How Many Patients Have Congenital Neutropenia? a Population-Based Estimation from the Nationwide French Severe Chronic Neutropenia Registry

Introduction: Congenital neutropenia (CN) is characterized by chronic neutropenia caused by a constitutional genetic defect and can be considered an orphan disease. Nationwide estimations of its incidence and prevalence are poorly documented but would provide key information to better follow-up of CN patients. Notably, orphan-drug status also is accorded based on such epidemiological parameters.

Methods: The French Severe Chronic Neutropenia Registry (FSCNR) has prospectively enrolled CN patients since 1993, with multiple source verifications in France of that information: pediatric and adult hemato-immunology units, diagnostic labs... We also actively collect all cases followed in France, regardless of the healthcare facility monitoring the patient. To calculate incidence at birth, we considered subjects born between 1/1/1995 and 12/31/2017, because information completeness has been validated for this 22-year period. Number of births per year was provided by the French National Institute of Statistics and Economic Studies (INSEE). We used American College of Medical Genetics class 4 and 5 variants for genetic classification and the overall CN classification developed elsewhere.¹ To estimate expected prevalence, we assumed 50-year life expectancy for these patients and compared ongoing enrolment to the prevalence estimation and calculated FNSCR coverage. A Poisson distribution was assumed.

Results: On 15 July 2020, the FSCNR had identified 3205 patients. Reasons for non-enrolment of 2096 were, mainly: autoimmune neutropenia (n=501), foreign residency (n=214), other diagnosis (n=882) and diagnostic work-up not completed (n=249). Among the 1109 patients who fulfilled Chronic Neutropenia criteria, 242 had idiopathic neutropenia² and 867 patients were considered to have CN¹. Global results are presented in Table 1. In France, the CN incidence at birth (all subtypes combined) was 2.6×10^–5 (95% CI: 2.04–2.8×10^–5), which represents a mean of 23 new cases/year in a country with ~870,000 births/year.

For all CN combined, the expected prevalence, assuming 50-year life expectancy, would be 1131 cases in a country of 65×10⁶ inhabitants while the FCSNR currently has 867 cases enrolled or an estimated 77% nationwide coverage. Based on our results and our assumptions for life expectancy, estimated prevalence of CN for 10 millions inhabitants is therefore 174 CN.

Genetic subtype representation is as follows: 20% SBDS, 17% ELANE (8% cyclic, 9% permanent), 9% GATA2, 7% SLC37A4, ~4–5% each of TAZ and CXCR4 and VPS13B, while the other subtypes are even rarer. At present, no cause has been identified for 25% of the cases.

Conclusion: The results of this analysis provide an estimation of the major CN-descriptive epidemiological parameters and the relative frequencies of several subtypes. Despite the FSCNR’s quite large registry, we estimate that about a quarter of the prevalent cases in France were missed, mainly those followed as adults.

References

1 Donadieu J, Beaupain B, Fenneteau O, Bellanne-Chantelot C. Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history. Br.J.Haematol. 2017; 179(4): 557-574.

2 Sicre De Fontbrune F, Moignet A, Beaupain B et al. Severe chronic primary neutropenia in adults: report on a series of 108 patients. Blood 2015; 126(14): 1643-1650.

Acknowledgments: The French SCN registry is supported by grants from Amgen, Chugai, Prolong Pharma, X4 Pharma, Inserm, the Association 111 les Arts, the Association RMHE, the Association Sportive de Saint Quentin Fallavier. The authors thank the association IRIS and Mrs Grosjean and Mr Gonnot(ASSQF), the association Barth France for their support.