Neutrophilia, Hereditary

A number sign (#) is used with this entry because of evidence that hereditary neutrophilia is caused by heterozygous mutation in the CSF3R gene (138971) on chromosome 1p34. One such family has been reported.

Clinical Features

Herring et al. (1974) described an apparently autosomal dominant form of lifelong, persistent neutrophilia in a mother and 3 of her 4 children. The neutrophils were morphologically and functionally normal. Associated findings were hepatosplenomegaly, histiocytes of Gaucher type, and thickened calvaria due to widened diploe. Leukocyte alkaline phosphatase, serum vitamin B12 levels and heat-labile serum alkaline phosphatase were elevated. The course was benign. No previous report was found. This disorder differs from the familial myeloproliferative syndrome (254700) by the mode of inheritance and benign course. It is also distinct from hereditary eosinophilia (131400).

Plo et al. (2009) described a 3-generation family in which 12 of 16 members had chronic neutrophilia, with median white blood cell (WBC) counts of 21,350 cells per cubic millimeter involving greater than 70% segmented neutrophils or band cells and less than 10% immature granulocytes; median neutrophil counts were 16,900 cells per cubic millimeter. All affected individuals were clinically asymptomatic except the proband, who presented with a unique episode of systemic inflammatory response syndrome that combined fever, tachycardia, dyspnea, pleural and pericardial effusion, hepatosplenomegaly, and weight loss. He had a WBC of 102,000 cells per cubic millimeter, with 75% segmented neutrophils and 20% immature granulocytes; bone marrow analysis showed an increase in granulocyte precursors without an excess of blasts. After this episode, the patient returned to chronic neutrophilia, but 18 months later he developed a myelodysplastic syndrome involving refractory anemia with an excess of blasts (RAEB); bone marrow aspirate showed marked dysgranulopoiesis but no dyserythropoiesis or dysmegakaryopoiesis, and cytogenetic analysis revealed a clonal abnormality (chromosome 3q26 deletion) in 70% of metaphases.

Inheritance

The families with neutrophilia reported by Herring et al. (1974) and Plo et al. (2009) indicated autosomal dominant inheritance.

Molecular Genetics

In a 3-generation family segregating autosomal dominant neutrophilia, Plo et al. (2009) sequenced the CSF3R gene and identified a heterozygous activating mutation (T617N; 138971.0001) in all 12 affected individuals that was not found in the 4 unaffected family members.