A novel immunodeficiency syndrome associated with partial trisomy 19p13

Abstract

Background: Subtelomeric deletions and duplications may cause syndromic disorders that include features of immunodeficiency. To date, no phenotype of immunological pathology has been linked to partial trisomy 19. We report here on two unrelated male patients showing clinical and laboratory signs of immunodeficiency exhibiting a duplication involving Chromosome 19p13.

Methods: Both patients underwent a detailed clinical examination. Extended laboratory investigations for immune function, FISH and array comparative genome hybridization (CGH) analyses were performed.

Results: The reported patients were born prematurely with intrauterine growth retardation and share clinical features including neurological impairment, facial dysmorphy and urogenital malformations. Array CGH analyses of both patients showed a largely overlapping terminal duplication affecting Chromosome 19p13. In both affected individuals, the clinical course was marked by recurrent severe infections. Signs of humoral immunodeficiency were detected, including selective antibody deficiency against polysaccharide antigens in patient 1 and reduced IgG1, IgG3 subclass levels and IgM deficiency in patient 2. Class-switched B memory cells were almost absent in both patients. Normal numbers of T cells, B cells and natural killer cells were observed in both boys. Lymphocytic proliferation showed no consistent functional pathology, however, function of granulocytes and monocytes as assessed by oxidative burst test was moderately reduced. Moreover, natural killer cytotoxicity was reduced in both patients. Immunoglobulin substitution resulted in a decreased number and severity of infections and improved thriving in both patients.

Conclusions: Partial trisomy 19p13 represents a syndromic disorder associating organ malformation and hitherto unrecognised immunodeficiency.

Keywords: 19p; array CGH; hypogammaglobulinemia; subtelomeric microduplication and microdeletion; syndrome with primary immunodeficiency (PID).

Figure 1

Images of phenotypical details. (A) facial dysmorphy and (B) perineal hypospadia in patient 1. (C) facial dsymorphy including long philtrum and narrow lips and (D) syndactylia of right third/forth toes in patient 2.

Figure 2

Immunological and genetic phenotype. Despite normal B lymphocyte cell counts, IgD+CD27 and IgD-CD27 memory B cells were nearly absent in patient 1 (A) as well as in patient 2 (B). FISH analysis of patient 1 showed partial trisomy 19 with additional material from chromosome 19p on the short arm of chromosome 14 (C). FISH analysis of patient 2 revealed an unbalanced translocation from chromosome 19 to chromosome 16 (D). A schematic display of Chromsome 19 with an illustration of the duplicated regions in patients 1 and 2, respectively (E).