Neutropenia and neutrophil disorders: Case

Clinical long case of an infant presenting with recurrent mouth ulcers and skin infections in whom severe congenital neutropenia is diagnosed, covering the recognition of a congenital production-failure neutropenia, the severity grading, the neutrophil kinetic model, the marrow maturation arrest, the inherited neutropenia gene panel with an ELANE result, the lifelong granulocyte colony-stimulating factor management and the annual marrow surveillance for myelodysplastic syndrome and acute myeloid leukaemia, and the family counselling.

Prompt

A previously well eleven-month-old boy is referred to the general paediatric clinic for recurrent mouth ulcers, two episodes of cellulitis of the leg in the past three months, and three courses of oral antibiotics for otitis media. He is growing along the tenth centile and is developmentally normal, with normal stools and no dysmorphism. His full blood count shows a haemoglobin of 112 g per litre, a platelet count of 320 times ten to the ninth per litre, and a white cell count of 2.0 times ten to the ninth per litre with 5 per cent neutrophils and no bands. The absolute neutrophil count is 0.1 times ten to the ninth per litre, confirmed on a repeat sample. The peripheral film shows no blasts, no dysplasia, and no giant granules. The parents are well and there is no family history of early infant death or leukaemia, though a paternal uncle had recurrent skin infections as a child.

This infant has a severe, isolated, persistent neutropenia presenting with recurrent pyogenic infections of the mucosa and skin, in a child with otherwise normal growth and cell lines. The pattern points away from a benign post-viral dip or an immune cause and toward a congenital production-failure neutropenia, most likely severe congenital neutropenia. The candidate should synthesise the problem representation aloud: a severe isolated chronic neutropenia with recurrent pyogenic infections in an infant is a congenital neutropenia syndrome, most often ELANE-related severe congenital neutropenia, until proven otherwise. ^[2]^[1]

Clinical findings and the differential

The key findings are the profound absolute neutrophil count of 0.1 times ten to the ninth per litre, confirmed on a repeat sample, with a normal haemoglobin and platelet count, and recurrent pyogenic infections of surfaces neutrophil defends: the mouth, the skin, and the ears. The severity grading places this firmly in the severe band, with infection risk at its highest and counts under 0.1 considered profound. The film excludes the acute alternative diagnoses: there are no blasts to suggest leukaemia, no dysplasia to suggest myelodysplasia, and no giant intracytoplasmic granules to suggest Chediak-Higashi. ^[1]

The differential of a severe isolated chronic neutropenia in an infant is led by the congenital disorders. Severe congenital neutropenia, most often ELANE-related and autosomal dominant, fits the severe persistent neutropenia, the early onset, and the recurrent pyogenic infections. The autosomal recessive HAX1 form (Kostmann disease) is possible but classically described in northern Scandinavian families. Cyclic neutropenia is excluded by the absence of a regular twenty-one day cycle. Autoimmune neutropenia of infancy usually gives a milder count and is confirmed by anti-neutrophil antibodies. The candidate should name the kinetic mechanism: this is a production failure, a maturation arrest in the marrow. ^[2]^[6]

References6Show

[1]Newburger PE, Dale DC Evaluation and management of patients with isolated neutropenia. Semin Hematol, 2013.PMID 23953336
[2]Welte K, Zeidler C, Dale DC Severe congenital neutropenia. Semin Hematol, 2006.PMID 16822461
[3]Dale DC, Cottle TE, Fier CJ, et al Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol, 2003.PMID 12555210
[4]Rosenberg PS, Alter BP, Bolyard AA, et al The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood, 2006.PMID 16497969
[5]Makaryan V, Zeidler C, Bolyard AA, et al The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Curr Opin Hematol, 2015.PMID 25427142
[6]Horwitz MS, Corey SJ, Grimes HL, et al ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology. Hematol Oncol Clin North Am, 2013.PMID 23351986

Neutropenia and neutrophil disorders: Case

Clinical findings and the differential

References6Show

[1]Newburger PE, Dale DC Evaluation and management of patients with isolated neutropenia. Semin Hematol, 2013.PMID 23953336
[2]Welte K, Zeidler C, Dale DC Severe congenital neutropenia. Semin Hematol, 2006.PMID 16822461
[3]Dale DC, Cottle TE, Fier CJ, et al Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol, 2003.PMID 12555210
[4]Rosenberg PS, Alter BP, Bolyard AA, et al The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood, 2006.PMID 16497969
[5]Makaryan V, Zeidler C, Bolyard AA, et al The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Curr Opin Hematol, 2015.PMID 25427142
[6]Horwitz MS, Corey SJ, Grimes HL, et al ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology. Hematol Oncol Clin North Am, 2013.PMID 23351986