Congenital neutropenia

Congenital neutropenia is present in the neonatal period or first months of life. Affected infants develop fever, omphalitis at birth, and recurrent infection of skin and oropharynx, including mouth ulcers, gingivitis, sinusitis, pharyngitis, and cervical adenopathy. Deep bacterial infections (pneumonia, hepatic, pulmonary, and subcutaneous abscesses) and severe diarrhoea are common in the early infantile period; infectious complications are generally more severe than in cyclic neutropenia.

The clinical spectrum encompasses both nonsyndromic forms, in which neutropenia is the predominant feature, and syndromic forms, in which neutropenia accompanies a broader phenotype with extrahaematopoietic involvement of the pancreas, heart, central nervous system, or other organ systems. Granulocyte colony-stimulating factor (G-CSF) raises blood neutrophil counts and reduces infectious complications in more than 90% of treated individuals; nevertheless, a substantial subset show progression to or acute myeloid leukaemia over time.

The estimated prevalence in the general population is 2 to 3 cases per 1,000,000. Reliable population-level estimates across the full clinical spectrum are limited.

More than 20 genes are currently associated with congenital neutropenia. The genetic forms of congenital neutropenia can be grouped into nonsyndromic and syndromic forms. The most common genetic cause is ELANE-related neutropenia (neutrophil elastase defect, classical autosomal dominant SCN). Other examples include HAX1-related severe congenital neutropenia (Kostmann-type neutropenia with neurodevelopmental features) and (exocrine pancreatic insufficiency with marrow dysfunction).

The genetic conditions associated with congenital neutropenia follow heterogeneous inheritance patterns. Autosomal dominant, autosomal recessive, and X-linked recessive forms are all recognised; pathogenic variants in ELANE represent the most frequent autosomal dominant cause and are substantially more common than autosomal recessive forms in simplex presentations.

• Where congenital neutropenia is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

• Dale DC, Makaryan V. ELANE-related neutropenia. 2018 Aug 23. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301705.
• Crisà E, Boggione P, Nicolosi M, Mahmoud AM, Al Essa W, Awikeh B, et al. Genetic predisposition to myelodysplastic syndromes: a challenge for adult hematologists. Int J Mol Sci. 2021;22(5):2525. doi:10.3390/ijms22052525. PMID:; PMCID: PMC7959319.
• Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022;42(7):1473-1507. doi:10.1007/s10875-022-01289-3. PMID:; PMCID: PMC9244088.
• Papadaki HA, Mavroudi I, Almeida A, Bux J, Cichy J, Dale DC, et al. Congenital and acquired chronic neutropenias: challenges, perspectives and implementation of the EuNet-INNOCHRON Action. HemaSphere. 2020;4(3). doi:10.1097/HS9.0000000000000406. PMID:; PMCID: PMC7306309