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A Novel BLNK Gene Mutation in a Four-Year-Old Child Who Presented with Late Onset of Severe Infections and High IgM Levels and Diagnosed and Followed as X-Linked Agammaglobulinemia for Two Years

A Novel BLNK Gene Mutation in a Four-Year-Old Child Who Presented with Late Onset of Severe... Hindawi Case Reports in Immunology Volume 2022, Article ID 7313009, 6 pages https://doi.org/10.1155/2022/7313009 Case Report A Novel BLNK Gene Mutation in a Four-Year-Old Child Who Presented with Late Onset of Severe Infections and High IgM Levels and Diagnosed and Followed as X-Linked Agammaglobulinemia for Two Years 1 1 1 2 2 Ezgi Topyildiz , Neslihan Edeer Karaca, Ayse Aygun, Ayca Aykut, Asude Durmaz, 1 1 Guzide Aksu, and Necil Kutukculer Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey Department of Medical Genetics, Faculty of Medicine, Ege University, Izmir, Turkey Correspondence should be addressed to Ezgi Topyildiz; ezgitopyildiz@gmail.com Received 10 November 2021; Revised 17 January 2022; Accepted 15 May 2022; Published 10 June 2022 Academic Editor: Ahmad Mansour Copyright © 2022 Ezgi Topyildiz et al. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Agammaglobulinemia is a rare inherited immunode ciency disorder. Mutations in the BLNK gene cause low levels of mature B lymphocytes in the peripheral blood leading to recurrent infections. We present a four-year-old Turkish boy who had recurrent respiratory tract infections in the last six months. He had very low IgG (81 mg/dl) and IgA levels (<5 mg/dl) with high IgM (258 mg/dl). Flow cytometric analysis of lymphocyte subsets showed low CD19+ B cells (0.05%). Homozygous c.790C > T (p.Gln264Ter) mutation was detected in the BLNK gene with Targeted Next Generation Sequencing (TNGS) gene analysis. Agammaglobulinemia may be due to dižerent genetic etiologies together with complex genetic events. Although the  rst diagnosis to be considered in male patients is Bruton’s agammaglobulinemia, patients with normal BTK sequence and/or expression should be investigated with a large genetic study such as TNGS in the early period to reach a de nitive diagnosis. is male case of agammaglobulinemia highlights the necessity of considering BLNK mutations in children with B cell de ciency, even though they are known to be rare causes of agammaglobulinemia. Our case is also remarkable with high IgM levels before intravenous immunoglobulin replacement therapy and with late-onset severe infections. BCR (BLNK, PIK3CD, PIK3R1, SLC39A7) cause autosomal 1. Introduction recessive (AR) agammaglobulinemia (ARA). Recently, Agammaglobulinemia is a rare hereditary primary immu- TOP2B mutations with autosomal dominant inheritance node ciency disorder (PID) characterized by recurrent in- and TCF3 mutations with both autosomal dominant and fections associated with low or absent circulating mature autosomal recessive inheritance have also been identi ed in B cells and severe antibody de ciency. Approximately 85% agammaglobulinemia cases [3, 4]. e BLNK gene (SLP-65 or BASH) encodes a 65 kDa of congenital agammaglobulinemia patients have X-linked agammaglobulinemia (XLA, Bruton’s agammaglobulin- B cell adapter molecule on chromosome 10q24.1, containing emia) disease due to hemizygous mutations in the BTK gene 18 exons, and plays a critical role in B lymphopoiesis [5]. [1, 2]. Genetic defects identi ed in most of the remaining While BLNK itself does not have any intrinsic enzyme ac- patients have been shown to create an early block in B cell tivity, it functions as a scažold for binding and assembly of development. Mutations in the genes that encode compo- molecular complexes involved in BCR-associated kinase nents of the pre-B cell receptor (BCR) complex (IGHM, activation. B cell signaling cascades are triggered by BLNK IGLL1, CD79A, CD79B) and signal transduction genes of binding to Igα, and phosphorylating by Syk on tyrosine 2 Case Reports in Immunology Table 1: Immunologic evaluations at admission and age-related residues that enable binding and activation of downstream normal levels. signaling molecules [6]. Activated BTK and phospholipase C gamma-2 bind to the BLNK/SLP65 adaptor protein. Sig- Patients Normal range naling through this complex results in the expression of the value RAG proteins, which induce IgG recombination and pro- 3 Leukocyte (10 /μL) 11,40 5–13 motes pre-B cell differentiation [5, 6]. Neutrophil (10 /μL) 4, 25 2–6, 9 Mutation in the BLNK gene (OMIM # 613502), first Lymphocyte (10 /μL) 5, 26 1, 5–3, 4 identified by Minegishi et al. in 1999 [5], had caused a failure Haemoglobin (g/dl) 11, 86 12–15 of B cell development leading to significantly lower levels of 'rombocyte (10 /μL) 483 142–424 IgG (mg/dl) 81 894± 157 mature B lymphocytes in the peripheral blood. 'ese B cells IgM (mg/dl) 258 92± 35 cannot form plasma cells, resulting in significantly reduced IgA (mg/dl) <5 72± 22 levels (hypogammaglobulinemia) or absence (agamma- Total IgE (IU/ml) 4, 1 2–307 globulinemia) of all immunoglobulin isotypes. 55–79/ Few patients with BLNK defects have been reported up CD3+ T cells ((%)/μL) 92, 1/4844 1900–3600 to date and it is a very rare form of agammaglobulinemia [1]. 11–31/ CD19+ B cells ((%)/μL) 0,05/2,6 Here, we report a child presenting atypically with late-onset 300–1200 XLA clinical findings, high IgM levels at admission, and a 26–49/ CD3+CD4+ T cells ((%)/μL) 59, 3/3119 novel homozygous mutation in the BLNK gene detected by 600–2000 targeted next-generation sequencing (TNGS). CD3+CD8+ T cells ((%)/μL) 29, 3/1541 9–35/300–1300 CD3-CD16+CD56+ NK cells 5, 7/299 5–28/200–1200 ((%)/μL) 2. Case Anti-HBs (mIU/ml) Negative 10–1000 Anti-HAV IgG Negative >0, 9 A 4-year-old boy was admitted with a history of recurrent Anti-CMV IgG (aU/ml) Negative 6–250 respiratory tract infections in the last six months. 'e parents were second-degree consanguineous and family history was unremarkable for PIDs. Physical examination was detected at 4 years of age and AR agammaglobulinemia was normal on admission. Initial immunologic evaluation (BLNK defect) was diagnosed at 6 years of age. 'e patient revealed very low IgG and IgA with very high IgM levels. has been treated with IVIG replacements for 4 years, and an Flow cytometric lymphocyte subsets analysis revealed very excellent response was obtained. To our knowledge, this low CD19+ B cells. Specific IgG antibodies against hepatitis patient with BLNK mutation is the ninth case in the liter- A and B vaccines were both undetectable. Other laboratory ature and the first case to be published from Turkey. 'e tests including leukocyte, lymphocyte, haemoglobin counts, patient is doing very well now and no major infectious liver and kidney function tests, serologic investigations for episodes and autoimmune manifestations were noted up to common viruses, were all normal (Table 1). Abdominal date. ultrasonography revealed mild hepatosteatosis and chest radiography was normal. CD40L level was evaluated on activated Tcells to exclude X-linked hiper IgM due to CD40L 3. Discussion deficiency and it was found to be normal. 'e case with recurrent respiratory infections, hypo- Herein, we present a male patient who admitted with typical gammaglobulinemia, and decreased B cells was diagnosed as XLA clinical findings and was found to have a novel, un- X-linked agammaglobulinemia (XLA) and intravenous identified, homozygous mutation (c.790C> T, p.Gln264Ter) immunoglobulin therapy (IVIG) (0, 4–0,8 g/kg/dose) once a in the BLNK gene. Eight patients with different BLNK gene month was started. Regular IVIG treatment provided IgG defects have been published previously. Five of them had serum levels higher than 400 mg/dl. Targeted next-genera- homozygous, one patient had heterozygous, and two pa- tion sequencing (TNGS) was performed in order to un- tients had compound heterozygous mutations. As far as we derstand the molecular pathology two years after admission know, our patient is the 9th patient with BLNK mutation to pediatric immunology clinic. TNGS workflow based on an reported in the literature and is the first patient reported Ion AmpliSeq Primary Immune Deficiency Research Panel from Turkey [5, 7–11] (Table 2). Two of the previously designed for sequencing 264 PID genes on Ion S5 Se- reported cases were Chinese, two were Arab, and two were quencer demonstrated a homozygous c.790 C>T Turkish. One of the Turkish patients is living in Europe and the second one is being followed up in a university pediatric (p.Gln264Ter) mutation in BLNK gene (Figure 1). 'is novel BLNK mutation was confirmed by Sanger sequencing. clinic in Turkey (2nd case in Table 2) (unpublished data). Analysis of familial segregation revealed that his mother and One patient’s ethnicity could not be learned and the last one father were heterozygous for the mutation. 'e patient’s was Scottish. parents were healthy and had normal concentrations of Children with autosomal recessive agammaglobulinemia serum immunoglobulins and normal number of B cells. present with recurrent bacterial infections, the absence of 'e clinical findings of this patient are similar to typical circulating B cells, and very severe hypogammaglobulinemia XLA patients and he was followed for two years with XLA similar to XLA. Patients are usually symptomatic in the first diagnosis before TNGS gene analysis. Agammaglobulinemia year of life, after the disappearance of maternal IgG, by an Case Reports in Immunology 3 (a) (b) Figure 1: (a) Patient’s BLNK gene sequence analysis images, homozygous c.790 C> T (p.Gln264Ter) mutation in exon 11. (b) His parents’ heterozygous c.790 C> T (p.Gln264Ter) mutation in exon 11. average of 6 months. Autosomal recessive forms of agam- 'e late onset of infections in this case is thought to be due to maglobulinemia have been shown to present a more severe being the first child of the family and very sterile life in the phenotype and earlier onset compared to XLA [2, 7]. infantile period. However, our patient, who was asymptomatic until the age It is known that BLNK defects affect B cell development, of 3.5, was diagnosed with agammaglobulinemia at the age of leading to low levels of mature B lymphocytes in peripheral 4 and was followed up with a relatively mild clinical course. blood; therefore plasma cells cannot be formed, thus causing 4 Case Reports in Immunology Table 2: Reported patients with BLNK protein deficiency. Age at onset Ig levels at Circulating Patient (years), Additional BLNK Infection profile diagnosis (mg/ CD19 B cells (reference) gender, manifestations Mutation dL) (%) ethnicity 8 months, Patient 1 male, Recurrent otitis and Homozygous Intermittent protein (Minegishi et al. Caucasian of pneumonia Undetectable 0.05 c.30 C> A (p.P10P)/ losing enteropathy [5]) Scot/Irish hepatitis C c.47 + 3 A> T ancestry Recurrent respiratory Patient 2 Resolved hepatitis IgG 111 8, female, infections, diarrhea, Homozygous c.367 C> T (Conley et al. with no clear IgA< 6 0.01 Turkish otitis, septic arthritis, (p.R123X) [2]) diagnosis IgM 10 and conjunctivitis Patient 3 (Lagresle- Recurrent otitis and Homozygous 6, male, NA None Undetectable 0 Peyrou et al. pneumonia c.844 C> T (p.R282X) [9]) Chronic Recurrent otitis Patient 4 polyarthritis, Homozygous c.435_436 0.5, male, media, chronic (NaserEddin dermatitis and Undetectable 0 del T CInsA Arab diarrhea, enteroviral et al. [8]) sensorineural (p.E145fs25∗) viremia hearing loss Patient 5 1, female Recurrent diarrhea, Homozygous c.435_436 Arthritis, (NaserEddin (elder sister of otitis media and sino- Undetectable 0 del T CInsA bronchiectasis et al. [8]) P4), Arab pulmonary infections (p.E145fs25∗) IgG 903 Compound No increased IgA 791 Patient 6 (Geier 28, male, Chronic renal heterozygous c328 C> G susceptibility to IgM 27 14 et al. [10]) Turkish insufficiency (pPro110Ala)/c472 infections (selective IgM G> T (pAla158Ser) deficiency) Compound Respiratory Epilepsy, allergic IgG 135 heterozygous c.676 + 1 Patient 7 (Niu 5, female, infections, including rhinitis and IgA< 6 3.5 G> A, exon 9 deletion, Li et al. [11]) Chinese sinusitis, bronchitis, wheezing IgM< 18 c.677_746del, and pneumonia p.R227Kfs ∗ 7 Heterozygous frameshift Recurrent bronchitis, Patient 8 (Niu 2, male, variant c.452_453dup pneumonia, and None Undetectable 3 Li et al. [11]) Chinese CC, (p.T152Pfs ∗ 6), c. acute lymphadenitis 525G> A IgG 81 Homozygous mutation Patient 9 (our 3.5, male, Recurrent respiratory None IgA< 5 0,05 c.790 C> T presented case) Turkish tract IgM 258 (p.Gln264Ter) a significant decrease in all immunoglobulin isotypes. Most of the patients with BLNK defect presented with However, there is no detailed information about the effect of bacterial respiratory tract infections. To prevent these in- BLNK defect on T cell development. A Chinese patient with fections, patients with agammaglobulinemia need lifelong immunoglobulin replacement therapy. Since immuno- BLNK defect was reported to have lower memory CD3+CD4+ and CD3+CD8+ T cells than healthy controls, globulin replacement reduces life-threatening infections, whereas naive T cells were higher levels than controls [11]. patients reach adulthood with regular treatment and follow- Although the cases generally present with low immuno- up, and quality of life of almost all of these cases is very good globulin values and low circulating B cell numbers, a 28- [12]. However, severe infections can also be observed in year-old BLNK patient with only low IgM was reported [10]. some cases. For example, systemic enteroviral infections Contrary to this finding, the IgM level in our patient’s first have been reported in patients previously diagnosed with admission was found to be high as compared to age-related agammaglobulinemia. One child with Igα deficiency, one of normal levels. Our patient was the first patient admitted with the different forms of ARA, had polio due to wild-type high IgM in the literature. After the control and manage- vaccine at the age of 12 months (M.E. Conley and ment of infections under regular IVIG treatment, the pa- V. Howard, unpublished observations), while another child had typical signs of enteroviral infection such as weakness tient’s IgM value decreased to undetectable values during follow-up (Table 3). and dermatomyositis-like syndrome [13]. Another patient Case Reports in Immunology 5 Table 3: Patient’s Ig levels by age. Initial visit Second visit 5-year-old 6-year-old 7-year-old 8-year-old IgG (mg/ 81 (n: 423 (n: 569 (n: 725 (n: 134 (n: 894± 157) 422 (n: 1008± 209) dl) 894± 157) 1008± 209) 1061± 203) 1061± 203) IgM (mg/ 258 (n: <17 (n: <17 (n: <19 (n: 131 (n: 92± 35) 18, 4 (n: 113± 40) dl) 92± 35) 113± 40) 106± 43) 106± 43) IgA (mg/ <5 (n: <27 (n: <28 (n: 6,6 (n: 72± 22) 6, 5 (n: 99± 37) 6, 5 (n: 99± 37) dl) 72± 22) 116± 42) 116± 42) Initiation of IVIG IVIG therapy (IVIG) (0, 5 g/kg/ Treatment — therapy dose) once a month reported by NaserEddin et al. showed skin and joint findings performed the genetic analysis. NEK, ET, AA, GA, and NK as described in patients with BTK deficiency despite regular managed the patient. NK and NEK revised the manuscript. IVIG therapy, and the patient’s peripheral blood was si- All authors read and approved the final manuscript. multaneously found to be positive for enterovirus shown by polymerase-chain reaction [8]. As a different finding, it has Acknowledgments been reported that neutropenia may also accompany BLNK deficiency. A patient with agammaglobulinemia and neu- 'e authors are deeply grateful to the patient and his family tropenia was reported but exact diagnosis could not be for participating in this study. established because of his death due to Pseudomonas sepsis at the age of 16 months, and this patient’s sibling was di- References agnosed as BLNK deficiency after a few years. Contrary to these reported cases, our patient did not have so much [1] T. Smith and C. Cunningham-Rundles, “Primary B-cell im- munodeficiencies,” Human Immunology, vol. 80, no. 6, serious infections and neutropenia was not observed. He is pp. 351–362, 2019. now living without severe infections and complications [2] M. E. Conley, A. Broides, V. Hernandez-Trujillo et al., “Ge- under regular IVIG replacement therapy. netic analysis of patients with defects in early B-cell devel- opment,” Immunological Reviews, vol. 203, no. 1, pp. 216–234, 4. Conclusion [3] M. E. Conley, “Genetics of hypogammaglobulinemia: what do we really know?” Current Opinion in Immunology, vol. 21, Agammaglobulinemia may be due to different etiologies no. 5, pp. 466–471, 2009. with complex genetic events. XLA is the first diagnosis to be [4] S. G. Tangye, W. Al-Herz, A. Bousfiha et al., “Human inborn considered in male cases. Patients with normal BTK se- errors of immunity: 2019 update on the classification from the quence should be investigated with a broad-spectrum ge- international union of immunological societies expert com- netic study for an exact and early diagnosis. 'is case of mittee,” Journal of Clinical Immunology, vol. 40, no. 1, agammaglobulinemia in a 4-year-old male patient highlights pp. 24–64, 2020. a novel autosomal recessive mutation in BLNK gene. Al- [5] Y. Minegishi, J. Rohrer, E. Coustan-Smith et al., “An essential though recessive BLNK mutations appear to be rare causes role for BLNK in human B cell development,” Science, of agammaglobulinemia (given the small number of re- vol. 286, no. 5446, pp. 1954–1957, 1999. ported cases), they should be considered in B-cell-deficient [6] T. Taguchi, N. Kiyokawa, H. Takenouch et al., “Deficiency of BLNK hampers PLC-gamma2 phosphorylation and Ca2+ children. While our presented child remains stable on influx in- duced by the pre-B-cell receptor in human pre- monthly immunoglobulin therapy, long-term follow-up will B cells,” Immunology, vol. 112, no. 4, pp. 575–582, 2004. be required to determine the outcome of this mutation and [7] M. E. Conley, A. K. Dobbs, D. M. Farmer et al., “Primary B cell other health outcomes, given the lack of published literature immunodeficiencies: comparisons and contrasts,” Annual on individuals with recessive BLNK mutations. Review of Immunology, vol. 27, pp. 199–227, 2009. [8] A. NaserEddin, O. Shamriz, B. Keller et al., “Enteroviral in- Data Availability fection in a patient with BLNK adaptor protein deficiency,” Journal of Clinical Immunology, vol. 35, no. 4, pp. 356–360, 'e data used to support the findings of this case report are included within the article. [9] C. Lagresle-Peyrou, M. Millili, S. Luce et al., “'e BLNK adaptor protein has a nonredundant role in human B-cell Conflicts of Interest differentiation,” +e Journal of Allergy and Clinical Immu- nology, vol. 134, no. 1, pp. 145–154.e3, 2014. 'e authors declare that they have no conflicts of interest. [10] C. B. Geier, K. M. T. Sauerwein, A. LeissPiller et al., “Hy- pomorphic mutations in the BCR signalosome lead to se- Authors’ Contributions lective immunoglobulin M deficiency and impaired B-cell homeostasis,” Frontiers in Immunology, vol. 9, p. 2984, 2018. ET and NEK wrote the manuscript. NEK and GA per- [11] N. Li, J. Wu, Y. Wu et al., “Further delineation of primary formed the immunological experiments. AD and AA B cell immunodeficiency caused by novel variants of the 6 Case Reports in Immunology BLNK gene in two Chinese patients,” Clinical Immunology, vol. 214, Article ID 108387, 2020. [12] I. Yıldırım, E. Topyıldız, R. B. G. Bilgin et al., “X-linked agammaglobulinemia: ınvestigation of clinical and laboratory findings, novel gene mutations and prevention of ınfective complications in long-term follow-up,” American Journal of Clinical and Experimental Immunology, vol. 10, no. 1, pp. 37–43, 2021. [13] Y. Wang, H. Kanegane, O. Sanal et al., “Novel Igα (CD79a) gene mutation in a Turkish patient with B cell–deficient agammaglobulinemia,” American Journal of Medical Genetics, vol. 108, no. 4, pp. 333–336, 2002. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Immunology Hindawi Publishing Corporation

A Novel BLNK Gene Mutation in a Four-Year-Old Child Who Presented with Late Onset of Severe Infections and High IgM Levels and Diagnosed and Followed as X-Linked Agammaglobulinemia for Two Years

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Abstract

Hindawi Case Reports in Immunology Volume 2022, Article ID 7313009, 6 pages https://doi.org/10.1155/2022/7313009 Case Report A Novel BLNK Gene Mutation in a Four-Year-Old Child Who Presented with Late Onset of Severe Infections and High IgM Levels and Diagnosed and Followed as X-Linked Agammaglobulinemia for Two Years 1 1 1 2 2 Ezgi Topyildiz , Neslihan Edeer Karaca, Ayse Aygun, Ayca Aykut, Asude Durmaz, 1 1 Guzide Aksu, and Necil Kutukculer Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey Department of Medical Genetics, Faculty of Medicine, Ege University, Izmir, Turkey Correspondence should be addressed to Ezgi Topyildiz; ezgitopyildiz@gmail.com Received 10 November 2021; Revised 17 January 2022; Accepted 15 May 2022; Published 10 June 2022 Academic Editor: Ahmad Mansour Copyright © 2022 Ezgi Topyildiz et al. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Agammaglobulinemia is a rare inherited immunode ciency disorder. Mutations in the BLNK gene cause low levels of mature B lymphocytes in the peripheral blood leading to recurrent infections. We present a four-year-old Turkish boy who had recurrent respiratory tract infections in the last six months. He had very low IgG (81 mg/dl) and IgA levels (<5 mg/dl) with high IgM (258 mg/dl). Flow cytometric analysis of lymphocyte subsets showed low CD19+ B cells (0.05%). Homozygous c.790C > T (p.Gln264Ter) mutation was detected in the BLNK gene with Targeted Next Generation Sequencing (TNGS) gene analysis. Agammaglobulinemia may be due to dižerent genetic etiologies together with complex genetic events. Although the  rst diagnosis to be considered in male patients is Bruton’s agammaglobulinemia, patients with normal BTK sequence and/or expression should be investigated with a large genetic study such as TNGS in the early period to reach a de nitive diagnosis. is male case of agammaglobulinemia highlights the necessity of considering BLNK mutations in children with B cell de ciency, even though they are known to be rare causes of agammaglobulinemia. Our case is also remarkable with high IgM levels before intravenous immunoglobulin replacement therapy and with late-onset severe infections. BCR (BLNK, PIK3CD, PIK3R1, SLC39A7) cause autosomal 1. Introduction recessive (AR) agammaglobulinemia (ARA). Recently, Agammaglobulinemia is a rare hereditary primary immu- TOP2B mutations with autosomal dominant inheritance node ciency disorder (PID) characterized by recurrent in- and TCF3 mutations with both autosomal dominant and fections associated with low or absent circulating mature autosomal recessive inheritance have also been identi ed in B cells and severe antibody de ciency. Approximately 85% agammaglobulinemia cases [3, 4]. e BLNK gene (SLP-65 or BASH) encodes a 65 kDa of congenital agammaglobulinemia patients have X-linked agammaglobulinemia (XLA, Bruton’s agammaglobulin- B cell adapter molecule on chromosome 10q24.1, containing emia) disease due to hemizygous mutations in the BTK gene 18 exons, and plays a critical role in B lymphopoiesis [5]. [1, 2]. Genetic defects identi ed in most of the remaining While BLNK itself does not have any intrinsic enzyme ac- patients have been shown to create an early block in B cell tivity, it functions as a scažold for binding and assembly of development. Mutations in the genes that encode compo- molecular complexes involved in BCR-associated kinase nents of the pre-B cell receptor (BCR) complex (IGHM, activation. B cell signaling cascades are triggered by BLNK IGLL1, CD79A, CD79B) and signal transduction genes of binding to Igα, and phosphorylating by Syk on tyrosine 2 Case Reports in Immunology Table 1: Immunologic evaluations at admission and age-related residues that enable binding and activation of downstream normal levels. signaling molecules [6]. Activated BTK and phospholipase C gamma-2 bind to the BLNK/SLP65 adaptor protein. Sig- Patients Normal range naling through this complex results in the expression of the value RAG proteins, which induce IgG recombination and pro- 3 Leukocyte (10 /μL) 11,40 5–13 motes pre-B cell differentiation [5, 6]. Neutrophil (10 /μL) 4, 25 2–6, 9 Mutation in the BLNK gene (OMIM # 613502), first Lymphocyte (10 /μL) 5, 26 1, 5–3, 4 identified by Minegishi et al. in 1999 [5], had caused a failure Haemoglobin (g/dl) 11, 86 12–15 of B cell development leading to significantly lower levels of 'rombocyte (10 /μL) 483 142–424 IgG (mg/dl) 81 894± 157 mature B lymphocytes in the peripheral blood. 'ese B cells IgM (mg/dl) 258 92± 35 cannot form plasma cells, resulting in significantly reduced IgA (mg/dl) <5 72± 22 levels (hypogammaglobulinemia) or absence (agamma- Total IgE (IU/ml) 4, 1 2–307 globulinemia) of all immunoglobulin isotypes. 55–79/ Few patients with BLNK defects have been reported up CD3+ T cells ((%)/μL) 92, 1/4844 1900–3600 to date and it is a very rare form of agammaglobulinemia [1]. 11–31/ CD19+ B cells ((%)/μL) 0,05/2,6 Here, we report a child presenting atypically with late-onset 300–1200 XLA clinical findings, high IgM levels at admission, and a 26–49/ CD3+CD4+ T cells ((%)/μL) 59, 3/3119 novel homozygous mutation in the BLNK gene detected by 600–2000 targeted next-generation sequencing (TNGS). CD3+CD8+ T cells ((%)/μL) 29, 3/1541 9–35/300–1300 CD3-CD16+CD56+ NK cells 5, 7/299 5–28/200–1200 ((%)/μL) 2. Case Anti-HBs (mIU/ml) Negative 10–1000 Anti-HAV IgG Negative >0, 9 A 4-year-old boy was admitted with a history of recurrent Anti-CMV IgG (aU/ml) Negative 6–250 respiratory tract infections in the last six months. 'e parents were second-degree consanguineous and family history was unremarkable for PIDs. Physical examination was detected at 4 years of age and AR agammaglobulinemia was normal on admission. Initial immunologic evaluation (BLNK defect) was diagnosed at 6 years of age. 'e patient revealed very low IgG and IgA with very high IgM levels. has been treated with IVIG replacements for 4 years, and an Flow cytometric lymphocyte subsets analysis revealed very excellent response was obtained. To our knowledge, this low CD19+ B cells. Specific IgG antibodies against hepatitis patient with BLNK mutation is the ninth case in the liter- A and B vaccines were both undetectable. Other laboratory ature and the first case to be published from Turkey. 'e tests including leukocyte, lymphocyte, haemoglobin counts, patient is doing very well now and no major infectious liver and kidney function tests, serologic investigations for episodes and autoimmune manifestations were noted up to common viruses, were all normal (Table 1). Abdominal date. ultrasonography revealed mild hepatosteatosis and chest radiography was normal. CD40L level was evaluated on activated Tcells to exclude X-linked hiper IgM due to CD40L 3. Discussion deficiency and it was found to be normal. 'e case with recurrent respiratory infections, hypo- Herein, we present a male patient who admitted with typical gammaglobulinemia, and decreased B cells was diagnosed as XLA clinical findings and was found to have a novel, un- X-linked agammaglobulinemia (XLA) and intravenous identified, homozygous mutation (c.790C> T, p.Gln264Ter) immunoglobulin therapy (IVIG) (0, 4–0,8 g/kg/dose) once a in the BLNK gene. Eight patients with different BLNK gene month was started. Regular IVIG treatment provided IgG defects have been published previously. Five of them had serum levels higher than 400 mg/dl. Targeted next-genera- homozygous, one patient had heterozygous, and two pa- tion sequencing (TNGS) was performed in order to un- tients had compound heterozygous mutations. As far as we derstand the molecular pathology two years after admission know, our patient is the 9th patient with BLNK mutation to pediatric immunology clinic. TNGS workflow based on an reported in the literature and is the first patient reported Ion AmpliSeq Primary Immune Deficiency Research Panel from Turkey [5, 7–11] (Table 2). Two of the previously designed for sequencing 264 PID genes on Ion S5 Se- reported cases were Chinese, two were Arab, and two were quencer demonstrated a homozygous c.790 C>T Turkish. One of the Turkish patients is living in Europe and the second one is being followed up in a university pediatric (p.Gln264Ter) mutation in BLNK gene (Figure 1). 'is novel BLNK mutation was confirmed by Sanger sequencing. clinic in Turkey (2nd case in Table 2) (unpublished data). Analysis of familial segregation revealed that his mother and One patient’s ethnicity could not be learned and the last one father were heterozygous for the mutation. 'e patient’s was Scottish. parents were healthy and had normal concentrations of Children with autosomal recessive agammaglobulinemia serum immunoglobulins and normal number of B cells. present with recurrent bacterial infections, the absence of 'e clinical findings of this patient are similar to typical circulating B cells, and very severe hypogammaglobulinemia XLA patients and he was followed for two years with XLA similar to XLA. Patients are usually symptomatic in the first diagnosis before TNGS gene analysis. Agammaglobulinemia year of life, after the disappearance of maternal IgG, by an Case Reports in Immunology 3 (a) (b) Figure 1: (a) Patient’s BLNK gene sequence analysis images, homozygous c.790 C> T (p.Gln264Ter) mutation in exon 11. (b) His parents’ heterozygous c.790 C> T (p.Gln264Ter) mutation in exon 11. average of 6 months. Autosomal recessive forms of agam- 'e late onset of infections in this case is thought to be due to maglobulinemia have been shown to present a more severe being the first child of the family and very sterile life in the phenotype and earlier onset compared to XLA [2, 7]. infantile period. However, our patient, who was asymptomatic until the age It is known that BLNK defects affect B cell development, of 3.5, was diagnosed with agammaglobulinemia at the age of leading to low levels of mature B lymphocytes in peripheral 4 and was followed up with a relatively mild clinical course. blood; therefore plasma cells cannot be formed, thus causing 4 Case Reports in Immunology Table 2: Reported patients with BLNK protein deficiency. Age at onset Ig levels at Circulating Patient (years), Additional BLNK Infection profile diagnosis (mg/ CD19 B cells (reference) gender, manifestations Mutation dL) (%) ethnicity 8 months, Patient 1 male, Recurrent otitis and Homozygous Intermittent protein (Minegishi et al. Caucasian of pneumonia Undetectable 0.05 c.30 C> A (p.P10P)/ losing enteropathy [5]) Scot/Irish hepatitis C c.47 + 3 A> T ancestry Recurrent respiratory Patient 2 Resolved hepatitis IgG 111 8, female, infections, diarrhea, Homozygous c.367 C> T (Conley et al. with no clear IgA< 6 0.01 Turkish otitis, septic arthritis, (p.R123X) [2]) diagnosis IgM 10 and conjunctivitis Patient 3 (Lagresle- Recurrent otitis and Homozygous 6, male, NA None Undetectable 0 Peyrou et al. pneumonia c.844 C> T (p.R282X) [9]) Chronic Recurrent otitis Patient 4 polyarthritis, Homozygous c.435_436 0.5, male, media, chronic (NaserEddin dermatitis and Undetectable 0 del T CInsA Arab diarrhea, enteroviral et al. [8]) sensorineural (p.E145fs25∗) viremia hearing loss Patient 5 1, female Recurrent diarrhea, Homozygous c.435_436 Arthritis, (NaserEddin (elder sister of otitis media and sino- Undetectable 0 del T CInsA bronchiectasis et al. [8]) P4), Arab pulmonary infections (p.E145fs25∗) IgG 903 Compound No increased IgA 791 Patient 6 (Geier 28, male, Chronic renal heterozygous c328 C> G susceptibility to IgM 27 14 et al. [10]) Turkish insufficiency (pPro110Ala)/c472 infections (selective IgM G> T (pAla158Ser) deficiency) Compound Respiratory Epilepsy, allergic IgG 135 heterozygous c.676 + 1 Patient 7 (Niu 5, female, infections, including rhinitis and IgA< 6 3.5 G> A, exon 9 deletion, Li et al. [11]) Chinese sinusitis, bronchitis, wheezing IgM< 18 c.677_746del, and pneumonia p.R227Kfs ∗ 7 Heterozygous frameshift Recurrent bronchitis, Patient 8 (Niu 2, male, variant c.452_453dup pneumonia, and None Undetectable 3 Li et al. [11]) Chinese CC, (p.T152Pfs ∗ 6), c. acute lymphadenitis 525G> A IgG 81 Homozygous mutation Patient 9 (our 3.5, male, Recurrent respiratory None IgA< 5 0,05 c.790 C> T presented case) Turkish tract IgM 258 (p.Gln264Ter) a significant decrease in all immunoglobulin isotypes. Most of the patients with BLNK defect presented with However, there is no detailed information about the effect of bacterial respiratory tract infections. To prevent these in- BLNK defect on T cell development. A Chinese patient with fections, patients with agammaglobulinemia need lifelong immunoglobulin replacement therapy. Since immuno- BLNK defect was reported to have lower memory CD3+CD4+ and CD3+CD8+ T cells than healthy controls, globulin replacement reduces life-threatening infections, whereas naive T cells were higher levels than controls [11]. patients reach adulthood with regular treatment and follow- Although the cases generally present with low immuno- up, and quality of life of almost all of these cases is very good globulin values and low circulating B cell numbers, a 28- [12]. However, severe infections can also be observed in year-old BLNK patient with only low IgM was reported [10]. some cases. For example, systemic enteroviral infections Contrary to this finding, the IgM level in our patient’s first have been reported in patients previously diagnosed with admission was found to be high as compared to age-related agammaglobulinemia. One child with Igα deficiency, one of normal levels. Our patient was the first patient admitted with the different forms of ARA, had polio due to wild-type high IgM in the literature. After the control and manage- vaccine at the age of 12 months (M.E. Conley and ment of infections under regular IVIG treatment, the pa- V. Howard, unpublished observations), while another child had typical signs of enteroviral infection such as weakness tient’s IgM value decreased to undetectable values during follow-up (Table 3). and dermatomyositis-like syndrome [13]. Another patient Case Reports in Immunology 5 Table 3: Patient’s Ig levels by age. Initial visit Second visit 5-year-old 6-year-old 7-year-old 8-year-old IgG (mg/ 81 (n: 423 (n: 569 (n: 725 (n: 134 (n: 894± 157) 422 (n: 1008± 209) dl) 894± 157) 1008± 209) 1061± 203) 1061± 203) IgM (mg/ 258 (n: <17 (n: <17 (n: <19 (n: 131 (n: 92± 35) 18, 4 (n: 113± 40) dl) 92± 35) 113± 40) 106± 43) 106± 43) IgA (mg/ <5 (n: <27 (n: <28 (n: 6,6 (n: 72± 22) 6, 5 (n: 99± 37) 6, 5 (n: 99± 37) dl) 72± 22) 116± 42) 116± 42) Initiation of IVIG IVIG therapy (IVIG) (0, 5 g/kg/ Treatment — therapy dose) once a month reported by NaserEddin et al. showed skin and joint findings performed the genetic analysis. NEK, ET, AA, GA, and NK as described in patients with BTK deficiency despite regular managed the patient. NK and NEK revised the manuscript. IVIG therapy, and the patient’s peripheral blood was si- All authors read and approved the final manuscript. multaneously found to be positive for enterovirus shown by polymerase-chain reaction [8]. As a different finding, it has Acknowledgments been reported that neutropenia may also accompany BLNK deficiency. A patient with agammaglobulinemia and neu- 'e authors are deeply grateful to the patient and his family tropenia was reported but exact diagnosis could not be for participating in this study. established because of his death due to Pseudomonas sepsis at the age of 16 months, and this patient’s sibling was di- References agnosed as BLNK deficiency after a few years. Contrary to these reported cases, our patient did not have so much [1] T. Smith and C. Cunningham-Rundles, “Primary B-cell im- munodeficiencies,” Human Immunology, vol. 80, no. 6, serious infections and neutropenia was not observed. He is pp. 351–362, 2019. now living without severe infections and complications [2] M. E. Conley, A. Broides, V. 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'is case of mittee,” Journal of Clinical Immunology, vol. 40, no. 1, agammaglobulinemia in a 4-year-old male patient highlights pp. 24–64, 2020. a novel autosomal recessive mutation in BLNK gene. Al- [5] Y. Minegishi, J. Rohrer, E. Coustan-Smith et al., “An essential though recessive BLNK mutations appear to be rare causes role for BLNK in human B cell development,” Science, of agammaglobulinemia (given the small number of re- vol. 286, no. 5446, pp. 1954–1957, 1999. ported cases), they should be considered in B-cell-deficient [6] T. Taguchi, N. Kiyokawa, H. Takenouch et al., “Deficiency of BLNK hampers PLC-gamma2 phosphorylation and Ca2+ children. While our presented child remains stable on influx in- duced by the pre-B-cell receptor in human pre- monthly immunoglobulin therapy, long-term follow-up will B cells,” Immunology, vol. 112, no. 4, pp. 575–582, 2004. be required to determine the outcome of this mutation and [7] M. E. Conley, A. K. Dobbs, D. M. 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LeissPiller et al., “Hy- pomorphic mutations in the BCR signalosome lead to se- Authors’ Contributions lective immunoglobulin M deficiency and impaired B-cell homeostasis,” Frontiers in Immunology, vol. 9, p. 2984, 2018. ET and NEK wrote the manuscript. NEK and GA per- [11] N. Li, J. Wu, Y. Wu et al., “Further delineation of primary formed the immunological experiments. AD and AA B cell immunodeficiency caused by novel variants of the 6 Case Reports in Immunology BLNK gene in two Chinese patients,” Clinical Immunology, vol. 214, Article ID 108387, 2020. [12] I. Yıldırım, E. Topyıldız, R. B. G. Bilgin et al., “X-linked agammaglobulinemia: ınvestigation of clinical and laboratory findings, novel gene mutations and prevention of ınfective complications in long-term follow-up,” American Journal of Clinical and Experimental Immunology, vol. 10, no. 1, pp. 37–43, 2021. [13] Y. Wang, H. Kanegane, O. 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Case Reports in ImmunologyHindawi Publishing Corporation

Published: Jun 10, 2022

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