Жұқпалы нейтропения түрлері және генетикалық себептері

Most cases of SCN respond to treatment with granulocyte colony stimulating factor (filgrastim), which increases the neutrophil count and decreases the severity and frequency of infections.

Subtypes of SCN OMIM Name Gene Chromosome Gene/Locus MIM number SCN1 ELANE 19p13.3 130130 SCN2 GFI1 1p22.1 SCN3 HAX1 1q21.3 SCN4 G6PC3 17q21.31 SCN5 VPS45 1q21.2 SCNX WASP Xp11.23 300392

Kostmann disease, SCN3, is inherited in an autosomal recessive manner, but the commonest subtype of Kostmann syndrome, SCN1, is autosomal dominant. The recognized subtypes of Kostmann syndrome are:
SCN1 is the commonest form of SCN, which accounts for 60 80% of SCN, This same gene is mutated in cyclic neutropenia. GFI1 is a repressor of several transcriptional processes, including ELANE, SCN4 is associated with structural cardiac abnormalities, enlarged liver, intermittent thrombocytopenia and a prominent superficial venous pattern. Unlike classical Kostmann disease, SCN5 also has defective platelet aggregation (thrombasthenia) and myelofibrosis. This type is refractory to granulocyte colony stimulating factor. There is an absence of lysosomes in fibroblasts and depletion of alpha granules in platelets. Accelerated apoptosis occurs in the neutrophils and bone marrow. X linked SCN (SCNX) is caused by mutation in the WASP gene on Xp11. SCN occasionally may arise from SBDS mutations. Kostmann disease is a form of severe congenital neutropenia (SCN), specifically type 3 (SCN3), which is a rare autosomal recessive condition in which severe chronic neutropenia is detected soon after birth. The disorder was discovered in 1956 in an extended family in northern Sweden by Rolf Kostmann, a Swedish doctor. Although mutations of more than 15 genes cause severe congenital neutropenia (in a general sense) not all of these are usually considered as SCN. Clinical usage excludes two broad categories of congenital neutropenia. Diseases are excluded that overtly affect multiple systems rather than impacting myelopoiesis most prominently. Thus SCN excludes the severe neutropenia which can occur in congenital diseases such as Shwachman–Diamond syndrome, Barth syndrome, Chédiak–Higashi syndrome, WHIM syndrome, and glycogen storage disease type Ib.

The various mutations are responsible for the untimely initiation of apoptosis in myelocytes, usually at the promyelocyte stage, leading to their premature destruction or maturation arrest in the bone marrow. The ineffective production of neutrophils leads to a decrease in the absolute neutrophil count and a subsequent increased susceptibility to infections. There may be, in addition, other underlying molecular/genetic changes producing DNA mutations and genome instability, which contribute to initiation and progression of this disease.

An absolute neutrophil count (ANC) chronically less than 500/mm3, usually less than 200/mm3, is the main sign of Kostmann's. Other elements include the severity of neutropenia, the chronology (from birth; not emerging later), and other normal findings (hemoglobin, platelets, general body health). Isolated neutropenia in infants can occur in viral infections, autoimmune neutropenia of infancy, bone marrow suppression from a drug or toxin, hypersplenism, and passive placental transfer of maternal IgG. Over 90% of SCN responds to treatment with granulocyte colony stimulating factor (filgrastim), which has significantly improved survival.