Clinical Guidance

Genotype-phenotype correlations are only roughly defined for ELANE-related neutropenia. Although the patterns of pathogenic variants in ELANE-associated cyclic neutropenia and congenital neutropenia are distinct on a population basis, the patterns of pathogenic variants do overlap, indicating that the distinction between cyclic neutropenia and congenital neutropenia is primarily based on clinical findings and only secondarily on genotype . identified individuals with the same pathogenic variant who had different clinical phenotypes. The risk of developing myelodysplasia or acute myelogenous leukemia varies considerably depending on the specific ELANE variant .

Source: GeneReviews — "ELANE-Related Neutropenia"

Diagnostic Criteria

ELANE-related neutropenia represents a clinical spectrum that includes congenital neutropenia, cyclic neutropenia, and intermediate findings between these two phenotypes. Identification of the precise clinical phenotype is helpful for diagnosis, prognosis, and management.

Suggestive Findings

ELANE-related neutropenia should be suspected in individuals with the following clinical and supportive laboratory findings.

Clinical features

• Severe or recurrent infections

• Congenital neutropenia. Recurrent fevers, sinusitis, gingivitis, and chronic and severe infections in the lung, liver, and soft tissues occurring at irregular intervals

• Cyclic neutropenia

Source: GeneReviews — "ELANE-Related Neutropenia"

Differential Diagnosis

Congenital Neutropenia

The differential diagnosis of congenital neutropenia includes the following disorders.

Isolated neutropenia

• Kostmann disease (OMIM 610738), an autosomal recessive form of severe congenital neutropenia caused by biallelic pathogenic variants in HAX1

Note: De novo heterozygous ELANE pathogenic variants (autosomal dominant severe congenital neutropenia) are much more common than HAX1 pathogenic variants (autosomal recessive congenital neutropenia) as a cause of simplex cases of severe congenital neutropenia (i.e., a single occurrence in a family) . For this reason, it is usually best to first sequence ELANE in seeking to determine the genetic basis for severe congenital neutropenia.

Source: GeneReviews — "ELANE-Related Neutropenia"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with ELANE-related neutropenia, the following are recommended if they have not already been completed:

• Dental examination for gingival and periodontal disease

• Evaluation (particularly of those with severe congenital neutropenia) by an otolaryngologist and a pulmonologist for chronic sinopulmonary inflammation and deep abscesses

• Evaluation of individuals with severe congenital neutropenia for evidence of myelodysplasia or leukemia with bone marrow aspirate and biopsy

• Consultation with a clinical hematologist, geneticist, and/or genetic counselor for specific clinical advice

Treatment of Manifestations

Fevers require prompt evaluation and empiric treatment until the source of the fever can be definitively identified, at which time targeted treatment may be possible:

• Initiation of broad-spectrum antibiotics is important, even lifesaving, when an affected individual has signs of serious infection, which may be caused by either aerobic or anaerobic pathogens. Coverage matching local patterns for infections in immunosuppressed individuals should initially be given for both aerobic and anaerobic organisms.

• Granulocyte colony-stimulating factor (G-CSF), given subcutaneously, should also be administered daily starting immediately to promote increased neutrophil production and deployment.

Source: GeneReviews — "ELANE-Related Neutropenia"

Clinical Guidance

Most infections are caused by common organisms on body surfaces including Clostridia species and other anaerobes in the intestinal biota. For this reason it is of little or no benefit to avoid public places.

Source: GeneReviews — "ELANE-Related Neutropenia"

Therapies Under Investigation

Unrelated cord blood transplantation for neutropenia is being investigated; outcome appears to depend on the closeness of the match . Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "ELANE-Related Neutropenia"

Surveillance Guidelines

For those individuals with congenital neutropenia not undergoing HSCT, surveillance for evidence of malignant transformation to MDS/AML is critical to allow early therapeutic intervention. Observation should include the following:

• General evaluations by parents and medical personnel several times a year

• Blood counts several times a year

• Annual bone marrow cytogenetic studies because of the frequent association of monosomy 7 and malignant transformation

Note: Although sequencing of the receptor for G-CSF (CSF3R) from peripheral blood may also provide evidence of evolution to MDS/AML , its clinical utility is not yet clearly established .

Source: GeneReviews — "ELANE-Related Neutropenia"