved the lymphadenop-athy. However, multiple focal-infiltrative lesions persisted inboth lungs and did not improve despite of steroids and intra-venous immunoglobulin (Fig. 1b left/right).Soon after the AIHA episode, the patient developed atopicdermatitis and diarrhea, which led to electrolytic disturbances,malabsorption syndrome, and rectal prolapse at age 9. As stoolsamples tested negative for common pathogens, he was diag-nosed with non-specific autoimmune colitis. The combinationof systemic inflammation, chronic malabsorption, and high-dose steroids stunted his growth (20.5 kg/119 cm, 9 years old)and caused Cushing syndrome, hyperparathyroidism, and sec-ondary osteoporosis at age 8. Despite prophylactic antibioticsand immunoglobulin therapy, the patient regularly had sinus-itis, ethmoiditis, and repeated pneumonias, as well as an epi-sode of disciform keratitis.Due to his severe disease, the patient received allogeneicstem cell transplant (HSCT) from a fully matched unrelateddonor at age 10, in the absence of a definitive molecular di-agnosis (Table S1). The donor cells did not engraft, and fullautorecovery was evident at day 42. P1 died at 72 days post-HSCT due to systemic inflammatory response syndrome andmulti-organ failure.Electronic supplementary material The online version of this article(https://doi.org/10.1007/s10875-018-0515-x) contains supplementarymaterial, which is available to authorized users.* Svetlana O. Sharapovasharapovasv@gmail.com1 Research Department, Immunology Laboratory, Belarusian ResearchCenter for Pediatric Oncology, Hematology and Immunology,223053 Borovliani, Minsk Region, Belarus2 Department of Hematology and Regenerative Medicine, KarolinskaInstitutet, Huddinge, Sweden3 Genome-Scale Biology Program, University of Helsinki,Helsinki, Finland4 Center for Chronic Immunodeficiency,Medical Center, University ofFreiburg, Freiburg im Breisgau, GermanyJournal of Clinical Immunology (2018) 38:471–474https://doi.org/10.1007/s10875-018-0515-xThe initial basic immunologic screening (Table S2) identi-fied a normal percentage of lymphocyte subsets and normalimmunoglobulin levels for his age. Within 5 years after B celldepleting therapy, the patient had full B cell deficiency inperipheral blood and profound hypogammaglobinemia.Progression of the disease was interpreted as an adverse reac-tion to rituximab treatment (Table S2).Patient 2 (P2), female, was born 2 years after the death ofher brother. At age 8 months, she had a spontaneous episodeof bloody diarrhea in the absence of any detectableinfection. Serologic testing for celiac disease was negative,and streaks of blood in stool persisted despite gluten-freediet. Duodenal biopsy at age 5 years revealed partial villousatrophy with eosinophils, neutrophils, and inflammatorylymphocytic infiltrate in the lamina propria, as well as mildintraepithelial lymphocytic infiltration.At the age of 2 years and 9 months, her growth stunted,and she developed lymphadenopathy, hepatosplenomegaly,and paronychia of the 3rd finger of her right hand. At age 5,she developed polyarthritis (both ankles, right knee andFig. 1 Family tree and pulmonary alterations. a Pedigreewith sequencingdetails. b (left) Chest computed tomography (CCT) of P1 at the age of5 years revealed increased number of focal lesions, mainly in the lowerlobes. b (right) Positive dynamics was achieved, with the reduction ofmajor lesions and disappearance ofminor ones. c (left) CCTof P2 (5 yearsold) showed generalized lymphadenopathy and multiple focal lesions upto 10 mm in both lungs. c (right) Improved of mean lung density due topneumofibrotic changes and a decrease of focal lesions by 1–2 mm. dLung biopsy showed interstitial pneumonia and follicular bronchiolitis.Histology of P2 lung biopsy specimens showed bronchiolitis with exten-sive fibrosis, and polymorphic lymphoid (CD3+ and СD20+ cells) infil-tration with no granulomas was seen. Stains for bacteria, fungi, andmycobacteria were negative (H&E, Hematoxylin and eosin).472 J Clin Immunol (2018) 38:471–474interphalangeal joints) and was diagnosed with juvenilerheumatoid arthritis (RF = 14 IU/ml). Over time, a persis-tent cough and finger clubbing appeared. Chest computedtomography revealed extensive lymphocytic infiltration inboth lungs, and she was diagnosed with granulomatous-lymphocytic interstitial lung disease (GLILD) (Fig. 1cleft). She received several courses of steroids and immuno-globulin replacement therapy, which temporarily improvedthe situation.Immunologic test panel at the age of 2 years 9 monthsrevealed low levels of IgG and memory B cells (Table S2).B cell subset profiling revealed increased numbers of CD21lowB cells and naïve B cells, and a reduction in switched memoryB cells. At the age of 5, additional abnormalities were noticedin recent thymic emigrants and tregs (Table S2).P2 underwent HSCT from a fully matched unrelated BMdonor (details in Table S1). The patient is alive and well,7 months after the transplant.Whole exome sequencing and subsequent computationalanalysis of patient 1 (P1) revealed homozygous nonsense mu-tation in LRBA (Chr 4:151788827, C>G, p.Ser921Stop).Sequence data has been deposited at the European Genome-phenome Archive (EGA [23] under accession numberEGAS00001002961). The mutation was validated by Sangersequencing in both siblings. Expression of the correspondingprotein product was nearly absent in P2 when measured byflow cytometry (Fig. S1). The father tested heterozygous forthe observed mutation, but the mother’s genomic DNA, DNAfrom sorted T and B, NK lymphocytes, monocytes, buccalmucosa, and fibroblasts, did not contain the mutation. Wild-type alleles were also detected in the stepsister’s genomicDNA (Fig. 1a). Therefore, a heterozygous mosaic mutation(p.Ser921Stop) in mother oocytes (maternal gonadal mosai-cism) was suspected to cause the sibling recurrence. Apparenthomozygosity in exome sequencing can also be the result ofan underlying heterozygous deletion—however, read countswere identical in all LRBA exomes and the nearby genomicregions and did not suggest deletion. Exome sequencing,however, cannot exclude the presence of a complex genomicrearrangement as a cause for the apparently homozygousmutation.Germline or gonadal mosaicism, where gametes harborgenetic variants that are not present in other tissues, resultsfrom somatic mutations during the development of the repro-ductive organs [24]. The prevalence of this phenomenon isunknown in families with primary immunodeficiency dis-eases. Several conditions, in contrast, harbor de novo germlinemutations, and it is possible that a proportion of the mutationsare gonadal in either of the parents. As an example, in activat-ed phosphoinositide 3-kinase (PI3K) δ syndrome (APDS I),syndrome de novo germline mutations in PIK3CD are presentin approximately 30% of the affected families [25, 26]. Thesubject of gonadal mosaicism requires further study in PIDDsand other genetic diseases.In line with previous reports [1–22], this family case dem-onstrates phenotypic variability between the siblings withLRBA deficiency. The first patient (P1), male, presented withsevere AIHA, colitis, and bacterial infection susceptibility anddied following HSCT at age 10. He did not develophypogammaglobulinemia until after two courses of rituximabtherapy. His sister did not suffer from severe bacterial infec-tions, but developed hypogammaglobulinemia at an early age.Her autoimmune features included colitis, juvenile rheuma-toid arthritis, and GLILD at the age of 5. This condition istypically a complication of CVID and mostly seen in olderpatients and adults [27]. The patient underwent a successfulHSCT after her diagnosis, underscoring the importance ofgenetic studies prior transplant.The children were born to non-consanguineous parents butwith a homozygous mutation. To study the frequency of ho-mozygosity in non-consanguineous families, we havereviewed all the published cases of LRBA deficiency, withthe key findings summarized in Table S3. Among 95 (93published + 2 Belarusian) patients described in literature, 82(86%) of the children had homozygous abnormalities inLRBA gene. Ninety-four percent of these were born in con-sanguineous families, mostly from Saudi Arabia, Palestine,Turkey, Libya, Lebanon, Egypt, Morocco, Oman, Iran, andPakistan, where marriages between relatives are part of thenational culture. Homozygous mutations in non-consanguineous families were only described in twoAmerican families (patient 31, 32a, 32b). We conclude thathomozygous mutations are very infrequent outside consan-guineous marriages and founder populations.In conclusion, we describe the first Belarusian family withLRBA deficiency, featuring a novel homozygous mutation inLRBA gene (Chr 4:151788827, C>G, p.Ser921Stop). Thephenotype is consistent with the previous reports of LRBAdeficiency. In our experience, definitive genetic diagnosisshould be actively sought when preparing patients forHSCT.We also highlight the possibility of gonadal mosaicismin cases where the disease recurs in siblings, but one or bothparents have wild-type genetic alleles.Acknowledgments We sincerely thank all our patients and their familymembers for their trust, cooperation, and consent to perform genetic andfunctional assays and the referring doctors for their help. We are alsograteful to doctor Polina Stepensky and Professor Markus Seidel for theconsultation on our Pt2.Compliance with Ethical StandardsConflict of Interest The authors declare that they have no conflicts ofinterest.J Clin Immunol (2018) 38:471–474 473References1. Lopez-Herrera G, Tampella G, Pan-Hammarström Q, Herholz P,Trujillo-Vargas CM, Phadwal K, et al. Deleterious mutations inLRBA are associated with a syndrome of immune deficiency andautoimmunity. Am J Hum Genet. 2012;90:986–1001.2. Burns SO, Zenner HL, Plagnol V, Curtis J, Mok K, Eisenhut M, etal. LRBA gene deletion in a patient presenting with autoimmunitywithout hypogammaglobulinemia. J Allergy Clin Immunol.2012;130(6):1428–32.3. Azizi G, Abolhassani H, Mahdaviani SA, Chavoshzadeh Z, EshghiP, Yazdani R, et al. Clinical, immunological, molecular analysesand outcomes of Iranian patients with LRBA deficiency: a longitu-dinal study. Pediatr Allergy Immunol. 2017;28(5):478–84.4. 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Novel LRBA Mutation and Possible Germinal Mosaicism in a Slavic Family

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Helsingin yliopiston digitaalinen arkisto