ELANE-Related Neutropenia

Clinical characteristics: ELANE-related neutropenia includes congenital neutropenia and cyclic neutropenia, both of which are primary hematologic disorders characterized by recurrent fever, skin and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis), and cervical adenopathy. Infectious complications are generally more severe in congenital neutropenia than in cyclic neutropenia.

In congenital neutropenia, omphalitis immediately after birth may be the first sign; in untreated children diarrhea, pneumonia, and deep abscesses in the liver, lungs, and subcutaneous tissues are common in the first year of life. After 15 years with granulocyte colony-stimulating factor treatment, the risk of developing myelodysplasia (MDS) or acute myelogenous leukemia (AML) is approximately 15%-25%.

Cyclic neutropenia is usually diagnosed within the first year of life based on approximately three-week intervals of fever and oral ulcerations and regular oscillations of blood cell counts. Cellulitis, especially perianal cellulitis, is common during neutropenic periods. Between neutropenic periods, affected individuals are generally healthy. Symptoms improve in adulthood. Cyclic neutropenia is not associated with risk of malignancy or conversion to leukemia.

Diagnosis/testing: The diagnosis of ELANE-related neutropenia is established in a proband with suggestive clinical findings and the identification of a heterozygous pathogenic variant in ELANE through molecular genetic testing.

Management: Treatment of manifestations: All fevers and infections require prompt evaluation and treatment. Abdominal pain requires evaluation for the potentially lethal complications of peritonitis and bacteremia. Immediate treatment with granulocyte colony-stimulating factor (G-CSF) and broad-spectrum antibiotics is important, even lifesaving, when an affected individual has signs of serious infection, which may be caused by both aerobic and anaerobic pathogens.

Prevention of primary manifestations: Treatment with G-CSF ameliorates symptoms and reduces infections in almost all affected individuals. Once absolute neutrophil count (ANC) levels normalize, resistance to infection greatly improves, such that affected individuals should be able to attend school, work, and recreational activities without specific concern. For affected individuals with a well-matched donor, hematopoietic stem cell transplantation (HSCT) may be the preferred treatment option. HSCT is the only alternative therapy for individuals with congenital neutropenia who are refractory to high-dose G-CSF or who undergo malignant transformation.

Prevention of secondary complications: Good dental hygiene; routine immunizations.

Surveillance: Those with congenital neutropenia not undergoing HSCT require surveillance for malignant transformation to MDS/AML.

Agents/circumstances to avoid: There is no need to avoid public places, as most infections are as a result of common organisms that occur on body surfaces.

Pregnancy management: Pregnancies in women with severe chronic neutropenia are at substantial risk for miscarriage; treatment with G-CSF may reduce this risk.

Evaluation of relatives at risk: Evaluate sibs and other at-risk relatives by molecular genetic testing for the ELANE pathogenic variant found in the proband to identify those with previously unrecognized mild or moderately severe disease who may benefit from treatment. Serial ANCs can also be used for evaluation of family members.

Genetic counseling: ELANE-related neutropenia is inherited in an autosomal dominant manner. One parent of a proband is usually affected. De novo pathogenic variants have been identified; their frequency is unknown. Each child of an individual with an ELANE pathogenic variant has a 50% chance of inheriting the variant. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the family-specific pathogenic variant is known.