Barth syndrome (BTHS) is an X-linked disease characterized by defective remodeling of phospholipid side chains in mitochondrial membranes. Major features include neutropenia, dilated cardiomyopathy, motor delay and proximal myopathy, feeding problems, and constitutional growth delay. We conducted this review of neutropenia in BTHS to aid in the diagnosis of this disease, and to improve understanding of both the consequences of neutropenia and the benefits of treatment with granulocyte colony-stimulating factor (G-CSF).
In 88 patients with BTHS, neutropenia, that is, at least one count below 1.5 × 109/l, was detected in 74 (84%) and 44% had severe chronic neutropenia, with multiple counts below 0.5 × 109/l. The pattern of neutropenia varied between intermittent and unpredictable, chronic and severe, or cyclical with mathematically regular oscillations. Monocytosis, that is, monocytes more than 1.0 × 109/l, was observed at least once in 64 of 85 (75%) patients. G-CSF was administered to 39 of 88 patients (44%). Weekly average G-CSF doses ranged from 0.12 to 10.92 μg/kg/day (mean 1.16 μg/kg/day, median 1.16 μg/kg/day). Antibiotic prophylaxis was additionally employed in 21 of 26 neutropenic patients. Pretreatment bone marrow evaluations predominantly showed reduced myeloid maturation which normalized on G-CSF therapy in seven of 13 examined. Consistent clinical improvement, with reduced signs and symptoms of infections, was observed in response to prophylactic G-CSF ± prophylactic antibiotics. However, despite G-CSF and antibiotics, one adult patient died with multiple infections related to indwelling medical devices and gastrostomy site infection after 15.5 years on G-CSF and a pediatric patient required gastrostomy removal for recurrent abdominal wall cellulitis.
BTHS should be considered in any men with neutropenia accompanied by any of the characteristic features of this syndrome. Prophylaxis with G-CSF ± antibiotics prevents serious bacterial infections in the more severe neutropenic patients although infections remain a threat even in patients who are very compliant with therapy, especially in those with indwelling devices.
aNHS Specialised Services Barth Syndrome Service, Royal Hospital for Children
bSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
cDepartment of Pediatrics, Division of Cardiology, Children's Hospital, Medical University of South Carolina, Charleston, South Carolina
dNatera, San Carlos, California, USA
eDepartment of Immunology/Hematology and BMT, University Medical Center Utrecht, Utrecht, The Netherlands
fDepartment of Clinical Genetics, St Michael's Hospital, Bristol, UK
gFormer: University Children's Hospital, Geneva; Present: Swissmedic, Bern, Switzerland
hBarth Syndrome Trust, Romsey, UK
iBarth Syndrome Foundation, Inc., Larchmont, New York, USA
jDepartments of Physiology, Physics, and Mathematics, Centre for Applied Mathematics in Bioscience and Medicine, McGill University, Montreal, Québec, Canada
kSevere Chronic Neutropenia International Registry
lDepartment of Medicine, University of Washington, Seattle, Washington, USA
Correspondence to Professor Colin G. Steward, PhD, Emeritus Professor of Paediatric Stem Cell Transplantation, School of Cellular and Molecular Medicine, Medical Sciences Building, University of Bristol, University Walk, Bristol BS8 1TD, United Kingdom. E-mail: firstname.lastname@example.org