In this report, we describe the clinical features, laboratory findings, genotypes, and treatment responses in 30 Chinese patients with DADA2. This constitutes the largest cohort study on DADA2 from China to date. The mortality of DADA2 in our cohort is 6.7%, similar to another study (8.4%) [33–38]. The skin and nervous system were the most commonly involved organs. LR and nonspecific rash were common features in cutaneous involvement. Vasculitis involved almost all organs was identified in all patients, which also confirms that DADA2 is a systemic disease.
Systemic inflammation was noted in 93.3% of patients. CRP is the more sensitive index for inflammation compared to ESR. DADA2 is now a well-recognized mimic of PAN with systemic inflammation and vasculitis features [1, 2, 10, 15, 25, 27, 37]. Biallelic mutations in ADA2 gene were identified in 25–31% of childhood PAN [7, 36–38]. Therefore, genetic testing and/or ADA2 activity detection should be considered in patients with recurrent fever accompanied unexplained elevated ESR and/or CRP, and in patients with recurrent fever and livedo racemosa/reticularis or rash, especially in children with PAN-like vasculitis.
The prevalence of hypogammaglobinemia in our cohort is 73.3%, which is similar to the general estimate for 13 cohorts range from 40–100% [1, 2, 5, 7, .9, 11, 33–37]. The prevalence of hypogammaglobinemia is high, but recurrent infection or severe infection was not noted in all patients with hypogammaglobinemia in other studies [1, 5, 34, 36], so is our cohort. There seven patients with recurrent infections in our cohort, which are respiratory tract infection, and are easy to be controlled by antibiotics. Interestingly, one patients (P28) only had recurrent fever and respiratory tract infection without LR, rash and other organ involvement after age of 15. He was diagnosed with immune deficiency disease because of low level of IgM, IgA and IgG, and diagnosed with DADA2 by WES until adulthood. Now, more and more studies reveal mild humoral immunodeficiency with low immunoglobulin levels represents a common clinical feature of DADA2 regardless of the presenting phenotype [10, 27, 38]. Therefore, patients with antibody deficiencies should also be considered to screen gene testing.
Hematologic abnormalities are primary presentation in some patients, even without vasculitis or systemic inflammation [5, 8]. PRCA and BMF with variable cytopenia was observed in one patient in our cohorts, without vasculitis and systemic inflammation. Mild to moderate anemia and leukopenia/neutropenia was noted in 73.0% and 20% of patients, respectively. Frequency of anemia is consistent with that of recurrent fever (90.0%), and it may be caused by recurrent chronic systemic inflammation.
Patients in our cohort show no response to glucocorticoid, NSAIDs, IVIG, and traditional DMARDs. TNF inhibitors were given to 23 patients with disease flare. Our study revealed TNF inhibitors have the effect of controlling the fever episodes and vasculitis in 23 patients. In addition, all patients treated with TNF inhibitors do not develop stroke or relapse during follow-up duration, which ranges from 5 to 36 months. Three patients received thalidomide, and clinical symptoms were also improved significantly. HSCT is an alternative choice for patients with refractory to TNF inhibitors or hematological disorders, which not only rescues the hematological and immunological phenotype, but also vascular phenotype in DADA2[8, 9, 37, 42–45].
In total, 39 variants were detected in our cohort. Of these variants, six variants are novel (Table 2), which expands the spectrum of known mutations in ADA2. Mutations detected in our cohort are in each coding exon of the ADA2 gene, and involved in four domains of protein encoded by ADA2. None hot spots were found in our cohort. The most common variant is the mutation p.T33Nfs*29 identified in four patients, which located in dimerization domain. The p.G47R mutation frequently seen in Georgian, Jewish and Turkish, the p.R169Q variant mainly noted in the Netherlands, Belgium and Finland, and the p.T360A mutation more common in Italy were all observed in our cohort [2, 7, 34, 46].
Currently, the diagnosis of DADA2 is established in a proband with suggestive clinical and laboratory findings. Most patients with DADA2 from all over the world are from department of rheumatology in different centers [1, 2, 5, 7, .9, 11, 33–37, 47, 48]. Patients with haematological abnormalities, or humoral immunodeficiency, and/or early stroke may likely to be misdiagnosed. Early diagnosis of ADAD2 is important as it provides the chance of a timely treatment to improve the patient outcome and as the attainment of an early response dampens the disease course by minimizing organ damage. Therefore, we propose flow chart of diagnosis of DADA2 in Fig. 2. Molecular diagnosis should be performed in patients with at least one of followings, unexplained reason of systemic inflammation, or vasculitis, or humoral immunodeficiency, or severe hematologic abnormalities, especially in children.
Limitation
Most patients of this study are from rheumatology department, and some patients with hematologic abnormalities, stroke and recurrent infection as the first symptoms may be not included. It is necessary to improve the understanding of DADA2 among pediatric neurology, hematology and immunology specialists in China.