Molecular basis and therapy of disorders associated with chronic neutropenia

Abstract

There have been many recent advances in our understanding of the molecular basis of neutropenia disorders, primarily through advances in genetic analysis of inherited disorders. Molecular and cellular studies now suggest that accelerated apoptosis of neutrophil precursors in the bone marrow is the common pathophysiologic mechanism. Severe congenital neutropenia and cyclic neutropenia, both usually inherited as autosomal-dominant disorders, are caused by mutations in the neutrophil elastase gene. Myelokathexis is attributed to the downregulation of the bcl-x protein, but the genetic basis is not yet known. The genes for several diseases with more complex phenotypes (eg, glycogen storage disease type 1b, Chediak-Higashi syndrome, Shwachman-Diamond syndrome, dyskeratosis congenita, Griscelli syndrome, Barth syndrome, and Wiskott-Aldrich syndrome) have all been identified recently. The molecular mechanisms for most acquired disorders causing neutropenia (eg, idiopathic neutropenia, pure white-cell aplasia, myelodysplasia, and aplastic anemia) are not yet known. Granulocyte colony stimulating factor (G-CSF) is effective treatment for several of these conditions. Through better understanding of these disorders, we anticipate that better treatments will be found in the future.

Síndrome de Shwachman-Diamond

“…El hallazgo hematológico más frecuente es una neutropenia intermitente que aparece en el 85-100 % de los casos 2,15,16 . Independientemente del número total de neutrófilos existe también una alteración de la migración de los mismos, por lo que existe un riesgo aumentado de infecciones bacterianas graves aún con una cifra normal de neutrófilos 11,17 .…”

“…La neutropenia grave o las infecciones recurrentes pueden ser tratadas con factor estimulante de colonias de granulocitos (G-CSF) 16 . Sin embargo, existe controversia sobre la posibilidad de acelerar el desarrollo de síndromes mieloproliferativos 2,11 .…”

Eponym

“…Placement of an internal cardiac defibrillator for life-threatening arrhythmias in BTHS was documented to prevent from sudden death [22]. Neutropenia can be usually managed with parenteral antibiotics and administration of granulocyte colony-stimulating factor [23]. Growth hormone therapy is discouraging for growth-retarded children with BTHS.…”