Barth Syndrome: An Under-Recognized Cause of Chronic Neutropenia

Barth syndrome is an X-linked disease characterized by defective remodeling of phospholipid side chains in mitochondrial membranes.  Major features include neutropenia, fetal or childhood onset dilated cardiomyopathy, motor delay and proximal myopathy, feeding problems and constitutional growth delay.  Improved diagnostic testing, recognition of the wide disease phenotype and a worldwide patient/family support network have recently facilitated much more rapid ascertainment, now with at least 186 living males diagnosed worldwide.  We provide a comprehensive survey of neutropenia seen in Barth syndrome and its management based on the study of 90 patients. Neutropenia (i.e. at least one count less than 1.5 x 10⁹/L) was detected in 74 of 90 (82%) patients; 28 of 90 (31%) patients had a mean neutrophil count less than 1.5 x 10⁹/L; 13 of 90 (14%) had a mean count less than 0.5 x 10⁹/L.  Neutropenia may be the sole presenting feature in Barth syndrome.  Importantly, it can take on any form: intermittent and unpredictable, chronically severe or cyclical, thus mimicking other diseases. Eighty-seven patients had reported monocyte data.  Monocytosis was seen in 65 of 87 (75%) patients with at least one monocyte count greater than 1.0 x 10⁹/L and 23 of 87 (26%) had at least one monocyte count greater than 3.0 x 10⁹/L.   

Some patients who were neutropenic and had a bone marrow evaluation showed myelocyte arrest.  Neutropenic Barth patients are highly responsive to granulocyte colony-stimulating factor, although dosing can be challenging because of innate variations in their neutrophil counts.  Clinical improvement with reduced signs and symptoms of infections is the usual response to this treatment.  Barth syndrome should be considered in any male with neutropenia accompanied by any of the characteristic features of Barth syndrome and in those with idiopathic neutropenia.