Severe congenital neutropenia

Did You Know?

• Infants with SCN have frequent infections: 50% have a significant infection within one month, most others by six months.
• Infections are usually bacterial, especially staphylococcal, and commonly involve abscesses, pneumonia, mastoiditis, and sepsis.
• Regular administration of granulocyte colony-stimulating factor may increase risk for myelofibrosis and acute myeloid leukemia in the long term.

Genetics

Severe congenital neutropenia (SCN) is the broad term for disorders that primarily disrupt myelopoiesis. Kostmann syndrome is sometimes used interchangeably with SCN, though it can also refer specifically to the SCN3 subtype. The most common form, SCN1, accounts for 60 to 80 percent of cases and is autosomal dominant, caused by over one hundred possible mutations in the ELANE gene on chromosome 19p13.3. The same gene is also mutated in cyclic neutropenia. SCN2 is autosomal dominant from a heterozygous GFI1 gene mutation on chromosome 1p22. SCN3 is the classic autosomal recessive Kostmann disease, resulting from homozygous HAX1 gene mutations on chromosome 1p22.1; about one third of these patients have neurological issues such as seizures or developmental delay. SCN4 is autosomal recessive from G6PC3 mutations on 17q21 and involves cardiac defects, enlarged liver, intermittent low platelet counts, and a visible superficial vein pattern; some cases also feature severe pulmonary hypertension. SCN5 is autosomal recessive from a specific VPS45 mutation on 1q21.2, causing defective platelet aggregation, myelofibrosis, and resistance to granulocyte colony-stimulating factor. X-linked SCN results from WASP gene mutations on Xp11. Rarely, SBDS mutations can also cause SCN. A notable portion of SCN cases have no identified mutation.

Pathophysiology

In this condition, genetic mutations cause myelocytes, often at the promyelocyte stage, to undergo early apoptosis, resulting in their premature destruction or a halt in their maturation within the bone marrow. This ineffective neutrophil production lowers the absolute neutrophil count and raises infection risk. Additional molecular or genetic changes can cause DNA mutations and genome instability, helping to start and worsen the disease.

Diagnosis

Diagnosis involves a systematic approach including clinical examination, blood tests, and genetic testing to confirm neutrophil deficiency. Initial steps include a complete blood count to assess neutrophil levels; an absolute neutrophil count chronically less than 500/mm3, usually less than 200/mm3, is the main sign. Other elements include the severity of neutropenia, its chronology from birth, and normal findings for hemoglobin, platelets, and general health. Isolated neutropenia in infants can also occur from viral infections, autoimmune neutropenia of infancy, bone marrow suppression from drugs or toxins, hypersplenism, or passive placental transfer of maternal IgG. A bone marrow biopsy is recommended to evaluate function and rule out other disorders; it typically shows early granulocyte precursors with maturation arrest at the promyelocyte or myelocyte stage. Genetic testing detects mutations in genes such as ELANE, HAX1, G6PC3, and GFI1, distinguishing SCN from other neutropenia disorders and revealing inheritance patterns.