Clinical Symptoms, Laboratory Parameters and Long-Term Follow-up in a National DADA2 Cohort

Abstract

Deficiency of adenosine deaminase-2 (DADA2) is an autosomal recessive autoinflammatory disease with an extremely variable disease presentation. This paper provides a comprehensive overview of the Dutch DADA2 cohort. We performed a retrospective cohort study in 29 ADA2-deficient patients from 23 families with a median age at inclusion of 26 years. All patients had biallelic pathogenic variants in the ADA2 gene. The most common clinical findings included cutaneous involvement (79.3%), (hepato)splenomegaly (70.8%) and recurrent infections (58.6%). Stroke was observed in 41.4% of the patients. The main laboratory abnormalities were hypogammaglobulinemia and various cytopenias. Patients presented most often with a mixed phenotype involving vasculopathy, immunodeficiency and hematologic manifestations (62.1%). In this cohort, malignancies were reported in eight patients (27.6%), of whom five presented with a hematologic malignancy and two with a basal cell carcinoma. Four patients developed hemophagocytic lymphohistiocytosis (HLH) or an HLH-like episode, of whom three passed away during or shortly after the occurrence of HLH. TNF-inhibitors (TNFi) were effective in treating vasculopathy-associated symptoms and preventing stroke, but were hardly effective in the treatment of hematologic manifestations. Three patients underwent hematopoietic cell transplantation and two of them are doing well with complete resolution of DADA2-related symptoms. The overall mortality in this cohort was 17.2%. In conclusion, this cohort describes the clinical, genetic and laboratory findings of 29 Dutch DADA2 patients. We describe the occurrence of HLH as a life-threatening disease complication and report a relatively high incidence of malignancies and mortality.

Keywords: DADA2; HLH; complications; follow-up; treatment.

Fig. 1

A Residual ADA2 activity in a cohort of 29 DADA2 patients before initiation of TNFi. Empty columns indicate a missing value. Mixed phenotype indicates a combination of two or three phenotypes (vasculopathy, hematologic manifestations, immunodeficiency). Residual ADA2 activity in healthy controls was based on the mean residual activity and range of 11 healthy controls (mean 5.46 U/L, range 3.4–7.2 U/L). Residual ADA2 activity in heterozygotes was based on the mean residual activity and range of 15 carriers of pathogenic ADA2 variants (mean 1.45 U/L, range 0.0–3.4 U/L). B Residual ADA2 activity in DADA2 patients with a vasculopathy phenotype (with or without immunodeficiency) versus hematologic phenotype (with or without immunodeficiency). * Only residual ADA2 activity values measured before initiation of TNFi are used

Fig. 2

A Current treatment in a cohort of 29 DADA2 patients. B Currently prescribed TNF-inhibitors in 19 DADA2 patients