Hypomorphic homozygous mutations of LIG4, encoding DNA ligase IV, cause a wide spectrum of developmental and immune defects, from SCID presentations to a phenotype resembling other chromosomal instability syndromes. Most patients present growth failure, microcephaly, facial dysmorphism, mental retardation, diverse skin and bone manifestations, and immunodeficiency ranging from SCID to humoral deficiency. Isolated bone marrow failure and hematological malignancies have also been reported.
Whole exome sequencing (WES) was performed in a 24-year-old man who was healthy until the age of 16 years-old, when he manifested hidradenitis suppurativa. At 18, he was hospitalized for pneumonia, which resolved uneventfully. At the age of 21 he had a complicated Haemophilus influenzae pneumonia. At that time he was found to have absent IgG, IgA and IgM, no responses to recall antigens, no B cells yet normal T-cell subset. He is a tall, overweight patient with no dysmorphic features and no bone abnormalities, but presenting vitiligo. The patient has been on SCIg replacement and is asymptomatic since diagnosis.
WES identified a homozygous mutation in LIG4 (p.R278H), previously reported as pathogenic, resulting in radiosensitivity and in a subtle VDJ recombination defect. Two other homozygous patients have been described, with very different phenotypes: one with normal development and radiosensitivity manifested as detrimental response to acute leukemia therapy, and one with developmental delay, dysmorphic features and pancytopenia.
We report the first DNA Ligase IV deficient patient with isolated late-onset agammaglobulinemia as unveiled by an unbiased sequencing approach.