A wide spectrum of phenotype of deficiency of deaminase 2 (DADA2): a systematic literature review

Abstract

Introduction Deficiency of adenosine deaminase 2 (DADA2) is a rare monogenic autoinflammatory disease, whose clinical phenotype was expanded since the first cases, originally described as mimicker of polyarteritis nodosa, with immunodeficiency and early-onset stroke. Methods A systematic review according to PRISMA approach, including all articles published before the 31st of August 2021 in Pubmed and EMBASE database was performed. Results The search identified 90 publications describing 378 unique patients (55.8% male). To date 95unique mutations have been reported. The mean age at disease onset was 92.15 months (range 0–720 months), 32 (8.5%) showed an onset of the first signs/symptoms after 18 years old and 96 (25.4%) after 10 years old. The most frequent clinical characteristics described were cutaneous (67.9%), haematological manifestations (56.3%), recurrent fever (51.3%), neurological as stroke and polyneuropathy (51%), immunological abnormalities (42.3%), arthralgia/arthritis (35.4%), splenomegaly (30.6%), abdominal involvement (29.8%), hepatomegaly (23.5%), recurrent infections (18.5%), myalgia (17.9%), kidney involvement (17.7%) etc. Patients with skin manifestations were older than the others (101.1 months SD ± 116.5, vs. 75.3 SD ± 88.2, p 0.041), while those with a haematological involvement (64.1 months SD ± 75.6 vs. 133.1 SD ± 133.1, p < 0.001) and immunological involvement (73.03 months SD ± 96.9 vs. 103.2 SD ± 112.9, p 0.05) are younger than the others. We observed different correlations among the different clinical manifestations. The use of anti-TNFα and hematopoietic cell stems transplantation (HCST) has improved the current history of the disease. Conclusion Due to this highly variable phenotype and age of presentation, patients with DADA2 may present to several type of specialists. Given the important morbidity and mortality, early diagnosis and treatment are mandatory.

Cutaneous vasculitis in autoinflammatory diseases

“…37 The onset of most monogenic AIDs mainly appear in childhood; however, clinical signs and symptoms of DADA2 syndrome may also start in adulthood and up to 8.5% of patients may have the first signs or symptoms after 18 years old. 38 DADA2 has a wide spectrum of clinical presentations that range from fatal systemic vasculitis with multiple strokes, especially in pediatric patients, to limited cutaneous disease in middle-aged patients. 39 Clinical manifestations of DADA2 can be grouped into three categories: (1) inflammatory (vasculitis/vasculopathy/rash); (2) immune dysregulation; and (3) hematologic abnormalities.…”

“…Although patients often present with primary features of one of these categories, considerable overlapping of the subgroups has been observed. Skin involvement is the most common clinical manifestation, ranging from 90% 40 (52 to 58) to 67.9% 38 (257 to 378) of patients with DADA2. Among them, livedo racemosa is the most common skin manifestation (43 of 58 [74%] 40 and 180 of 257 [70%]), 38 followed by cutaneous nodules resembling PAN/nodules (33 of 58…”

“…The onset of most monogenic AIDs mainly appear in childhood; however, clinical signs and symptoms of DADA2 syndrome may also start in adulthood and up to 8.5% of patients may have the first signs or symptoms after 18 years old 38 …”

“…Skin involvement is the most common clinical manifestation, ranging from 90% 40 (52 to 58) to 67.9% 38 (257 to 378) of patients with DADA2. Among them, livedo racemosa is the most common skin manifestation (43 of 58 [74%] 40 and 180 of 257 [70%]), 38 followed by cutaneous nodules resembling PAN/nodules (33 of 58 [57%]) 40 maculopapular erythema, livedoid lesions, Raynaud phenomena, and digital cyanosis with gangrene ulcers were occasionally found 40 …”