1851: Phenotype and Genotype of Adult-onset Adenosine Deaminase 2 Deficiency Patients

Beibei Zu¹, rongrong wang², Xiaorou Wang³, Bingqing Zhang⁴, Na Xu⁴, Chengjin Huang⁴, Min Shen⁵ and Xuejun Zeng⁴, ¹Department of Rheumatology, Xuzhou Central Hospital, XuZhou, China, ²Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China, ³Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Beijing, China, ⁴Department of General Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China, ⁵Department of Rheumatology, Peking Union Medical College Hospital, Beijing, China

Background/Purpose: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disease, characterized by early‑onset vasculopathy, fever, strokes, livedoid rash, hepatosplenomegaly, and hematologic dysfunction, associated with mutations in the ADA2 gene, which was first described in 2014, DADA2 is usually reported in pediatric patients, with 77% before the age of 10 years. Adult-onset DADA2 patients have also been occasionally reported. However, DADA2 patients have been hardly reported in the Chinese population. We sought to identify the phenotype and genotype of adult-onset DADA2 patients.

Methods: We recorded the clinical data and genotype of three Chinese adult-onset DADA2 patients(≥16 years) were diagnosed and followed up in our tertiary medical center from 2015 to 2021. Whole-exome sequencing and adenosine deaminase 2 (ADA2) enzyme activity were performed in all patients. We also searched the case reports of Chinese childhood-onset DADA2 and adult-onset DADA2 from other populations. Their phenotypes and genotypes were further summarized and compared.

Results: Our patients had all main clinical manifestations of DADA2 including vasculopathy and inflammation, hematological disorder and immunodeficiency, and serum ADA2 levels were almost undetectable. Two patients had gastrointestinal involvement (Patient 1 and Patient 3), one patient had arthritis (Patient 2), and another one had ophthalmological abnormalities (Patient 3). The phenotypes of the Chinese adult-onset DADA2 patients were similar to those of pediatrics, while the occurrence of fever, immunodeficiency and hematological abnormalities was higher than that in adult-onset patients from other populations. Compared to adult-onset patients from other populations, our patients had a smaller disease-onset age (median: 18 years old vs. 28 years old), higher frequency of immunodeficiency (100% vs. 24.1%), hematological involvement (100% vs. 31.0%), and fever (100% vs. 31.0%). Two SNPs and three deletion variants in the ADA2 gene were identified in our patients. In patient 1, R169G and exon 7 deletion were found. In patient 2, V372M were detected. In patient 3, exon 7 deletion was identified. Two of our adult-onset patients and all nine childhood-onset patients had compound heterozygous for missense variants, In the 29 adult-onset DADA2 patients from other populations, the most common variants are homozygous variants, 20 out of 29 (69.0%) patients carried homozygous variants. Deletion of exon 7 was detected only in one patient.

Conclusion: In our study, adult-onset DADA2 patients had a broad range of phenotypes. Vasculopathy, inflammation, stroke were the most frequent symptoms. DADA2 is not only seen in young children, and adult providers need to be aware of this monogenic syndrome as well. DADA2 has a broad range of phenotypes, and other genetic and epigenetic modifications, the amount of remaining ADA2 activity, and environmental factors may influence the clinical phenotype of DADA2, and it makes the diagnosis a huge challenge. Early diagnosis through gene sequencing and ADA2 activity assay, followed by initiation of anti-TNF therapy, can significantly improve the prognosis of DADA2 patients.
Figure 1: Clinical manifestations of DADA2 patients. A: Brain MRI of Patient 1 showed ischemic infarct at the thalamus (red arrow); B: Brain MRI of Patient 1 revealed ischemic infarct at the medulla oblongata (red arrow); C: Livedo reticularis and vasculitis rash on the lower limbs of Patient 2 with scarring and pigmentation; D: Brain MRI of Patient 2 showed multiple lacunar infarcts in bilateral basal ganglia (red arrow); E: Head CT of Patient 3 showed massive hemorrhage in the right temporal lobe (red arrow); F: Livedo reticularis on the lower limbs of Patient 3

Table 1 Clinical characteristics of adult-onset DADA2 patients
Disclosures: B. Zu, None; r. wang, None; X. Wang, None; B. Zhang, None; N. Xu, None; C. Huang, None; M. Shen, None; X. Zeng, None.