DADA2 is a monogenic autoinflammatory disorder with broad and variable signs and symptoms, which can be categorized into three main phenotypes: vasculitis, hematologic abnormalities, and immunodeficiency [11]. This phenotypic variability often leads to diagnostic challenges, as DADA2 can mimic a wide range of other diseases depending on its predominant manifestations. For instance, in patients presenting primarily with hematologic abnormalities such as cytopenia, pure red cell aplasia, or lymphoproliferation, they may be misdiagnosed initially with Diamond-Blackfan anemia or Evans syndrome. Similarly, the immunodeficient phenotype of DADA2, characterized by hypogammaglobulinemia, recurrent infections, and/or lymphopenia, can overlap with conditions such as combined immunodeficiency, common variable immunodeficiency (CVID), or autoimmune lymphoproliferative syndrome (ALPS). Finally, the vasculitic phenotype that includes features like recurrent fever, livedo reticularis, and early-onset strokes, can mimic systemic vasculitis like PAN or monogenic lupus [11, 24,25,26,27,28]. These overlapping features underscore the importance of considering DADA2 in the differential diagnosis of patients with early-onset systemic inflammation, particularly when the clinical presentation does not fully align with classic diagnostic criteria for these conditions.

In this article, we reported a family of three siblings with genetically confirmed DADA2, two of whom were initially misdiagnosed with Behçet’s disease (BD) due to the striking overlap in clinical features, including recurrent oral ulcers, cutaneous lesions, and HLA-B51 positivity. We therefore reviewed the literature using the PubMed database, restricted to English-language articles, and identified eight additional DADA2 patients from five unrelated families [24,25,26,27,28], all of whom were initially labeled with BD before being found to carry pathogenic ADA2 mutations (Table 1).

Both DADA2 and BD are complex conditions that can present with a range of overlapping symptoms, with the inflammatory manifestations being the major clinical feature of both diseases. As shown in Table 1, almost all the patients exhibited a combination of fever, livedo reticularis, cutaneous ulcers, arthritis/arthralgia, with symptoms typically beginning in early childhood. This early age of onset is a notable feature, as BD is more commonly diagnosed in adulthood or late childhood [17], whereas DADA2 often presents in the first decade of life, particularly in populations with a high prevalence of consanguinity, which increases the likelihood of autosomal recessive conditions. The median time from the onset of symptoms to reaching the final diagnosis of DADA2 was 7 years, underscoring the diagnostic challenges posed by the overlapping clinical features of these conditions. In addition to the clinical phenotype, we believe that the positivity of HLA-B51 (8/10) further contributed to the initial misdiagnosis of BD in these cases, as HLA-B51 is a well-established genetic susceptibility factor for BD [18,19,20]. This highlights the importance of considering genetic and molecular testing, particularly in pediatric patients with early-onset inflammatory symptoms and/or a family history of consanguinity, to differentiate between these clinically similar disorders.

Conversely, uveitis is rarely associated with DADA2 disease. In fact, it has been reported in only four cases of DADA2 [29,30,31,32]. This trend was also observed in Table 1 as none of the patients who were misdiagnosed with BD had uveitis, a hallmark commonly seen in BD patients [33]. We believe that the absence of uveitis could serve as a key clinical clue in differentiating between DADA2 patients presenting with a BD-like phenotype and those with true early-onset BD.

In general, the diagnosis of DADA2 is often challenging due to its broad spectrum of clinical manifestations including hematologic, immunodeficiency, inflammatory and/or vasculitic phenotypes [11]. Moreover, the absence of standardized diagnostic criteria and the limited availability of ADA2 enzyme activity tests in most centers complicate the process. The high costs and need for sending samples abroad for testing also contribute to these challenges [27, 34]. In such cases, genetic testing may be the only viable diagnostic option. However, it is time-consuming and may not always yield definitive results, which can to delays in managing those patients.

Once the diagnosis is confirmed, establishing a prompt and effective treatment plan is crucial for managing DADA2 patients, aiming to address its diverse clinical manifestations and minimize disease-associated morbidity and mortality. It involves a range of therapeutic options to control the symptoms and prevent disease progression. The international DADA2 Consensus Committee considers anti-TNF therapy as the treatment of choice for patients with inflammatory and vasculitic phenotype [11]. Lifelong anti-TNF therapy demonstrated a desirable effect in achieving remission and decreasing the risk for strokes and other vasculitic complications [11, 35]. As shown in Table 1, all the patients were started on TNF inhibitors except for three related individuals (E6, E7, and E8). The first patient (E6) passed away before reaching to the diagnosis, while the other two (E7 and E8) refused anti-TNF treatment as they became asymptomatic after starting Colchicine [27]. Allogeneic hematopoietic stem cell transplantation (HSCT) may emerge as a necessary intervention when having a severe form of the disorder such as bone marrow failure and refractory cytopenia [11]. A recent systematic review showed that among 25 patients who underwent HSCT, a complete resolution of the disease manifestations was reported in 22 cases [35].

Following the discussion of treatment options for symptomatic DADA2 patients, a significant clinical dilemma arises regarding whether anti TNF therapy should be started in all asymptomatic patients for stroke prevention. The DADA2 Consensus Committee was unable to provide a strong recommendation for treating such patients, advising only to consider it, likely due to the unpredictable nature of DADA2 and the lack of natural history data [11]. In the case of our asymptomatic patient (A3), her parents opted to delay starting the medication. For the past four years, she has been regularly monitored in the clinic, remaining stable with normal blood counts and inflammatory markers. Additionally, MRI/MRA scan was performed and did not identify any abnormalities. Until larger prospective studies provide clearer guidance, we believe the decision should be made collaboratively between the provider and the patient’s family. Clinicians must carefully weigh the risks and benefits, balancing the need for indefinite therapy in an asymptomatic individual against the potential for a catastrophic event as the first manifestation of the disease.

Our study has several limitations to consider. First, the limited number of patients, particularly asymptomatic individuals like Patient A3, restricts our ability to generalize management recommendations for presymptomatic DADA2 cases. Second, while genetic testing confirmed the ADA2 variant, ADA2 enzyme activity was not assayed to confirm functional deficiency in multiple patients. Third, the role of HLA-B*51 in driving the BD-like phenotype remains unclear. Lastly, the retrospective nature of our analysis may introduce selection bias, particularly in identifying DADA2 cases initially misdiagnosed as BD.

In conclusion, DADA2 is an inherited disease associated with significant morbidity and mortality, and it can present with a wide range of clinical manifestations, including a Behcet’s disease-like phenotype. The presence of HLA-B*51 in such patients may mislead clinicians and delay the diagnosis of DADA2, as highlighted in the reported cases. Physicians should consider alternative diagnoses to BD in cases of poor response to treatment, early age of symptom onset, or a family history of consanguinity and/or BD. Notably, none of the patients misdiagnosed with BD in our review had a history of uveitis, a common feature in BD. The absence of uveitis may serve as a useful clinical clue for identifying DADA2 in patients presenting with a BD-like phenotype. Finally, prospective studies are urgently needed to refine recommendations for monitoring and potentially treating presymptomatic DADA2 patients.