Mutations in <i>CHD7</i> in patients with CHARGE syndrome cause T–B + natural killer cell + severe combined immune deficiency and may cause Omenn-like syndrome

TLDR

Severe combined immunodeficiency arises from multiple genetic defects, including T‑B+NK phenotypes seen in 22q11.2 deletion and rare cases of CHARGE syndrome, with Omenn syndrome representing a distinct, autosomal recessive SCID variant. The study reports four CHD7‑mutated CHARGE patients, two with T‑B+NK SCID and two with Omenn‑like disease. The authors examined these four patients, documenting their clinical features and immunologic profiles. CHARGE syndrome should now be recognized as a cause of T‑B+NK SCID, and CHD7 mutations may be associated with Omenn‑like syndrome.

Abstract

More than 11 genetic causes of severe combined immunodeficiency (SCID) have been identified, affecting development and/or function of T lymphocytes, and sometimes B lymphocytes and natural killer (NK) cells. Deletion of 22q11.2 is associated with immunodeficiency, although less than 1% of cases are associated with T-B + NK + SCID phenotype. Severe immunodeficiency with CHARGE syndrome has been noted only rarely Omenn syndrome is a rare autosomal recessive form of SCID with erythroderma, hepatosplenomegaly, lymphadenopathy and alopecia. Hypomorphic recombination activating genes 1 and 2 mutations were first described in patients with Omenn syndrome. More recently, defects in Artemis, RMRP, IL7Ralpha and common gamma chain genes have been described. We describe four patients with mutations in CHD7, who had clinical features of CHARGE syndrome and who had T-B + NK + SCID (two patients) or clinical features consistent with Omenn syndrome (two patients). Immunodeficiency in patients with DiGeorge syndrome is well recognized--CHARGE syndrome should now be added to the causes of T-B + NK + SCID, and mutations in the CHD7 gene may be associated with Omenn-like syndrome.