Kostmann syndrome

First described in 1956, Kostmann syndrome, also called congenital neutropenia, is characterized as "is characterized by an arrest of the maturation of neutrophil precursors at the promyelocytic stage of differentiation and low levels of mature neutrophils in peripheral blood." It was generally lethal before treatment with granulocyte colony-stimulating factor was available, although some individuals were protected with antibiotics.

Genetics and molecular biology

As mentioned, the disease was first described in a group with considerable intermarriage. It had been believed to be an autosomal recessive disorder, but two suggested genes, ELA-2, the neutrophil elastase gene, or G-CSFR, which defines the G-CSF receptor, are normal in the survivors with the disease. One patient had an ELA-2 defect but her parents did not, suggesting a spontaneous mutation.

While the G-CSFR gene may be normal, G-CSF an intracellular signal transduction pathway may be abnormal. "Neutrophils from patients are shown to have dramatically increased levels of 2 cytosolic protein tyrosine phosphatases that contain src-homology 2 (SH2): SHP-1 and SHP-2. One hypothesis is that overexpression of these proteins, which are involved in cytokine receptor signaling, plays a role in altering intracellular signal transduction processes.

"A selective decrease of B-cell lymphoma-2 (Bcl-2) expression in myeloid cells and an increase in apoptosis in bone marrow progenitor cells have been observed."

Diagnosis

The disease is usually detected after an infant presents with a severe infection, with severe neutropenia and:

• Temperature instability in newborn period
• Fever
• Irritability
• Localized site(s) of infection

No cases have been reported in an infant of less than 33 weeks, but diagnosis of may have been missed in neonates who died of overwhelming sepsis. In one case, the syndrome was noted only because a twin did not have sepsis.

"Their bone marrow examination is characterized by normal concentrations of granulocyte progenitors and precursors, but an arrested neutrophil development at the promyelocyte or myelocyte stage."

Differential diagnosis

To be considered are:

Agammaglobulinemia Severe combined immunodeficiency disease Autoimmune neutropenia Chronic benign neutropenia Shwachman-Diamond syndrome Glycogen-storage disease Type I Methylmalonic acidemia Pearson syndrome Cyclic neutropenia Chediak-Higashi syndrome Myelokathexis Treatment G-CSF, often in high dosage, is the core of treatment, although stem cell transplantation has an increasing role. References