Increased PI3K/Akt activity and deregulated humoral immune response in human PTEN deficiency

To the Editor: Autosomal-dominant germline mutations in PTEN are associated with phosphate and tensin homologue deleted on chromosome 10 (PTEN) hamartoma tumor syndromes (PHTS), including Cowden syndrome, characterized by hamartomas, malignant tumors, macrocephaly, and neurodevelopmental delay.1 Imm...

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Published in:Journal of allergy and clinical immunology 2016-12, Vol.138 (6), p.1744-1747.e5
Main Authors: Driessen, Gertjan J., MD, PhD, IJspeert, Hanna, PhD, Wentink, Marjolein, MD, Yntema, Helger G., MD, PhD, van Hagen, P. Martin, MD, PhD, van Strien, Arthur, MSc, Bucciol, Giorgia, MD, Cogulu, Ozgur, MD, Trip, Margreet, MD, Nillesen, Willy, MD, PhD, Peeters, Els A., MD, PhD, Pico-Knijnenburg, Ingrid, BSc, Barendregt, Barbara H., BSc, Rizzi, Marta, MD, PhD, van Dongen, Jacques J., MD, PhD, Kutukculer, Necil, MD, PhD, van der Burg, Mirjam, PhD
Format: Article
Language:English
Subjects:
Age
Allergy and Immunology
Immunoglobulins
Infections
Mutation
Patients
Studies
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Summary:To the Editor: Autosomal-dominant germline mutations in PTEN are associated with phosphate and tensin homologue deleted on chromosome 10 (PTEN) hamartoma tumor syndromes (PHTS), including Cowden syndrome, characterized by hamartomas, malignant tumors, macrocephaly, and neurodevelopmental delay.1 Immunodeficiency has recently been reported in PHTS,2 but the mechanism of disease is not clear. [...]we performed a detailed study of the peripheral B-cell development of 9 patients with PHTS, to explore the role of phosphatidyl inositol 3-kinase (PI3K)/Akt signaling in the humoral immune response in these patients (details are described in this article's Methods section in the Online Repository at www.jacionline.org). Sex Age (y) PTEN mutation Clinical diagnosis B cells[low *] T cells[low *] CD4[low *] CD8[low *] CD4/CD8 ratio NK cells[low *] IgG (g/L) IgA (g/L) IgM (g/L) 1 F 43 c.389G>C p. Arg130Pro PHTS, hypogammaglobulinemia 0.16 (0.1-0.4) 1.37 (0.7-2.1) 0.58 (0.3-1.4) 0.71 (0.2-1.2) 0.82 0.06 (0.09-0.6) 4.7 (6.0-12.3) C p.Arg130Pro PHTS, hypogammaglobulinemia 0.38 (0.2-2.1) 1.18 (0.8-3.5) 0.53 (0.4-2.1) 0.51 (0.2-1.2) 1.03 0.26 (0.07-1.20) 5.5 (6.0-12.3) 0.16 (0.3-1.6) 0.65 (0.5-2.0) 3 M 6 c.302T>C p.Ile101Thr PHTS, hypogammaglobulinemia 0.41 (0.2-1.6) 1.77 (0.7-4.2) 0.93 (0.3-2.0) 0.68 (0.3-1.8) 1.38 0.36 (0.09-0.9) 1.5 (4.0-11.0) 0.07 (0.1-1.6) 0.69 (0.5-1.8) 4 M 6 c.464A>G p.Tyr155Cys PHTS 1.01 (0.2-1.6) 3.20 (0.7-4.2) 1.69 (0.3-2.0) 0.95 (0.3-1.8) 1.78 1.29 (0.09-0.9) 9.0 (4.0-11.0) 0.80 (0.3-1.6) 0.90 (0.5-1.8) 5 M 37 c.464A>G p.Tyr155Cys PHTS 0.18 (0.1-0.4) 1.01 (0.7-2.1) 0.68 (0.3-1.4) 0.28 (0.2-1.2) 2.41 0.43 (0.09-0.6) 14.0 (7.0-16.0) 2.60 (0.7-4.0) 1.80 (0.4-2.3) 6 M 8 c.103A>G p.Met35Val PHTS 0.76 (0.2-1.6) 2.25 (0.7-4.2) 1.25 (0.3-2.0) 0.85 (0.3-1.8) 1.48 0.16 (0.09-0.9) 10.0 (4.0-11.0) 0.70 (0.3-2.0) 0.50 (0.5-2.0) 7 M 7 c.877G>T p.Gly293X PHTS 0.91 (.2-2.6) 1.50 (0.7-4.2) 0.97 (0.3-2.0) 0.42 (0.3-1.8) 2.32 0.33 (0.09-0.9) 7.0 (4.0-11.0) 0.50 (0.3-2.0) 1.70 (0.5-2.0) 8 F 18 c.388C>T p.Arg130X PHTS 0.20 (0.1-0.4) 1.28 (0.7-2.1) 0.78 (0.3-1.4) 0.23 (0.2-1.2) 1.83 0.11 (0.09-0.6) 12.4 (7.0-16.0) 0.82 (0.7-4.0) 1.68 (0.4-2.3) 9 F 32 c.369C>G p.His123Gln PHTS 0.23 (0.1-0.4) 1.07 (0.7-2.1) 0.70 (0.3-1.4) 0.31 (0.2-1.2) 2.27 0.12 (0.09-0.6) 13.7 (7.0-16.0) 1.12 (0.7-4.0) 1.58 (0.4-2.3) Table E1 Characteristics of patients with PHTS Mutation nomenclature is according to HGVS guidelines (http://www.hgvs.org).
ISSN:0091-6749
1097-6825
DOI:10.1016/j.jaci.2016.07.010