Combined microdeletions and CHD7 mutation causing severe CHARGE/DiGeorge syndrome: clinical presentation and molecular investigation by array-CGH

Abstract

Phenotypic variation in CHARGE syndrome remains unexplained. A subcategory of CHARGE patients show overlapping phenotypic characteristics with DiGeorge syndrome (thymic hypo/aplasia, hypocalcemia, T-cell immunodeficiency). Very few have been tested or reported to carry a mutation of the CHD7 (chromodomain helicase DNA-binding domain) gene detected in two-thirds of CHARGE patients. In an attempt to explore the genetic background of a severe CHARGE/DiGeorge phenotype, we performed comparative genomic array hybridization in an infant carrier of a CHD7 mutation. The high-resolution comparative genomic array hybridization revealed interesting findings, including a deletion distal to the DiGeorge region and disruptions in other chromosomal regions of genes implicated in immunological and other functions possibly contributing to the patient's severe phenotype and early death.

CHARGE syndrome: a review of the immunological aspects

“…For 23 of 26 (88%) patients, T-cell lymphopenia was concomitant with T-cell dysfunction. 14,17,18,20,[22][23][24][25][26][27][28][29][30][31]33,[35][36][37] In our collected cohort, B-and/or NK-cell numbers were reported in only 29 of 59 patients, and of these 29 patients, 1 had low B-cell numbers, 1 had high B-cell numbers, 1 had low NK-cells numbers and 3 had high NK-cell numbers. The reported B-and NK-cells numbers of other patients were normal.…”

“…14,[16][17][18][19][20][21][22] Three patients had features resembling Omenn syndrome, a form of severe combined immune deficiency, characterized by autoimmune-like features and macular skin rash due to the formation of abnormal, autoreactive T cells. 18,23 Other severe presentations included a patient with recurrent oral candidiasis, recurrent severe infections, and septic shock due to colonization with multiresistant species of Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Acinobacter (Janda et al, 22 Table 1B); another patient with severe general dermatitis and ulcers of the colon (Boudny et al, 24 Table 1B); and a patient with CHARGE association and T-cell deficiency with a chronic viral infection of the gut (Wood et al, 25 Table 1C). …”

“…T-cell lymphopenia in our collected cohort was associated with thymic aplasia or hypoplasia in 21 of 22 (95%) patients. [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] T-cell function by response on mitogens was available for 28 of 59 patients and of these 28 patients 24 (86%) had a low or absent response on mitogen. For 23 of 26 (88%) patients, T-cell lymphopenia was concomitant with T-cell dysfunction.…”

“…14,17,[22][23][24][25][26][27][28][29]35,36 Thirteen of 33 (39%) patients with known immunoglobulin levels had IgG deficiency and 2 of these patients had received immunoglobulin replacement therapy. 14,[16][17][18][22][23][24][25][26][27][28][29]38 Of these 13 patients with IgG deficiency, 6 had recurrent or chronic infections and 1 had absent specific antibody responses. 14,[16][17][18]22,24,25 Isolated immunoglobulin deficiencies were rarely reported in CHARGE syndrome.…”

“…14,[16][17][18][22][23][24][25][26][27][28][29]38 Of these 13 patients with IgG deficiency, 6 had recurrent or chronic infections and 1 had absent specific antibody responses. 14,[16][17][18]22,24,25 Isolated immunoglobulin deficiencies were rarely reported in CHARGE syndrome. One patient with an isolated IgG2 subclass deficiency 17 and two patients with an isolated IgA deficiency 14 were reported.…”