Neutropenia in Barth syndrome: characteristics, risks, and management

Abstract

Purpose of review: 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).

Recent findings: In 88 patients with BTHS, neutropenia, that is, at least one count below 1.5 × 10/l, was detected in 74 (84%) and 44% had severe chronic neutropenia, with multiple counts below 0.5 × 10/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 × 10/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.

Summary: 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.

Figure 1. A. Range of ANC in 15 individual patients with more than 10 individual CBC readings who never received G-CSF B. Differences between CBC readings within one family

Details are shown of ANCs from CBCs taken principally from times of cardiac review, clinic visits and inpatient admissions. The dotted line indicates the threshold for neutropenia (ANC <1.5 × 10⁹/L). UPN35 and 36 are brothers, and UPN46 a maternal cousin with BTHS. The earliest DCM occurred in UPN36 who has only been minimally neutropenic (at 1.35 × 10⁹/L) on one of 72 CBC tests. By contrast his brother has significant proximal myopathy but only mild DCM, yet has intermittent neutropenia down to 0.2 × 10⁹/L. Their cousin (UPN46) had a minimum ANC of 0.95 × 10⁹/L from 84 observations taken over 16 years; he has never received G-CSF or had a significant bacterial infection despite disease of sufficient severity to require cardiac transplantation at 3.5 years of age.

Figure 2.. Examples of extensive neutrophil profiles in BTHS patients

(A and B) UPN37 and 80 respectively did not satisfy mathematical criteria for cycling. (A) UPN37 appeared to cycle at an average of 25 days (range 23–28 days). His G-CSF response is shown in Figure 4A. (B) UPN48 showed spontaneous variability between an ANC of zero and 5.3 × 10⁹/L over a period of 61 days; Unpredictable variation in this manner is the most common pattern seen in BTHS patients. (C and D) Two patients (UPN35 & 36 respectively) exhibited periods of rhythmic “microcycling” over periods averaging 8–9 days either around (in C) or above (in D) the threshold of neutropenia.

Figure 3.. G-CSF responses

(A) Neutropenia resolved after treatment with G-CSF in UPN10, the only patient who satisfied strict mathematical criteria for cyclical neutropenia, with an average periodicity of 23.3 days. Doses of G-CSF were steadily titrated down from 5 to 0.5 mcg/kg/day in order to keep ANC above 1.5 × 10⁹/L (note logarithmic scale with ANC ranging up to 33.9 × 10⁹/L). (B) By contrast, UPN69 continues to show irregular periods of neutropenia after commencement of G-CSF at 3mcg/kg/dose three times weekly. (C) Effect of G-CSF on range of ANC in 14 other patients (UPN 5, 8, 13, 19, 20, 23, 34, 38, 39, 40, 41, 44, 58 and 67) with the largest numbers of on- and off-therapy CBC.

Figure 4.. Exuberant responses to G-CSF

UPN37 showed a range of ANC of 0.1 to 5.9 × 10⁹/L in the year before commencing G-CSF at 3mcg/kg/dose thrice weekly. His ANC ranged from 0.2 to 79.9 in the 6 weeks afterwards, although renal transplantation (required as a consequence of previous Haemophilus sepsis) may have contributed to these dramatic changes. By contrast, no events occurred in UPN51 (shown in B), whose ANC rose to 64 × 10⁹/L, from a maximum ANC of 0.6 × 10⁹/L in nine CBCs taken at regular intervals over the previous two months, after G-CSF was introduced at 10mg/kg/day; this necessitated switching to alternate daily dosing.