We read the article, ‘A decision tree for the genetic diagnosis of deficiency of adenosine deaminase 2 (DADA2): a French reference centres experience’ with great interest [1]. The authors have proposed a preliminary decision tree for DADA2 genetic testing. According to this algorithm, they suggested genetic analysis for DADA2 in presence of at least one item from each of three categories: signs of inflammation (fever and/or elevated C-reactive protein); signs of vasculitis (cutaneous and/or neurologic), and recurrent or chronic course (only for adults).
We applied this decision tree retrospectively to our pediatric patients (0-18 years) who were followed-up in Pediatric Rheumatology Outpatient Clinics of Hacettepe University between January 2010 and January 2018 with the diagnosis of DADA2 (n = 10) or polyarteritis nodosa (PAN) (n = 8). Three of these DADA2 patients were previously reported [2, 3]. Sanger sequencing for CECR1 (cat eye syndrome chromosome region candidate 1) mutations had been performed in all of these patients before; nine DADA2 patients were homozygous and one was heterozygous for G47R mutation in CECR1. All PAN patients were negative for CECR1 mutations. All DADA2 patients but one met the prerequisites of the decision tree, while all PAN patients fulfilled the prerequisites. The DADA2 patient who did not meet the prerequisites, presented with only hematologic manifestation (aplastic anemia). And there was parental consanguinity in 9 DADA2 patients, while it was present in only two PAN patients. When we added the presence of parental consanguinity and hematologic manifestations to the prerequisites, all DADA2 patients fulfilled the prerequisites; however, none of the PAN patients except two of them met the new prerequisites. Both PAN patients who met the criteria for Sanger sequencing of CECR1 had parental consanguinity and lymphopenia. Mutations in RAG1 (recombination-activating 1) were demonstrated with whole exome sequencing in one of these patients [4]. The genetic analysis is ongoing for the other patient.
DADA2 is a rare autoinflammatory disease with an expanding phenotype. Although it was first described in patients with PAN-like phenotype [3, 5], recent reports have shown that DADA2 patients may present with isolated hematologic manifestations such as bone marrow failure or red cell aplasia [6,7,8,9]. Some of these patients lack signs of inflammation or vasculopathy [8, 10]. Thus, it is important to include this feature as a prerequisite to the decision DADA2 testing.
DADA2 is an autosomal recessive disease. Clues that suggest autosomal recessive disorders such as parental consanguinity or family history of similar phenotype could be important to differentiate DADA2 from PAN. Thus, this may be added to the decision tree, as well.
In conclusion, modifying the prerequisites in the decision tree for DADA2 by adding hematologic manifestations and parental consanguinity will prevent us from overlooking DADA2 patients with atypical presentations.
References
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Sönmez, H.E., Batu, E.D., Taşkıran, E.Z. et al. Genetic testing for DADA2: How can we avoid missing patients?. Eur J Hum Genet 26, 1563–1565 (2018). https://doi.org/10.1038/s41431-018-0240-1
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DOI: https://doi.org/10.1038/s41431-018-0240-1
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