Increased susceptibility of a carrier of X-linked chronic granulomatous disease (CGD) to Aspergillus fumigatus infection associated with age-related skewing of lyonization

Abstract

Chronic granulomatous disease (CGD) is an inherited disorder characterized by the inability of phagocytes to generate normal amounts of superoxide (O2-), leaving patients susceptible to life-threatening infections. It was previously assumed that once carriers of the X-linked form of CGD were found to have 30% or more of functionally normal neutrophils, they would be free of risk for infection because the lyonization ratio was believed to be constant. Our report strongly contradicts this assumption. A 45-year-old X-CGD carrier had approximately 40% of normal neutrophils in her peripheral blood at age 21 years. Recently, she contracted a life-threatening pulmonary infection with Aspergillus fumigatus. After recovery, the ratio of normal-to-nonfunctional neutrophils was re-evaluated. She was found to have only 6-8% of normal neutrophils, suggesting that a striking decrease in the number of normal cells over the past 25 years was the reason for an increased susceptibility to Aspergillus infection. We conclude that age-related acquired skewing of the lyonization ratio can result in an increased susceptibility to life-threatening infections in X-CGD carriers.

Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB

“…[41][42][43] Two recent reports describe this phenomenon as the cause of X-CGD in adult females, at age 45 and 43, respectively. 44,45 Apparently, in our patient, it took even longer before the X-chromosome inactivation pattern was skewed to a degree that caused the clinical problems.…”

Adult Onset X-Linked Chronic Granulomatous Disease in a Woman Patient Caused by a de novo Mutation in Paternal-Origin CYBB Gene and Skewed Inactivation of Normal Maternal X Chromosome

“…(6) (10). To date, the presence of adult onset X-linked CGD has been reported in only 3 woman patients (2)(3)(4). The precise mechanism by which the disease occurs in adults remains unclear but a positive correlation was observed between age and degree of skewing in X-inactivation (11).…”

“…For many years the onset of Xlinked CGD was thought to occur early in infancy in man patients, with a fatal outcome in adolescence due to recurrent severe bacterial or fungal infections. However, late onset cases of X-linked CGD have been recently reported in some adult woman (2)(3)(4). While it has been assumed that the late onset of woman X-linked CGD could be associated with age-related skewing of lyonization (2), the detailed mechanism of onset in adult woman patients remains obscure.…”

“…However, late onset cases of X-linked CGD have been recently reported in some adult woman (2)(3)(4). While it has been assumed that the late onset of woman X-linked CGD could be associated with age-related skewing of lyonization (2), the detailed mechanism of onset in adult woman patients remains obscure. Here, we report a woman patient with adult onset Xlinked CGD caused by a de novo mutation in the paternalorigin CYBB gene and skewed inactivation of normal maternal X chromosome.…”

Systemic high-dose methotrexate plus ifosfamide is highly effective for central nervous system (CNS) involvement of lymphoma

“…However, there is growing evidence linking it to delayed neurotoxicity in these cases [28][29][30]. On the other hand, different salvage chemotherapy regimens have proven effective for PCNSL [31]. Thus, delaying WBI in relapsed PCNSL seems a reasonable approach.…”