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

The literature search produced 1420 records (Embase: 1005, PubMED: 415). After deduplication, 1123 papers have been screened for title and abstract evaluation and 116 papers have been included for full text evaluation. One thousand and seven papers were excluded based on the title and abstract evaluation because 380 were not eligible for publication type, 236 for wrong outcomes and 391 for population not eligible.

After full text screening 90 papers have been used in our systematic review [1,2,3,4,5,6,7,8,9,10,11,12,13, 15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91]: 8 papers were excluded for the publication type and 18 because they did not report the clinical phenotype or the confirmatory genetic mutations.

Figure 1 represented the PRISMA flow diagram demonstrating the process of study selection.

Fig. 1figure 1

PRISMA flow diagram. From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. DOI: 10.1371/journal.pmed1000097

Genetic characteristics of the populations

Ninety-five unique pathogenetic/likely pathogenetic mutations have been reported to date (see Additional file 1: Table S1). Two-hundred and fifteen patients showed a homozygous mutation, 122 showed a compound heterozygosity (biallelic mutation with two different mutations) and 2 a heterozygosity for a single mutation. In 39 patients the mutations reported are not described in the papers, but they specified that patients had a genetically confirmed diagnosis. Among the 329 eligible patients, information regarding the ADA2 enzymatic activity was available only for 175 subjects. In 174/175 patients (99.5%), including the 2 with a single mutation in heterozygosis [62], a decreased activity of Adenosine Deaminase 2 was reported. In one patient, with confirmed homozygous mutation, the ADA2 activity that resulted at normal ranges, was detected after bone marrow transplantation [10].

Clinical characteristics

Three-hundred and seventy-eight patients have been identified, of whom 211 male (55.8%), with a mean age at disease onset of 92.15 months (SD ± 108.2, range 0–720 months), at immunodeficiency onset of 85.4 months (SD ± 114, range 3–480 months) and at first stroke 82.9 (SD ± 139.4, range 5–768 months). Among the 378 patients, 32 (8.5%) showed an onset of the first signs/symptoms after 18 years old and 96 (25.4%) after 10 years old. The spectrum of manifestations at disease onset were widely variables including recurrent fever, cutaneous involvement as panarteritis nodosa-like, recurrent infections, haematological findings, strokes or immunodeficiency or polyneuropathies.

The most frequent clinical characteristics described were the cutaneous (257/378, 67.9%) as livedo reticularis/racemose (180/378, 47.6%), the haematological manifestations (213/378, 56.3%), recurrent fever (194/378, 51.3%), the neurological as stroke and polyneuropathy (193/378, 51%), immunological abnormalities (160/378, 42.3%), arthralgia/arthritis (134/378, 35.4%), splenomegaly (116/378, 30.6%), abdominal involvement (113/378, 29.8%), hepatomegaly (89/378, 23.5%), recurrent infections (70/378, 18.5%), myalgia (68/378, 17.9%), kidney involvement (67/378, 17.7%), oral ulcers (45/378, 11.9%), failure to thrive (36/378, 9.5%), ocular findings (29/378, 7.6%), testicular involvement (13/378, 3.4%), myositis (10/378, 2.6%) (see Fig. 2A and B, Table 1).

Fig. 2figure 2

A shows a schematic representation of the main signs and symptoms of DADA2 patients included in this systematic review; B shows how the different manifestations overlap among them. Each color represents one manifestation as reported in the legend of the picture and the different points of each color the number of patients with the specific feature

Table 1 Main features of DADA2 syndrome

Among the 378 eligible patients, patients with skin manifestations were older than the others (mean 101.1 months SD ± 116.5, vs mean75.3 SD ± 88.2, p 0.041), while those with a haematological involvement (mean 64.1 months SD ± 75.6 vs mean133.1 SD ± 133.1, p < 0.001) and immunological involvement (mean 73.03 months SD ± 96.9 vs mean103.2 SD ± 112.9, p 0.05) are younger than the others. Age at the onset of the disease was not different in patients who displayed recurrent fever, neurological, ocular, abdominal, testicular and nephrological involvement.

Among the different clinical characteristics, we observed that patients with haematological manifestations showed a positive correlation with patients with immunological abnormalities (ρ = 0.417, p < 0.001), failure to thrive (ρ = 0.171, p < 0.001), recurrent infections (ρ = 0.344 p < 0.001) and a negative correlation with skin and abdominal involvement (ρ = 0.282, p < 0.001, ρ = 0.142 p 0.008 respectively) (Table 2).

Table 2 Table of the identified correlations among the different clinical presentations

On the other hand, patients with neurologic involvement with stroke or neuropathy showed a positive correlation with patients who showed skin manifestations (ρ = 0.183, p < 0.001), abdominal involvement (ρ = 0.142, p 0.008), recurrent fever (ρ = 0.192 p < 0.001), ocular (ρ = 0.145, p0.007), while negatively with recurrent infections (ρ = 0.141, p 0.009).

Furthermore, patients with skin manifestations showed a positive correlation with neurologic (ρ = 0.183, p < 0.001), abdominal (ρ = 0.195, p < 0.001), ocular (ρ = 0.160, p 0.003) and testicular involvement (ρ = 0.138, p 0.01), recurrent fever (ρ = 0.341, p < 0.001), failure to thrive (ρ = 0.125, p0.02),), and a negative correlation with recurrent infections (ρ = 0.113, p0.035) and haematological involvement (ρ = 0.282, p < 0.001).

While among patients with immunological abnormalities we evaluated a positive correlation with recurrent infections (ρ = 0.338, p < 0.001) and haematological alterations (ρ = 0.417, p < 0.001) and negatively with a testicular involvement (ρ = 0.107, p 0.048).

Cutaneous manifestations

Cutaneous manifestations were reported in 257 patients (67.9%), and the mean age at onset of the disease was 101.1 months (SD ± 116.5) that is significantly higher than in the other subjects (p 0.041).

Skin manifestations, of note panarteritis nodosa-like lesions, have been reported from the first descriptions [1, 2]. Among the 257 patients with a cutaneous involvement, 180 showed a livedo reticularis or livedo racemose (47.1% of all DADA2 patients) [1, 2, 4, 9, 11, 12, 15, 16, 22, 23, 25, 26, 28,29,30,31, 34,

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