Identification of a Btk mutation in a dysgammaglobulinemic patient with reduced B cells: XLA diagnosis or not? Simona Graziani a,1 , Gigliola Di Matteo a,1 , Luigi Benini b , Silvia Di Cesare a , Maria Chiriaco a , Loredana Chini a , Marco Chianca a , Fosca De Iorio b , Maria La Rocca a , Roberta Iannini a , Stefania Corrente a , Paolo Rossi a,c , Viviana Moschese a, ⁎ a Department of Pediatrics, University of Rome Tor Vergata, Italy b Department of Gastroenterology, University of Verona, Italy c Division of Immunology and Infectious Diseases, Children’s Hospital Bambino Gesù, Rome, Italy Received 16 April 2008; accepted with revision 28 May 2008 Abstract The identification of a Btk mutation in a male patient with b 2% CD19 + B cells warrants making the diagnosis of X-linked Agammaglobulinemia (XLA). Herein we report the case of a 31 year-old male with a gradual decline of peripheral B lymphocytes and low IgA and IgM but normal IgG levels. His clinical history revealed recurrent respiratory and skin infections, sclerosing cholangitis and chronic obstructive pancreatitis. Molecular studies revealed a novel aminoacidic substitution in Btk protein (T316A). His mother, maternal aunts and a maternal female cousin were heterozygotes for the same Btk mutation and were variably affected with pulmonary emphysema. This is a puzzling case where the patient's clinical history and laboratory findings divorce molecular genetics. Either this case confirms the variable expressivity of XLA disease or the T316A change in Btk SH2 domain is a novel non-pathogenic mutation and another unknown gene alteration is responsible for the disease. © 2008 Elsevier Inc. All rights reserved. KEYWORDS XLA; Btk; Sclerosing cholangitis; Chronic obstructive pancreatitis Introduction X-Linked or Bruton's Agammaglobulinemia (XLA) is an X-linked recessive humoral immunodeficiency disease caused by mutations in the gene coding for the Bruton's Tyrosine kinase (Btk), which is implied in the development of B cells. Mutations of Btk gene cause the incomplete differentiation of B cell precursors to mature B cells or the inefficient expansion of pre-B cells into later B cell stages [1,2]. XLA is characterized by a defect in peripheral blood B lymphocytes (CD19 + b 2%) and very low levels of all classes of immunoglo- bulins, resulting in increased susceptibility to bacterial infections (sinusitis, pneumonia, pyogenic dermatitis, osteo- myelitis) [3–5]. Patients usually become symptomatic in ⁎ Corresponding author. Department of Pediatrics, Policlinico Tor Vergata, Viale Oxford 81, 00133 Rome, Italy. Fax: +39 06 20900530. E-mail address: moschese@med.uniroma2.it (V. Moschese). 1 SG and GDM equally contributed to this work. 1521-6616/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.clim.2008.05.012 available at www.sciencedirect.com www.elsevier.com/locate/yclim Clinical Immunology (2008) 128, 322–328