ELANE – Cyclic Neutropenia

ELANE-related cyclic neutropenia is an autosomal dominant disorder marked by regular oscillations in blood neutrophil counts and recurrent infections ([PMID:11001877]). Heterozygous ELANE mutations lead to periodic neutropenia and associated clinical features, including fever, oral ulceration, and severe periodontitis, typically with 21- to 28-day cycles of neutrophil nadirs ([PMID:23463630]; [PMID:29517659]). Genetic testing for ELANE variants is therefore essential in patients with unexplained periodic neutropenia.

Clinical validity is definitive based on >200 unrelated cyclic neutropenia probands with ELANE variants, segregation in at least 5 multiplex families, and concordant cellular and biochemical studies demonstrating pathogenicity ([PMID:11001877]; [PMID:23463630]).

Inheritance is autosomal dominant, with segregation documented in multiple generations. Over 26 distinct ELANE mutations have been identified in 51 cyclic neutropenia patients, including missense, frameshift, and splice-site variants; recurrent frameshift mutation c.538del (p.Leu180SerfsTer11) is reported in severe oral and gingival manifestations ([PMID:31574885]).

Phenotypic spectrum includes periodic neutropenia (HP:0001875), recurrent infections (HP:0002719), fevers (HP:0001945), and oral ulcers (HP:0000155). Complications such as amyloidosis, IgA nephropathy, and secondary HLH have been observed in longstanding or untreated cases ([PMID:21161286]; [PMID:37138249]; [PMID:39676859]).

Functional studies demonstrate that ELANE mutations induce an unfolded protein response, mislocalization of neutrophil elastase, and premature apoptosis of myeloid precursors. In vitro assays of multiple ELANE variants show endoplasmic reticulum stress and reduced granule enzyme activity ([PMID:15657182]; [PMID:26567890]).

Conflicting evidence arises from murine models: V72M knock-in mice exhibit normal granulopoiesis without cycling, highlighting species-specific differences in neutrophil elastase biology ([PMID:12384420]).

In summary, heterozygous ELANE mutations cause cyclic neutropenia via dominant-negative effects on neutrophil elastase processing, leading to periodic granulopoiesis arrest. Early diagnosis by genetic testing enables G-CSF therapy to normalize neutrophil counts and prevent severe complications. Key take-home: ELANE testing is critical for confirming cyclic neutropenia and guiding timely G-CSF intervention.

References

• Blood • 2000 • Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. PMID:11001877
• Human Mutation • 2013 • The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia. PMID:23463630
• Blood • 2005 • Aberrant subcellular targeting of the G185R neutrophil elastase mutant associated with severe congenital neutropenia induces premature apoptosis of differentiating promyelocytes. PMID:15657182
• British Journal of Haematology • 2016 • ELANE mutant-specific activation of different UPR pathways in congenital neutropenia. PMID:26567890
• PLoS One • 2016 • Characterisation of Neutropenia-Associated Neutrophil Elastase Mutations in a Murine Differentiation Model In Vitro and In Vivo. PMID:27942017
• Journal of Clinical Immunology • 2015 • Mosaicism of an ELANE mutation in an asymptomatic mother in a familial case of cyclic neutropenia. PMID:25912133
• Pediatric Nephrology • 2011 • A case of systemic amyloidosis associated with cyclic neutropenia. PMID:21161286
• BMC Nephrology • 2023 • Cyclic neutropenia and concomitant IgA nephropathy: a case report. PMID:37138249
• Frontiers in Immunology • 2024 • Case report: A cyclic neutropenia patient with ELANE mutation accompanied by hemophagocytic lymphohistiocytosis. PMID:39676859
• Medicine • 2019 • Management of tooth extraction in a patient with ELANE gene mutation-induced cyclic neutropenia: A case report. PMID:31574885

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