Printer Friendly

X-linked agammaglobulinemia - first case with Bruton tyrosine kinase mutation from Pakistan.

Byline: Samreen Kulsom Zaidi, Sonia Qureshi and Farah Naz Qamar


X-linked agammaglobulinemia (XLA) is a primary immunodeficiency with more than 600 mutations in Bruton tyrosine kinase (Bkt) gene which are responsible for early-onset agammaglobulinemia and repeated infections. Herein we present a case of a 3-year-old boy with history of repeated diarrhoea and an episode of meningoencephalitis with hemiplegia. The workup showed extremely low levels of immunoglobulin with low CD+19 cells. Genetic analysis showed Btk mutation 18 c.1883delCp.T628fs. To the best of our knowledge this is the first report of a case of XLA confirmed by molecular technique from Pakistan.

Keywords: Bruton type agammaglobulinemia, Bruton tyrosine Kinase mutation, Whole exome sequencing, Diarrhoea.


X-linked agammaglobulinemia (XLA) / hypogammaglobulinemia, also known as Bruton's agammaglobulinemia is a prototype of humoral immunodeficiency first described by Bruton in 1952.1 It is an uncommon congenital disease and is the major primary immunodeficiency recognised in childhood. As an x-linked recessive disorder, the incidence rate of XLA is around 0.5/100,000.2 XLA is caused by mutations in the Bruton tyrosine kinase (Bkt) gene. Patients classically show <2% of the peripheral B cells and decreased levels of all immunoglobulins3 that influence the affected patients to repeated, severe bacterial infections, principally invasive extracellular pyogenic organisms.4 The most common presenting problems are bronchiectasis, recurrent pneumonia and recurrent upper respiratory tract infections, including sinusitis, otitis media and pharyngitis. Btk mutation also plays a key role in signal transduction of pre-B-cell receptor (BCR).

In one case report, it was noted that XLA is also associated with precursor B-cell acute lymphoblastic leukaemia, which is the most common malignancy in children.5 XLA is caused by 600 different mutations in the Bruton tyrosine kinase (Bkt) gene. The Bkt gene is mapped on X chromosome at Xq21.3-Xq22. It has five domains (PH, TH, SH3, SH2, and TK) and XLA is caused by mutation in all these five structural domains.6 Herein, we report a case of a child with repeated diarrhoea since the age of eighteen months and diagnosed to have XLA with Btk mutation on gene sequencing.

Case Report

A 3-year-old boy presented to the Emergency Department at Aga Khan University Hospital in the month of January 2013 with complaints of diarrhoea and fever for 3 days. The child had a significant past history with recurrent diarrhoea since the age of eighteen months. For this complaint, he was treated by multiple doctors with oral and intravenous antibiotics and usually got relief for few days before becoming symptomatic again. One year prior to presenting at our department, he had been hospitalised for one month due to meningoencephalitis which resulted in right-sided hemiplegia. He was treated with intravenous antibiotics and physiotherapy. Family history was also remarkable. He was born to consanguineous parents and has three sisters and two brothers, alive. One brother was treated for tuberculosis (TB). Two elder brothers had died in infancy, one due to diarrhoea and the other due to pneumonia.

On examination his height and weight were below the fifth percentile, was moderately dehydrated, and was also anaemic. No lymphadenopathy or enlarged tonsils were noted. Systemic examination showed protuberant abdomen with no visceromegaly. He had decreased power and tone in the right upper and lower limbs. Laboratory investigations showed normal absolute neutrophil count and absolute lymphocyte count, and hypokalaemia with normal renal function. He was also screened for TB due to its endemicity in our region and history of contact but the result was negative. Due to history of repeated infections and family history of male deaths, there was a strong suspicion of immunodeficiency. Evaluation showed markedly low immunoglobulins: IgG: <0.7, IgM: <0.08, and IgA: 400 mg/kg every 3 weeks) is more effective than low-dose (<200mg/kg) in patients with XLA.14 In our patient we have given immunoglobulins every 3-4 weeks. His serum IgG levels were also monitored and sustained above 5 g/L. These therapies are effective; nevertheless they are costly and non-curative.

There is no definitive cure for XLA, yet the likelihood of using gene-corrected haematopoietic stem cells to complement the immune defects in mouse models has been studied. It may be hopeful to initiate stem cell-based therapy for XLA using gene-corrected autologous haematopoietic stem cells.15


Flow cytometric assessment of Btk expression in monocytes may set up a speedy and sensitive approach for recognition of XLA patients and female carriers, and support the clinicians to execute IVIG replacement therapy in an appropriate manner which might considerably decline the incidence of complications and the death rate.


We are grateful to The Jeffrey Modell Foundation and Dr. Raif and his team from the Immunology Division, Boston Children's Hospital, for their support in accomplishment of molecular testing.

Competing Interests: All the authors declare that they have no competing interests.


1. Bruton OC. Agammaglobulinemia. Pediatrics.1952; 9:722-8.

2. Vihinen M, Mattsson PT, Smith CI. Bruton tyrosine kinase (BTK) in X-linked agammaglobulinemia (XLA). Front Biosci. 2000 Dec 1;5:D917-28. Front Biosci 2000; 5:D917-28.

3. Garcia-Garcia E, Staines-Boone AT, Vargas-Hernandez A, Gonzalez-Serrano ME, Carrillo-Tapia E, Mogica-Martinez D, et al. Clinical and mutational features of X-linked agammaglobulinemia in Mexico. Clin Immunol. 2016; 165:38-44.

4. Usui K, Sasahara Y, Tazawa R, Hagiwara K, Tsukada S, Miyawaki T, et al. Recurrent pneumonia with mild hypogammaglobulinemia diagnosed as X-linked agammaglobulinemia in adults. Respir Res. 2001; 2:188-92.

5. Hoshino A, Okuno Y, Migita M, Ban H, Yang X, Kiyokawa N, et al. X-linked agammaglobulinemia associated with B-precursor acute lymphoblastic leukemia. J Clin Immunol. 2015; 35:108-11.

6. Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 1993; 72:279-90.

7. Sideras P, Smith CI. Molecular and cellular aspects of X-linked agammaglobulinemia. Adv Immunol. 1995; 59:135-223.

8. Ohta Y, Haire RN, Litman RT, Fu SM, Nelson RP, Kratz J, et al. Genomic organization and structure of Bruton agammaglobulinemia tyrosine kinase: localization of mutations associated with varied clinical presentations and course in X chromosome-linked agammaglobulinemia. Proc Natl Acad Sci U S A. 1994; 91:9062-6.

9. Mohamed AJ, Yu L, Backesjo CM, Vargas L, Faryal R, Aints A, et al. Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 2009; 228:58-73.

10. Tzeng SR, Pai MT, Lung FD, Wu CW, Roller PP, Lei B, et al. Stability and peptide binding specificity of Btk SH2 domain: molecular basis for X-linked agammaglobulinemia. Protein Sci. 2000; 9:2377-85.

11. Bayrakci B, Ersoy F, Sanal O, Kilic S, Metin A, Tezcan I. The efficacy of immunoglobulin replacement therapy in the long-term follow-up of the B-cell deficiencies (XLA, HIM, CVID). Turk J Pediatr. 2005; 47:239-46.

12. Conley ME, Fitch-Hilgenberg ME, Cleveland JL, Parolini O, Rohrer J. Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase. Hum Mol Genet. 1994; 3:1751-6.

13. Merchant RH, Parekh D, Ahmad N, Madkaikar M, Ahmed J. X linked agammaglobulinemia: a single centre experience from India. Indian J Pediatr. 2014; 81:92-4. Indian J Pediatr. 2014; 81:92-4.

14. Liese JG, Wintergerst U, Tympner KD, Belohradsky BH. High- vs low-dose immunoglobulin therapy in the long-term treatment of X-linked agammaglobulinemia. Am J Dis Child. 1992; 146:335-9.

15. Howard V, Myers LA, Williams DA, Wheeler G, Turner EV, Cunningham JM, et al. Stem cell transplants for patients with X-linked agammaglobulinemia. Clin Immunol. 2003; 107:98-102.
COPYRIGHT 2017 Asianet-Pakistan
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2017 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Publication:Journal of Pakistan Medical Association
Date:Mar 31, 2017
Previous Article:A huge Thornwaldt's cyst causing hearing loss in an adult patient.
Next Article:Cubital tunnel syndrome secondary to gouty tophi: A case report.

Terms of use | Privacy policy | Copyright © 2022 Farlex, Inc. | Feedback | For webmasters |