Benign chronic neutropenia with abnormalities involving 16q22, affecting mother and daughter

Abstract

We report a case of familial, chronic, benign neutropenia in a 17-year-old female showing (1) the spontaneous expression of a heritable rare fragile site at 16q22 and (2) a deletion at the same region. The del(16)(q22), which most likely originated from the fragile site, was the main clonal abnormality detected in the patient's bone marrow cells, whereas a few cells with either del(16)(q22) or fra(16)(q22) were seen in the patient's peripheral blood. Interestingly, the del(16q) was also detected in the patient's uncultured cells, as demonstrated by FISH, excluding an in vitro origin of the del(16q) during culture. The bone marrow was hypocellular with decreased neutrophils and their precursors. Absolute neutrophil counts ranged from (0.62 to 1.24) 3 10 9 /L with a median value of 1.02 3 10 9 /L. The patient had a more severe neutropenia than her mother, which correlated with the presence of more cells with del(16q) in the marrow. The patient's mother, who was also diagnosed with neutropenia, revealed only a few cells with the rare fra(16)(q22) in her peripheral blood cells, whereas her bone marrow showed cells with both fra(16)(q22) and del(16)(q22), although the del(16q) was present in only 2/20 cells. Some possible candidate genes contributing to the pathogenesis of the neutropenia are discussed. Chromosome abnormalities involving the 16q22 breakpoint have been observed in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this patient, the del(16)(q22) risk factor is unknown for subsequent development of MDS or AML. Another point to consider is the need to determine the origin of a chromosome abnormality, particularly when the clinical picture does not fit the chromosome findings. Although, the observation of a constitutional structural abnormality in a mosaic form is an extremely rare event, it is somewhat different in the case of a fragile site expression, which can, as in this case, be present in some cells and not in others. Am. J. Hematol. 81:262-270, 2006. V V C 2006 Wiley-Liss, Inc.

Fragility Extraordinaire: Unsolved Mysteries of Chromosome Fragile Sites

“…However, later it was demonstrated that this fragile site is distal from the haptoglobin gene whose deficiency is linked to IgA deficiency, suggesting that the IgA condition in the propositus was likely a coincidence (Simmers et al 1986). Fragility at 16q22 has since been implicated in a wide spectrum of neurological disorders (Demirhan et al 2006; Kerbeshian et al 2000) as well as in other conditions such as neutropenia (Glasser et al 2006; Tassano et al 2010) and cleft palate (Bettex et al 1998; Dunner et al 1983; Janiszewska-Olszowska et al 2013; McKenzie et al 2002). A recent study also reported elevated fragile site formation at 16q22.1 in an embryo from a couple who had difficulty achieving pregnancy and in the sperm from the father (Martorell et al 2014).…”

Genetic Analysis of a Mosaic Fra(16)(q22)/Del(16)(q22) Karyotype in a Primary Infertile Woman

“…This suggests that fra(16)(q22) may be involved in the etiology of this condition. 13 There are reports suggesting a connection between fra(16)(q22) and acute nonlymphocytic leukemia. 14 Studies have indicated that fra(16)(q22) might serve as an induction factor for balanced translocations and inversions.…”

Febrile Neutropenia in an Infant

“…Despite being autoimmune, there may be a hereditary component with first-degree relatives commonly being affected and an autosomal dominant inheritance. 1…”