Novel CECR1 Gene Mutations Causing Deficiency of Adenosine Deaminase 2, Mimicking Antiphospholipid Syndrome

Letters to the Editor

10 Aggarwal R, Oddis CV, Goudeau D et al. Autoantibody vasculopathy, a possibility of DADA2 was considered. levels in myositis patients correlate with clinical response Plasma ADA2 activity was deficient in her (10.5 mU/g pro- during B cell depletion with rituximab. Rheumatology tein) and was in carrier range in her mother (76.7 mU/g). 2016;55:9919. Whole-exome sequencing detected a compound heterozygous genotype at the CECR1 gene. She had a p.(Leu188Val) missense variant (rs765219776) at exon 4 Rheumatology 2019;58:181182 and a c.753 + 2T>A variant at intron 4 of the CECR1 doi:10.1093/rheumatology/key258 gene. Her mother had a p.(Leu188Val) missense variant at Advance Access publication 24 August 2018 exon 4, confirming her carrier state. Experience from a small case series of patients with Novel CECR1 gene mutations causing deficiency DADA2 has shown that high-dose glucocorticoids and of adenosine deaminase 2, mimicking

TNF-a inhibitors are useful in controlling the disease ac- Downloaded from https://academic.oup.com/rheumatology/article/58/1/181/5079396 by guest on 30 September 2021 antiphospholipid syndrome tivity in these patients [2, 3, 5, 6]. A good response was achieved with the use of etanercept and adalimumab in Rheumatology key message these patients. Our patient was treated with adalimumab (40 mg subcutaneously) biweekly, which resulted in symp- . Two novel mutations causing deficiency of adenosine deaminase-2 mimicking APS with pregnancy tomatic improvement, with healing of the ulcer over the morbidity are reported. left tendoachilles. Our patient was unique and different from other patients SIR, Deficiency of adenosine deaminase 2 (DADA2) is a previously reported in the literature. First, the variants of recently identified hereditary autoinflammatory disease the CECR1 gene alleles identified in our patient have not characterized by mutations in the CECR1 (Cat Eye been reported in the literature till now [15]. Second, bad Syndrome Chromosome Region 1) gene [15]. Clinical obstetric history along with vascular thrombosis consist- features include recurrent fever, early-onset stroke, ent with clinical criteria for APS, have also not been peripheral neuropathy, livedo reticularis, ulcerations of described among DADA2 patients. We speculate that pre- extremities and hypogammaglobulinemia [13]. We eclampsia might have developed due to placental vascu- describe a case of DADA2 due to novel, yet unreported lar inflammation secondary to DADA2. This case CECR1 mutations clinically mimicking APS. highlights the expanding array of genetic mutations caus- A 35-year-old female living in North-West India and ing DADA2, which might present with diverse and hitherto belonging to the Aggarwal community, presented in unknown presentations. December, 2017 with complaints of non-healing ulcers preceded by nodules over the left leg for the preceding Acknowledgements 5 months. Examination revealed an ulcer over the left tendoachilles and livedo reticularis over the extremities. The We thank Dr Juan I. Aro´ stegui, Department of rest of the systemic examination was unremarkable. In ImmunologyCDB Hospital Clınic Barcelona, Spain for June 2014, she had left hemiparesis due to lacunar infarct carrying out the whole exome sequencing and Dr in the right medulla. She was treated with anticoagulation Michael Hershfield, Professor of Medicine and and improved over 3 months. In June 2015, she de- Biochemistry, Duke University Medical Center, Durham, veloped paraesthesia over her left hand and evaluation USA for measurement of ADA 2 activity. revealed 100% occlusion of the left ulnar artery, for Funding: No specific funding was received from which balloon angioplasty resulted in symptomatic im- any bodies in the public, commercial or not-for-profit sec- provement. In December 2016, she developed transient tors to carry out the work described in this manuscript. diplopia, vertigo and headache. At 25 years of age, she had obstetric morbidity in the form of preeclampsia and Disclosure statement: The authors have declared no preterm delivery of a female child. In 2009 she had one conflicts of interest. spontaneous first-trimester abortion, and in 2012 she had preterm delivery of a male child due to preeclampsia. Her Aman Sharma1, GSRSNK Naidu1, father had a stroke at the age of 40 years, but her mother Arghya Chattopadhyay1, Nupoor Acharya1, was asymptomatic. Saket Jha1 and Sanjay Jain1 Investigations showed an elevated erythrocyte sedimen- 1 tation rate (50 mm/h), C-reactive protein (5.18 mg/dl), nega- Clinical Immunology and Rheumatology Services, tive anti-nuclear and antineutrophil cytoplasmic antibodies, Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, and normal protein C, S and homocysteine levels. Lupus Chandigarh, India anticoagulant, and anticardiolipin antibodies (IgG and IgM) Accepted 17 July 2018 were negative on two occasions. A skin biopsy from the Correspondence to: Aman Sharma, Clinical Immunology and ulcer edge showed the presence of septal panniculitis, with Rheumatology Services, Department of Internal Medicine, no definite evidence of small-vessel vasculitis. In view of PGIMER, Chandigarh 160012, India. early-onset stroke, nonhealing ulcers, livedo reticularis and E-mail: [email protected]

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References increased ESR (39 mm/h; normal 210 mm/h) and elevated serum amyloid A (SAA) level (786 mg/ml; normal 1 Zhou Q, Yang D, Ombrello AK et al. Early onset stroke and 08 mg/ml). Urinalysis was negative for protein and vasculopathy associated with mutations in ADA2. N Engl J occult blood. Low-grade fever and severe chest pain Med 2014;370:91120. lasted for 7 days and improved spontaneously, but slight 2 Nanthapisal S, Murphy C, Omoyinmi E et al. Deficiency of chest pain persisted for 6 months and the CRP levels re- adenosine deaminase Type 2: a description of phenotype mained elevated. and genotype in fifteen cases. Arthritis Rheumatol The patient’s 51-year-old father had episodes of chest 2016;68:231422. pain persisting for 36 months, beginning during senior 3 Caorsi R, Penco F, Grossi A et al. ADA2 deficiency high school and lasting into his 40s. The attacks were (DADA2) as an unrecognised cause of early onset poly- occasionally accompanied by low-grade fever or abdom- arteritis nodosa and stroke: a multicentre national study. inal pain. He developed proteinuria at 18 years of age and Downloaded from https://academic.oup.com/rheumatology/article/58/1/181/5079396 by guest on 30 September 2021 Ann Rheum Dis 2017;76:164856. hypertension at 30 years of age. He was diagnosed 4 Fayand A, Sarrabay G, Belot A et al. Multiple facets with chronic renal failure and is currently on dialysis. of ADA2 deficiency: vasculitis, auto-inflammatory disease Chronic watery diarrhoea occurred at 49 years of age. and immunodeficiency: a literature review of 135 cases Kidney biopsy and endoscopy were recommended to from literature. Rev Med Interne 2018;39:297306. diagnose suspected amyloidosis, but he refused these 5 Caorsi R, Penco F, Schena F, Gattorno M. Monogenic examinations. polyarteritis: the lesson of ADA2 deficiency. Pediatr The patient’s grandfather had recurrent chest pain Rheumatol 2016;14:51. during childhood. Four other relatives also had similar 6 Batu ED, Karadag O, Taskiran EZ et al. A case series of chest pain, but we were unable to obtain clinical details. adenosine deaminase 2deficient patients emphasizing Genetic analyses for MEFV, MVK, TNFRSF1A, NLRP3, treatment and genotypephenotype correlations. NOD2, PSTPIP1, NLRP12, PSMB8, IL1RN, NLRC4 and J Rheumatol 2015;42:15324. PLCG2 were performed in the proband, his father and his grandfather by targeted next-generation resequen- cing, because the clinical features suggested an autoin- Rheumatology 2019;58:182184 flammatory disease. Tests for SAA1 alleles were also doi:10.1093/rheumatology/key283 conducted for susceptibility to amyloidosis. The subjects’ Advance Access publication 8 September 2018 peripheral blood mononuclear cells were analysed. This Expanding clinical spectrum of autosomal study was approved by the ethical committees of Kyoto dominant pyrin-associated autoinflammatory University and was conducted in accordance with the disorder caused by the heterozygous MEFV Declaration of Helsinki. Written informed consent was ob- p.Thr577Asn variant tained from all subjects. The genetic tests of the proband, his father and his grandfather showed a heterozygous p.Thr577Asn variant Rheumatology key message in exon 8 and a homozygous p.Glu148Gln variant in exon . The MEFV p.Thr577Asn variant causes low-grade 2ofMEFV. The p.Thr577Asn variant had not been reported fever and longer attack durations and may cause in the database of single-nucleotide polymorphisms amyloidosis. (dbSNP) nor in the Japanese Human Genetic Variation Database (http://www.hgvd.genome.med.kyoto-u.ac.jp/), SIR, FMF, a hereditary autoinflammatory disease caused whereas the p.Glu148Gln variant is a known SNP. No by MEFV variants, is characterised by recurrent fever and other disease-causing variant was identified in other genes. serositis [1]. Herein we report cases in a Japanese family After regular treatment with colchicine (0.020.03 mg/kg/ whose members have experienced recurrent chest pain day), the proband’s chest pain disappeared and his CRP and low or no fever caused by a heterozygous MEFV and SAA levels and ESR improved, reducing the attack fre- p.Thr577Asn variant. quency and severity. The father and grandfather have not A 7-year-old Japanese boy was admitted to the hospital yet received colchicine. due to recurrent chest pain beginning at 5 years of age. Autosomal dominantinherited FMF and MEFV-asso- The chest pain was occasionally accompanied by low- ciated autoinflammatory diseases have been recently grade fever, abdominal pain or conjunctival hyperaemia reported [24], including a patient with the same and lasted 37 days before improving spontaneously. p.Thr577Asn variant [2] identified in our patients. The Similar attacks had occurred eight times during the previ- p.Thr577Asn variant was identified as a disease-causing ous 21 months. Upon admission, his body temperature variant for recurrent chest pain and excessive secretion was 37.7C. He presented with severe chest pain in the of pro-inflammatory cytokines by peripheral blood mono- right precordium that worsened with respiratory move- nuclear cells. Patients with this variant did not meet ments and tenderness in the right hypochondrium. the Tel Hashomer criteria and were therefore diagnosed Laboratory findings revealed a normal leucocyte count with an MEFV-associated autoinflammatory disease (7700 cells/ml; neutrophils 59%, lymphocytes 38%), ele- with attack durations often longer than those typical of vated CRP level (8.8 mg/dl; normal 00.3 mg/dl), FMF [5], a feature shared by our patients (Table 1).