Atypical case of X‐linked agammaglobulinemia diagnosed at 45 years of age

Abstract

X-linked agammaglobulinemia (XLA) is a humoral inherited immunodeficiency, and mutations in Bruton's tyrosine kinase (BTK) gene have been identified to be responsible for XLA. We describe an atypical Japanese case of XLA diagnosed at 45 years of age. We think that it is the oldest case in Japan so far.A 45-year-old man was referred to our hospital because of recurrent bacterial infections. His family history demonstrated no Correspondence: Tao Fujioka, MD, Fig. 1 (a) Flow cytometric detection of BTK in monocytes from a normal donor and the patient. The closed and dashed lines indicate staining with anti-BTK (48-2H) and control immunoglobulin (Ig) G1 monoclonal antibodies in CD14-gated monocytes, respectively. (b) The alignment of the BTK family of tyrosine kinases (human ITK, TEC, BTK and BMX). Amino acids conserved in all four proteins are shown in colored boxes. Arrows indicate L32, T33, R525 and Y598, which are mutated in the adult-onset X-linked agammaglobulinemia patient.episodes of recurrent infections. He had become febrile once a month in his childhood. He was hospitalized at 8 years of age for about 1 year to investigate, however a clear diagnosis was not determined. The frequency of fever decreased to once a year after he turned 15 years old.At the age of 42 years, he was admitted because of fever and headache, and was diagnosed as having bacterial meningitis. Streptococcus anginosus was detected by blood and cerebrospinal fluid culture examination. After he was discharged he suffered from bacterial meningitis, coxitis and spondylitis. Because of recurrent serious bacterial infections, immunological studies were done at the age of 45 years. Laboratory tests were as follows: white blood cells, 4800/mL (neutrophils 62.6%, eosinophils 3.3%, basophils 0.6%, monocytes 12.4%, and lymphocytes 21.1%); hemoglobulin, 14.7 g/dL; platelets, 239 ¥ 10 3 /mL; serum immunoglobulin (Ig) G, IgA and IgM levels, 679 (normal range: 870-1700), 570 (110-410), and 17 (35-220) mg/dL, respectively. Serum IgE and allergen-specific IgE for cedar pollen and alternaria was detected. The percentage of T cells and B cells in peripheral blood were 85% and 1%, respectively. Flow cytometric analysis of the peripheral monocytes using the anti-BTK antibody showed BTK deficiency (Fig. 1a). The patient's BTK gene was sequenced and disclosed a nonsense mutation (637G>T, E169X) in exon 6, which has not been reported in the BTK database (http://bioinf.uta.fi/BTKbase/).There have been several reports of atypical cases of XLA that were diagnosed in adulthood. 1-3 In those cases, Ig levels were moderately low and the patients did not suffer from any severe infection during their childhood. Kanegane et al. 1 reported that higher concentrations (>300 mg/dL) of serum IgG were evident in the cases diagnosed among adults. Genotypephenotype correlations in XLA have been studied, 4,5 but have not been established clearly. classified the mutations of Spanish XLA patients according to their severity on the basis of the proposal by Conley and Howard 5 to...

Practice parameter for the diagnosis and management of primary immunodeficiency

“…304,305 Infections can be mild or occur late in life. 314,315 In all cases the number of peripheral blood CD19 1 B cells is low. Discordant phenotypes can also be observed in siblings and families with identical BTK mutations.…”

“…Some patients are not recognized to have XLA or other forms of agammaglobulinemia until after 5 years of age despite the presence of frequent infections and recurrent antibiotic use; others have a milder clinical phenotype and are recognized only later in life. 314,315 The physical examination of patients with agammaglobulinemia usually reveals absence of lymph nodes and tonsils distinct from other forms of antibody deficiency. Small or absent tonsils can also be seen in patients with some CIDs and other congenital agammaglobulinemias.…”

Research-based flow cytometry assays for pathogenic assessment in the human B-cell biology of gene variants revealed in the diagnosis of inborn errors of immunity: a Bruton’s tyrosine kinase case-study

“…Classical male XLA patients present severe agammaglobulinemia due to the severe reduction or absence of peripheral B cells, and experience frequent infections ( 7 ). However, BTK variants associated with atypical XLA case presentations have been reported, in patients with normal: IgG levels ( 21 ), selective IgM deficiency ( 22 ) with a leaky phenotype (in a Japanese family) ( 23 ), a diagnosis in adulthood but with a history of recurrent infections ( 24 ) and with impaired polysaccharide responsiveness without marked hypogammaglobulinemia ( 25 ). Although the gene variant present in our patient (R562Q) had not been previously described, other variants have been reported in the same residue as being probably pathogenic (R562W, R562L, R562P) ( 26 – 30 ).…”

Case Report: A Case of X-Linked Agammaglobulinemia With High Serum IgE Levels and Allergic Rhinitis

“…Besides, IgE mediated allergy have been reported in two different studies ( 17 , 18 ) describing two XLA patients with a severe course of disease, low serum immunoglobulin isotypes except for normal IgE levels, and hypersensitivity to several allergens. Recently, another study ( 19 ) identified an atypical case of XLA diagnosed at the age of 45, characterized by CD19+ B cells 1%, mild hypogammaglobulinemia and detection of serum IgE and allergen-specific IgE for cedar pollen and alternaria.…”