CHARGE (Coloboma, Heart Defect, Atresia Choanae, Retarded Growth and Development, Genital Hypoplasia, Ear Anomalies/Deafness) Syndrome and Chromosome 22q11.2 Deletion Syndrome: A Comparison of Immunologic and Nonimmunologic Phenotypic Features

Abstract

Objectives CHARGE syndrome and chromosome 22q11.2 deletion syndrome are known to have significant clinical overlap including cardiac anomalies, ear abnormalities, hearing loss, developmental delay, renal abnormalities, hearing loss, and cleft palate. Immunodeficiency has been well documented in 22q11.2 deletion, but there is limited recognition of this potentially serious complication in CHARGE syndrome. The goals of our study were to identify clinical features unique to CHARGE syndrome or 22q11.2 deletion and to describe the spectrum of immune deficiency found in CHARGE patients. Methods This study includes 25 children diagnosed with CHARGE syndrome with positive CHD7 mutations, through the Children’s Hospital of Philadelphia genetics program. Clinical features and laboratory findings were reviewed retrospectively. We compared our findings to data available for a large cohort of 22q11.2 deletion syndrome patients followed in our clinical genetics program. Results Features found more commonly in CHARGE syndrome included coloboma, choanal atresia, facial nerve palsy, tracheoesophageal fistula, and genital hypoplasia in males. A high incidence of marked hypocalcemia was observed in our study group (72%). We found a spectrum of cell-mediated immune deficiency in our study group, which ranged from lymphopenia (60%) to severe-combined immune deficiency (8%). Defects in humoral immunity were documented in 4 patients and included severe hypogammaglobulinemia with decreased T-cell numbers, transient hypogammaglobulinemia during infancy, and IgA deficiency. Conclusion The presence of coloboma, choanal atresia, facial nerve palsy, tracheoesophageal fistula, or genital hypoplasia in males should alert the clinician to the possibility of CHARGE syndrome rather than the 22q11.2 deletion. Molecular testing for CHD7 mutations may help to confirm the diagnosis. In this study, significant hypocalcemia and lymphopenia occurred more frequently in CHARGE syndrome patients than in 22q11.2 deletion syndrome patients. Early inclusion of immunologists to the multi-disciplinary care team (as with 22q11.2 deletion) may be of great benefit to affected patients.

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.…”

“…The reported B-and NK-cells numbers of other patients were normal. 14,23,[26][27][28][34][35][36] Immunoglobulin levels were reported in 33 of 59 patients and in 20 of 36 patients with a proven variant in CHD7. Hypogammaglobulinaemia was reported in 20 of 33 (61%) patients and measured along with T-cell lymphopenia in 14 of 18 (78%) patients.…”

“…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).…”

“…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.…”

“…8,9,13 Furthermore, deficits in the immune system have been described in CHARGE patients, which might lead to morbidity and even mortality. 14 Here, we provide an overview of the current literature on immunological dysfunction in CHARGE syndrome. We also explore what can be learned from the clinical overlap between CHARGE syndrome and other multiple congenital anomaly (MCA) syndromes.…”