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• W2017101919 abstract "To the Editor: X-linked agammaglobulinemia (XLA) was first described by Bruton in 1952 as an X-linked recessive disorder characterized by recurrent bacterial infections, usually presenting in the first few years of life. Immunologic testing typically demonstrates a profound decrease in Ig levels of all isotypes and a marked decrease in the number of B cells. The gene for XLA has been identified and mapped to the Xq21.3-q22. It was known before the discovery of the gene that there was wide variability in the clinical presentation, even within the members of the one family who were likely to be carrying the same gene.1.Schroeder H.W Primary antibody deficiencies.in: Rich R.R Fleisher T.A Shearer W.T Kotzin B.L Schroeder jr., H.W Clinical immunology principles and practise. 2nd ed. Mosby, New York2001: 34.5-34.6Google Scholar In this report we present a family with Bruton's XLA in whom the index case presented with recurrent bacterial infections at the age of 6 years. At that time the maternal grandfather was being treated with replacement Ig for common variable immunodeficiency after presenting in his 60th year with recurrent pneumococcal infection and normal gamma globulin levels that subsequently decreased. The 6-year-old boy was found to have a mutation in exon 10 of the BTK gene. The same mutation was found in the maternal grandfather and in a 1-year-old asymptomatic brother. This case describes the oldest patient in the literature to present with immunodeficiency associated with a BTK gene mutation and highlights the heterogeneity of presentation and phenotype that can occur within the same family. We describe a family of patients with XLA with phenotypic variability. The index patient presented at age 6 years with complicated pneumococcal pneumonia. This required prolonged admission to hospital, intravenous antibiotics, thoracostomy, and drainage of an empyema. He had a history of recurrent chest and sinus infections, none of which required hospitalization. Investigations showed panhypogammaglobulinemia (Table I). Lymphocyte studies showed absence of CD19+ cells. Other immune function studies were normal. DNA sequencing of his BTK gene showed a point mutation at gene position 994 showing a substitution of C to T. This results in a change from arginine to tryptophan at amino acid residue 288 (994C > T [R228W]), thus confirming the diagnosis of XLA.Table IImmunoglobulin levelsBrother 1, age 6 yBrother 2, age 1 yGrandfather, age 56 yGrandfather, age 58 yTotal IgG1.01 (>8.6 g/L)1.08 (>2.08 g/L)10.2 (7-14 g/L)4.29 (7-14 g/L) IgG10.51 (>4.2 g/L)1.37 (>1.84 g/L)Not tested3.2 (>4.2 g/L) IgG24.2 (>1.4 g/L)0.43 (>0.35 g/L)Not tested0.77 (>1.4 g/L) IgG30.09 (>0.63 g/L)0.05 (>0.08 g/L)Not tested0.63 (>0.28 g/L) IgG40.03 (>0.4 g/L)0.052 (>0.007 g/L)Not tested0.11 (>0.08 g/L)IgA<0.07 (>0.6 g/L)<0.007 (>0.17 g/L)<0.07 (>0.7 g/L)<0.07 (>0.7 g/L)IgM0.24 (>0.42 g/L)0.07 (>0.2 g/L)0.52 (>0.3 g/L)0.14 (>0.5 g/L)Immunoglobulins and subclasses measured by rate nephelometry (Beckman Coulter Image Immunochemistry System, Beckman Coulter, Sydney, Australia).Numbers in parentheses indicate lower limit of reference ranges. Open table in a new tab Immunoglobulins and subclasses measured by rate nephelometry (Beckman Coulter Image Immunochemistry System, Beckman Coulter, Sydney, Australia). Numbers in parentheses indicate lower limit of reference ranges. He was commenced on intravenous Ig (Intragam P, CSL) replacement treatment. He has not had recurrence of clinical chest infection but has required surgery for chronic sinus disease. His 1-year-old asymptomatic brother was investigated and found to be profoundly panhypogammaglobulinemic (Table I), and he was also commenced on intravenous Ig (Intragam P, CSL) replacement therapy. Genetic testing in the brother showed the same genetic mutation in the BTK gene as found in the index case. The maternal grandfather was diagnosed with common variable immunodeficiency at the age of 59 years after a long history of recurrent infections. His history before the diagnosis included 16 episodes of pneumonia to the age of 21 years, with childhood bronchiectasis and a lobectomy at age 9 years. He had frequent episodes of pneumonia throughout his adult life. He had an episode of spontaneous bacterial peritonitis at age 48 years; this was in association with heavy alcohol intake and possible alcoholic liver disease. He had an episode of pneumococcal diskitis at age 56 years. He had Igs tested with this episode (Table I). At age 58 years he had further complicated pulmonary infections, which resulted in a pneumonectomy. His Ig levels were repeated and showed panhypogammaglobulinemia as outlined in Table I. His total lymphocyte count was 0.5 (normal, 1 to 4), and subsequent lymphocyte studies showed absence of CD19+ cells. He was commenced on intravenous Ig replacement (Intragam P, CSL) and has remained relatively well since. Molecular studies of his BTK gene were undertaken after the diagnosis of XLA in his grandson, and these showed that he carried the same BTK gene mutation as his 2 grandsons. Genomic DNA was obtained from whole blood. All 19 exons of the BTK gene, including the exon-intron boundaries, were individually amplified. Primer sequences were based on Conely et al.2.Conely M.E Fitch-Hilgenberg M.E Cleveland J.L Parolini O Rohrer J Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.Hum Mol Genet. 1994; 3: 1751-1756Crossref PubMed Scopus (82) Google Scholar PCR was carried out in a 50 μL volume containing 2.5 μL of DNA, 37.5 pmol of each primer (Sigma Aldridge, Sydney, Australia), 0.25 mmol/L deoxynucleotide triphosphate (Astral Scientific, Sydney, Australia), 1× PCR buffer (Applied Biosystems, Sydney, Australia), 2.5 mmol/L MgCl2 (Applied Biosystems), and 1 U of AmpliTaq Gold Polymerase (Applied Biosystems). PCR products were purified by polyethylene glycol precipitation before cycle sequencing kit (Applied Biosystems) with an automated ABI373 DNA sequencer. Detected mutations were confirmed by sequencing in the opposite direction. In this report we describe a family spanning 3 generations who were confirmed to have a mutation in the BTK gene. The diagnosis of common variable immunodeficiency in the grandfather was made at the age of 58 years, although he had been symptomatic for many years. Previously a diagnosis of selective IgA deficiency had been made, because the IgG and IgM levels were normal. His 6-year-old grandson was diagnosed with XLA more than 1 year later when he presented with recurrent infections. This resulted in increased awareness and early investigation of his 1-year-old brother, who also had markedly low IgG. The increased awareness also prompted further investigation of the grandfather. The mutation identified in the family in exon 10 resulted in a nucleotide change from C to T at nucleotide position 994 of the BTK gene. This resulted in an arginine being substituted for a tryptophan at amino acid residue 288 (994C>T (R228W)). This mutation has previously been associated with a large Dutch XLA pedigree whose affected members exhibit heterogeneity in their clinical and immunologic phenotype.3.Bradley L.A Sweatman A.K Lovering R.C Jones A.M Morgan G Levinsky R.J et al.Mutation in the X linked agammaglobulinaemia gene, BTK, using single strand conformation polymorphism analysis.Hum Mol Genet. 1994; 3: 79-83Crossref PubMed Scopus (92) Google Scholar By x-ray crystallography and modeling of the Src/SH2 domain, it has been suggested that this domain forms a socket, which can bind specific phosphorylated tyrosine residues. The mutation R288W can be predicted to severely disrupt phosphotyrosine binding to the SH2 domain, disrupting the functional activity of BTK. The late presentation of the grandfather might imply that binding of BTK to Src through the SH2 domain might not be necessary for full function of the protein. Phenotypic variation within a 3-generation family has been previously described.4.Kornfeld S.J Haire R.N Strong S.J Brigino E.N Tang H Sung S.J et al.Extreme variation in X-linked agammaglobulinaemia phenotype in a three generation family.J Allergy Clin Immunol. 1997; 100: 702-706Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar They described a 51-year-old man with recurrent sinusitis and sporadic pneumonia who was confirmed to have a mutation resulting in a premature stop codon in BTK. The index patient was also initially diagnosed with isolated IgA deficiency, but when he was reinvestigated years later, he was found to be panhypoglobulinemic. On review of family members there was marked phenotypic variation within affected members confirmed to have the same mutation. Despite the establishment of an XLA mutation registry BTKbase (http://www.uta.fi/mut/bioinfo/BTKbase) in 1994,5.Vihinen M Brandau O Branden L.J Kwan S.P Lappalainen I Lester T et al.BTKbase, mutation database for X-linked agammaglobulinaemia (XLA).Nucl Acids Res. 1998; 26: 242-247Crossref PubMed Scopus (71) Google Scholar there have been no clear genotype-phenotype correlations established. Other factors such as infection exposures have been postulated as possible reasons for phenotypic variation. However, family members are likely to be exposed to similar infections, and older family members are less likely to have received frequent antibiotics in their youth, making this explanation less plausible. Other possible explanations for the phenotypic variability are interacting genetic factors including mannose-binding lectin variant alleles. A previous study has shown that the severity of lung disease in patients with cystic fibrosis can be associated with heterogeneity of the mannose-binding lectin,6.Garred P Pressler T Madsen H.O Frederiksen B Svejgaard A Hoiby N et al.Association of mannose binding lection heterogeneity with severity of lung disease and survival in cystic fibrosis.J Clin Invest. 1999; 104: 431-437Crossref PubMed Scopus (406) Google Scholar and several studies have looked at the risk of invasive pneumococcal disease and MBL genotype and have shown an increased susceptibility in patients who are MBL homozygotes.7.Roy S Knox K Segal S Griffiths D Moore C.E Welsh K.I et al.MBL genotype and risk of invasive pneumococcal disease: a case control study.Lancet. 2002; 359: 1569-1573Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar Summerfield et al8.Summerfield J.A Ryder S Sumiya M Thursz M Gorchein A Monteil M.A Turner M.W et al.Mannose binding protein gene mutations associated with unusual and severe infections in adults.Lancet. 1995; 345: 886-889Abstract PubMed Google Scholar have also reported a patient aged 56 years who presented with cryptosporidial diarrhea and was found to have MBL deficiency and isolated IgA deficiency. Factors such as this might be playing a role in the phenotypic variability in this and other families with XLA. This grandfather showed evidence of delayed onset to measurable hypogammaglobulinemia; however, he had a clear life-long history of infections that might be associated with Ig deficiency. His diagnosis was delayed because of lack of measurable gamma globulin deficiency. It raises the question about whether earlier testing for B-cell numbers or mutations in the BTK gene might have altered his treatment or subsequent life course. This patient also highlights the value of measuring Ig subclasses and specific antibody responses in patients with a suggestive history of immunodeficiency. Selective IgA deficiency might be associated with IgG2 subclass deficiency and greater risk of infection, despite normal total IgG levels. Patients with an IgG2 subclass deficiency might be unable to produce antibody to polysaccharide antigens such as pneumococcus. This ability can be tested by immunization with the currently available pneumococcal vaccinations, with levels of pneumococcal-specific antibody measured before and after vaccination. Antibody-specific responses can also be measured by using protein antigens such as tetanus toxoid and Haemophilus influenzae.9.Paul M.C Shearer W.T Approach to the evaluation of the immunodeficiency patient.in: Rich R.R Fleisher T.A Shearer W.T Kotzin B.L Schroeder Jr., H.W Clinical immunology principles and practice. 2nd ed. Mosby, New York2001: 33.1-33.11Google Scholar These additional measurements can clearly be of benefit in patients with a clinical history of recurrent infections in whom the total Ig levels might be normal. In summary, we present a set of cases reinforcing the absence of genotype phenotype correlation in patients with identical mutations in the BTK gene and highlight that late presentation of the disease might occur. XLA is not restricted to presentation in childhood, and patients with a characteristic clinical history and immunologic findings should be screened for this disease." @default.
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• W2017101919 title "Phenotypic variability: clinical presentation between the 6th year and the 60th year in a family with X-linked agammaglobulinemia" @default.
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