AB1300 AA AMYLOIDOSIS IN A PATIENT WITH MUTATIONS IN BOTH ADA2 AND A20 GENES

Abstract

BackgroundAdenosine Deaminase 2 Deficiency (DADA2) and Haploinsufficiency of A20 (HA20) are two recently described monogenic autoinflammatory diseases (AID). The uncontrolled inflammatory response has been associated with an increased risk of AA amyloidosis in other AID, but there are only two reported patients with DADA2-related amyloidosis so far.1,2ObjectivesWe herein report a patient with AA amyloidosis and AID associated with both DADA2 and HA20.MethodsWe used the Ion Torrent platform for deep sequencing.ResultsCase: A 20-year-old male patient born to consanguineous parents (Figure 1), was admitted to our hospital with fever and abdominal pain in June 2014. Peritonitis, hepatomegaly, and a palpable non-tender mass in the right axillary cavity were detected in physical examination, and his laboratory investigations revealed neutrophilic leukocytosis, high acute phase reactants (APR), and nephrotic range proteinuria. CT angiography showed multiple thrombotic microaneurysms in celiac, splenic, superior, and inferior mesenteric and bilateral renal arteries; and MRI documented an additional aneurysm in anterior communicating artery. No finding was detected in hepatitis serology. He had been diagnosed with polyarteritis nodosa, and prednisolone and azathioprine were started. Renal histopathology confirmed the AA amyloidosis. Genetic analysis revealed no pathogenic MEFV variant. Colchicine and anakinra 100 mg/day were added to his treatment. He experienced 1-2 abdominal episodes annually between 2014-2019, and APR were normal between attacks. In March 2019, he was admitted to the hospital because of abdominal pain, high APR, and iron deficiency anemia. No gross pathology was observed in endoscopic examination of gastrointestinal tract, but histopathological investigation of the gastric mucosa and terminal ileum showed AA amyloidosis. Multiple aneurysms were detected in renal arteries with angiography. Deep sequencing of the targeted genes revealed homozygous p.Pro251Leu in ADA2 gene and heterozygous p.Thr647Pro in TNFAIP3 gene encoding A20, confirming the molecular diagnosis of DADA2 and HA20. The patient described oral recurrent aphthous ulcers starting from his childhood, but he had no uveitis or genital ulcers. His mother and brother also had recurrent oral aphthous ulcers. Genetic analyses showed heterozygous p.Pro251Leu variant in ADA2 gene in his mother, and heterozygous p.Gln703Lys variant in NLRP3 gene as well as heterozygous p.Thr647Pro TNFAIP3 variant and heterozygous p.Pro251Leu ADA2 in his brother. An improvement in his findings was observed within 2 weeks after switching his anakinra to adalimumab 40 mg every other week. At his last visit in February 2021, the patient had no complaints with normal APR, and urinalysis analysis showed 200 mg/day proteinuria, which was regressed from 3 g/day.ConclusionThis is the first case of AA amyloidosis associated with ADA2 and TNFAIP3 (A20) variants. ADA2 p.Pro251Leu variant has previously been validated as likely pathogenic, and our patient’s clinical findings were mainly compatible with DADA2. On the other hand, TNFAIP3 gene p.Thr647Pro mutation has been reported as variant of unknown significance, but it may have contributed to the DADA2 associated increased risk of amyloidosis. A better response of proteinuria to adalimumab treatment indicates superiority of anti-TNFs in DADA2 patients compared to anti-IL-1 drugs.