Renal Amyloidosis in Deficiency of Rabia Miray Kisla Ekinci, MD, a Sibel Balci, MD, a Atil Bisgin, MD, b Michael Hershfield, MD, c AdenosineBahriye Atmis, MD, d Dilek Dogruel, Deaminase MD, e Mustafa Yilmaz, MDa 2: Successful Experience With Canakinumab abstract Deficiency of adenosine deaminase 2 (DADA2) is a rare autoinflammatory disease that was firstly described in patients with early-onset strokes, livedo reticularis, and periodic fever resembling polyarteritis nodosa.‍ In reported case series, researchers described highly variable manifestations, Departments of aPediatric Rheumatology, bMedical including autoimmunity, immunodeficiency, hepatosplenomegaly, Genetics, dPediatric Nephrology, and ePediatric Allergy and pancytopenia, ichthyosiform rash, and arthritis, in patients with DADA2.‍ Immunology, Faculty of Medicine, Çukurova University, Adana, Turkey; and cDepartment of Medicine and A thirteen-year-old female patient who was born to consanguineous Biochemistry, School of Medicine, Duke University, Durham, parents was admitted to our hospital with generalized edema and leg pain.‍ North Carolina A physical examination revealed splenomegaly and left knee arthritis.‍ Drs Kisla Ekinci and Yilmaz provided clinical care Nephrotic-range proteinuria and hypoalbuminemia were present, and a for the patient, interpreted data, and contributed renal biopsy revealed amyloidosis.‍ Despite the absence of periodic fever to writing and revising the initial draft; Drs Balci, Atmis, and Dogruel contributed to writing the and livedo reticularis, our patient had suggestive features of DADA2, initial draft and revised the manuscript; Dr Bisgin including low serum immunoglobulin G and immunoglobulin M levels, performed a genetic analysis of the patient, hepatosplenomegaly, and renal amyloidosis.‍ We found a heterozygote contributed to writing the initial draft, and revised the manuscript; Dr Hershfield provided the plasma Met694Val mutation in the Mediterranean fever gene and a novel level of adenosine deaminase 2 activity in the homozygote Thr317Argfs*25 (c.‍950-950delCys) mutation in the cat eye patient, interpreted data, and critically reviewed chromosome region 1 gene.‍ A functional analysis revealed absent plasma the manuscript for important intellectual content; and all authors approved the final manuscript adenosine deaminase 2 activity.‍ Canakinumab was administered because of as submitted and agree to be accountable for all unresponsive proteinuria despite 2 months of treatment with colchicine and aspects of the work. methylprednisolone.‍ Proteinuria improved after 7 doses of canakinumab.‍ DOI: https:// doi. org/ 10. 1542/ peds. 2018- 0948 In conclusion, DADA2 should be considered in the differential diagnosis of – Accepted for publication Jul 11, 2018 renal amyloidosis, particularly in the absence of homozygote Mediterranean Address correspondence to Rabia Miray Kisla fever mutations.‍ Although anti tumor necrosis factor agents are widely Ekinci, MD, Department of Pediatric Rheumatology, offered in DADA2 treatment, we speculate that canakinumab may be an Faculty of Medicine, Çukurova University, Balcali/ appropriate treatment of renal amyloidosis in DADA2.‍ Saricam 01330, Adana, Turkey. E-mail: mir_kisla@ hotmail.com PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Deficiency of adenosine deaminase 2 or absent ADA2 activity, possibly Copyright © 2018 by the American Academy of (DADA2) is a rare autoinflammatory leading to monocyte differentiation Pediatrics disease that was firstly described in toward M1-type proinflammatory FINANCIAL DISCLOSURE: The authors have patients with early-onset strokes, macrophages1, 3and endothelial indicated they have no financial relationships livedo reticularis, and periodic dysfunction.‍ Patients with decreased relevant to this article to disclose. fever, which are compatible1, 2 CECR1 with levels of serum immunoglobulin G FUNDING: No external funding. polyarteritis nodosa.‍ The cat (IgG) and immunoglobulin M (IgM), eye chromosome region 1 ( ) low switched memory B cells, and To cite: Kisla Ekinci RM, Balci S, Bisgin A, et al. (NM_001282225.‍1) gene encodes lymphopenia highlighted the presence – 4,5 Renal Amyloidosis in Deficiency of Adenosine adenosine deaminase 2 (ADA2), of mild immunodeficiency in DADA2.‍ Deaminase 2: Successful Experience With Canakinumab. Pediatrics. 2018;142(5):e20180948 CECR1a 511 amino acid protein that is Furthermore, in the reports in which essential for leukocyte development.‍ the patients with DADA2 who had only gene mutations cause reduced hematologic or dermatological findings Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 142, number 5, November 2018:e20180948 CASE REPORT were evaluated, attention was6,7 drawn (1.‍5 mg/day) was added to an oral polyarteritis nodosa.‍ The disease to the clinical heterogeneity.‍ Here, methylprednisolone treatment of is characterized by recurrent fever we present the first patient with 16 mg/day, and administration of and an elevation of acute-phase DADA2 in the literature in whom cyclosporine was ceased.‍ reactants usually associated with renal amyloidosis was successfully livedo reticularis and neurologic – β β Molecular studies revealed a 1,2 treated with canakinumab, a manifestations.‍ In case series, heterozygote Met694Val mutation human anti interleukin 1 (IL-1 ) researchers described highly in the Mediterranean fever (MEFV) monoclonal antibody.‍ variable manifestations, including gene and a novel homozygote CECR1 autoimmunity, immunodeficiency, CASE REPORT Thr317Argfs*25 (c.‍950-950delCys) hepatosplenomegaly, pancytopenia, mutation in the gene (Fig 1).‍ – ichthyosiform rash, and arthritis, Thus, we administered canakinumab 7 9 in DADA2.‍ Despite the (150 mg monthly) because of A 13-year-old female patient, absence of recurrent fever and unresponsive proteinuria despite previously healthy, who was born livedo reticularis, our patient 2 months of previous treatment.‍ to consanguineous parents was had hypogammaglobulinemia, Moreover, the tumor necrosis factor admitted to our hospital with hepatosplenomegaly, and renal receptor superfamily member 1A generalized edema, left knee swelling, amyloidosis possibly relevant to (TNFRSF1A) gene was sequenced CECR1 and pain.‍ She was diagnosed with DADA2, with a novel mutation in to determine if it was related to nephrotic syndrome and had been and functional confirmation.‍ amyloidosis, but sequencing revealed treated with prednisolone and no mutations.‍ The most common reported cyclosporine for the last 3 months in mutation among Turkish and another medical center.‍ A physical To identify and clarify the effect Georgian populations was Gly47Arg examination revealed cushingoid of the novel mutation foundCECR1 by a (c.‍139Gly>Ala), which was previously appearance, hepatosplenomegaly, targeted next-generation sequencing suggested to lead to a vasculopathy and left knee arthritis.‍ Skin (NGS) gene panel in the gene, phenotype.‍ Systemic steroids and appearance was normal, revealing parental tests were performed immunosuppressive drugs, including no livedoid changes or subcutaneous and revealed the heterozygosity azathioprine, methotrexate, calcineurin hyperemic nodules.‍ A neurologic of both parents.‍ More than that, as inhibitors, and cyclophosphamide, examination was also normal.‍ In a functional study, dried plasma were reported to have a partial benefit laboratory findings, complete blood samples of the patient were studied in the treatment of DADA2.‍ With – count, serum complement levels, and for ADA2 activity, and analysis introducing the use of biological drugs, liver and renal function tests were in revealed the complete absence of particularly anti tumor necrosis factor normal range.‍ Massive proteinuria ADA2 activity (Fig 2).‍ (anti-TNF) agents, more favorable (9.‍1 mg of protein per milligram of To sum up, the diagnosis was proven responses to etanercept have10 been creatinine in random urine; normal: to be DADA2 with renal amyloidosis reported in the literature.‍ <0.‍2 mg of protein per milligram in our patient.‍ Her arthritis and of creatinine), hypoalbuminemia Because little is still known on the – hepatosplenomegaly findings were pathogenesis of DADA2, Zhou et (albumin levels of 2.‍2 g/dL; normal: 1 β α improved, and she had a decreased 3.‍5 5.‍5 g/dL), and slightly elevated al showed increased staining for protein/creatinine level ratio (0.‍3 mg C-reactive protein levels (3.‍7 mg/ IL-1 , tumor necrosis factor- , and of protein per milligram of creatinine) dL; normal: <0.‍5 mg/dL) were found.‍ inducible nitric oxide, indicating the after 7 doses of canakinumab.‍ Also, Despite the absence of recurrent presence of inflammation in the skin immunodeficiency was indicated biopsy of the experimental models fever or infections, the patient had 11 β – by low serum IgG (616 mg/dL) and of DADA2.‍ Most recently, it was decreased serum IgG levels (496 mg/ α IgM levels (26 mg/dL) at the end of a dL; normal for age: 698 1194 mg/ also reported that serum IL-1 and 1-year follow-up without any related dL).‍ Serum IgM and immunoglobulin tumor necrosis factor- levels were symptoms.‍ A levels were normal.‍ Autoantibody higher in the active phase of a CECR1patient test results, including tests for DISCUSSION with homozygote deletion in both antinuclear antibody and anti-DNA, interleukin 17 receptor A and12 were negative.‍ A renal Doppler regions of chromosome 22.‍ Because anti-TNF agents are the most ultrasound did not reveal any CECR1DADA2