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Table of Contents
CASE REPORT
Year : 2021  |  Volume : 24  |  Issue : 3  |  Page : 410-412
 

‘More than just skin in the game’. DADA2 autoinflammatory syndrome and stroke in the young


1 Department of Neurology, Aster Medcity, Kothad, Kochi, Kerala, India
2 Department of Rheumatology, Aster Medcity, Kothad, Kochi, Kerala, India

Date of Submission02-Jul-2020
Date of Acceptance12-Oct-2020
Date of Web Publication04-Feb-2021

Correspondence Address:
Boby Varkey Maramattom
Department of Neurology, Aster Medcity, Kothad, Kochi, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.AIAN_716_20

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   Abstract 


A 21-year-old man had a long-standing history of leg ulcers and hyperpigmention over the feet. Over a span of 8 months, he had an acute ischemic stroke followed by a basal ganglia hemorrhage. He was finally diagnosed with DADA2 syndrome after genetic sequencing. The implications of this new syndrome and its links to stroke in the young are presented in this article.


Keywords: DADA2, DADA2, vasculopathy, stroke in the young, stroke, DADA2, stroke, livedo, stroke, skin ulcers, stroke, vasculitis


How to cite this article:
Varghese A, Thomas J, Maramattom BV. ‘More than just skin in the game’. DADA2 autoinflammatory syndrome and stroke in the young. Ann Indian Acad Neurol 2021;24:410-2

How to cite this URL:
Varghese A, Thomas J, Maramattom BV. ‘More than just skin in the game’. DADA2 autoinflammatory syndrome and stroke in the young. Ann Indian Acad Neurol [serial online] 2021 [cited 2021 Aug 3];24:410-2. Available from: https://www.annalsofian.org/text.asp?2021/24/3/410/308699





   Introduction Top


Deficiency of adenosine deaminase 2 (DADA2) is a recently described monogenic autoinflammatory childhood with small and medium vessel vasculopathy.[1] It was initially described as a syndrome of recurrent fever, livedo racemosa, early-onset strokes and peripheral vasculopathy. We describe a young man with recurrent strokes due to DADA2 mutation.


   Case Presentation Top


At 21 years of age, our patient developed an ischemic midbrain stroke with left ataxic hemiparesis and was started on 75 mg of Aspirin. He had painful ulcerative lesions on both legs of 12 years duration. Examination revealed erythematous macular lesions [livedo racemose] with shallow ulcers and hyperpigmenation on both legs. Work up including anti-phospholipid antibodies [APLA] was negative. Warfarin was added to prevent further thrombotic episodes. Eight months later, he developed a right basal ganglionic intra-cerebral haemorrhage [ICH] and left hemiplegia [grade 0/5 power MRC] [Figure 1] and [Figure 2]. Aspirin and Warfarin were discontinued. A muscle and skin biopsy were suggestive of vasculitis [Table 1]. Workup for lupus anticoagulant, APLA, ANA, anti ds-DNA antibodies, VDRL, cryoglobulins and hypercoagulable work-up were negative. Cardiac evaluation was normal. CT angiogram showed narrowing of the cavernous portion of right ICA, right MCA and its branches. The combination of livedo racemosa and multiple strokes suggested a diagnosis of Sneddon's syndrome, Childhood polyarteritis nodosa [c-PAN] or DADA 2 syndrome [Table 1].
Figure 1: (a) Rt midbrain Infarct [MRI DWI coronal image]. (b) Right basal ganglia hemorrhage

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Figure 2: (a) Hyperpigmentation and healed ulcers with scarring on both legs. (b) Livedo racemose

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Table 1: Differential diagnosis of vasculitic stroke syndromes

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He was started on baclofen and physiotherapy. Six years later, whole exome sequencing [WES] revealed a homozygous pathogenic missense variant, p.Gly47Arg exon 2 of the adenosine deaminase 2 [ADA2] gene.

He has remained asymptomatic but remains unemployed and dependent on parental support. Our patient was not started on any anti-TNF agents due to financial issues.


   Discussion Top


Monogenic autoinflammatory syndromes [MAIS] are characterized by periodic episodes of systemic inflammation of endogenous origin and can mimic systemic vasculitis. MAIS with cerebrovascular manifestations include DADA2 and Familial Mediterranean fever (FMF).[1],[2] Adenosine deaminases (ADA) are key enzymes in purine metabolism. Deficiency of ADA1, leads to severe combined immunodeficiency (SCID) in young children due to accumulation of cytotoxic intermediaries and death of developing lymphocytes. SCID patients present with profound lymphopenia, unlike DADA2. Deficiency of ADA2 causes DADA2 which resembles PAN, with multisystem involvement and features of medium and small vessel vasculitis or vasculopathy in >75% of cases. However, CNS involvement is commoner in DADA2 than PAN [50% v/s 5%]. Skin biopsy shows features of vasculitis or panniculitis. DADA2 is confirmed by gene sequencing or plasma ADA2 activity assay.[3] Our patients' homozygous variant is described in patients of Middle Eastern and South Asian ancestries. Biallelic pathogenic loss of function mutations in this gene causes a deficiency of ADA2. DADA2-associated mutations are inherited as homozygous or compound heterozygous variants. They can be identified by a single gene Sanger sequencing testing, or by next generation sequencing technologies such as WES. If genetic testing is inconclusive, protein test is recommended.[4],[5] DADA2 has a wide spectrum of clinical manifestations [Table 2]. The clinical features of DADA2 in childhood-onset and adult-onset cases are quite similar; however, children have an increased prevalence of constitutional symptoms and adults have an increased prevalence of anaemia or other hematologic manifestations.[6]
Table 2: Clinical features of DADA2

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Clear guidelines are not available regarding therapy in asymptomatic patients or stopping therapy in inactive disease although anti-TNF therapy is highly recommended in all cases with confirmed two pathogenic variants in ADA2 or very low ADA2 activity.[7],[8] Anti-TNF [TNFi] agents such as Etanercept or hematopoietic stem cell transplantation (HSCT) are useful in patients with severe hematological disease.[9] Other TNFi such as adalimumab, infliximab as well as biosimilar TNFi are equally useful. Antiplatelet and anticoagulant medications should be avoided.

There are multiple etiologies of ICH in DADA2 – including haemorrhagic conversion of ischemic strokes, use of antiplatelets or due to the primary vasculopathy itself.[10]

As our patient developed both an ischemic stroke and a haemorrhagic stroke within a span of 8 months, we discontinued both the antiplatelets and anticoagulants. We have initiated a discussion regarding further treatment options in our patient. Neurologists should be aware of these auto-inflammatory entities in the differential diagnosis of vasculitis and strokes. Stroke with DADA2 is underreported in the Indian literature.[6],[11]


   Summary Top


  • DADA2 is a rare cause of stroke in young.
  • DADA2 should be considered in the presence of Livedo racemosa, Stroke or multisystem involvement even without a family history.
  • Genetic testing can confirm the diagnosis
  • Therapeutic options include anti-TNF agents or HSCT.


Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Jain A, Misra DP, Sharma A, Wakhlu A, Agarwal V, Negi VS. Vasculitis and vasculitis-like manifestations in monogenic autoinflammatory syndromes. Rheumatol Int 2018;38:13-24.  Back to cited text no. 1
    
2.
Kalyoncu U, Eker A, Oguz KK, Ombrelio AK, Michael DG, Deuitch M, et al. Familial Mediterranean fever and central nervous system involvement: A case series. Medicine (Baltimore) 2010;89:75-84.  Back to cited text no. 2
    
3.
Caorsi R, Penco F, Grossi A, Insalaco A, Omenetti A, Alessio M, et al. ADA2 deficiency (DADA2) as an unrecognized cause of early onset polyarteritis nodosa and stroke: A multicentre national study. Ann Rheum Dis 2017;76:1648-56.  Back to cited text no. 3
    
4.
Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Stone DL, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med 2014;370:911-20.  Back to cited text no. 4
    
5.
Navon Elkan P, Pierce SB, Segel R, Walsh T, Barash J, Padeh S, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med 2014;370:921-31.  Back to cited text no. 5
    
6.
Sharma A, Naidu G, Sharma V, Jha S, Dhooria A, Dhir V, et al. Deficiency of adenosine deaminase 2 (DADA2) in Adults and Children: Experience from India. Arthritis Rheumatol 2020. doi: 10.1002/art. 41500.  Back to cited text no. 6
    
7.
Schnappauf O, Zhou Q, Moura NS, Ombrello AK, Michael DG, Deuitch N, et al. Deficiency of adenosine deaminase 2 (DADA2): Hidden variants, reduced penetrance, and unusual inheritance. J Clin Immunol 2020;40:917-26.  Back to cited text no. 7
    
8.
Ombrello AK, Qin J, Hoffmann PM, Kumar P, Stone D, Jones A, et al. Treatment strategies for deficiency of adenosine deaminase 2. N Engl J Med 2019;380:1582-4.  Back to cited text no. 8
    
9.
Caorsi R, Penco F, Schena F, Gattorno M. Monogenic polyarteritis: The lesson of ADA2 deficiency. Pediatr Rheumatol Online J 2016;14:51.  Back to cited text no. 9
    
10.
Lee PY, Huang Y, Zhou Q, Schnappauf O, Hershfield MS, Li Y, et al. Disrupted N-linked glycosylation as a disease mechanism in deficiency of ADA2. J Allergy Clin Immunol 2018;142:1363-5.  Back to cited text no. 10
    
11.
Sharma A, Naidu GSRSNK, Chattopadhyay A, Acharya N, Jha S, Jain S. Novel CECR1 gene mutations causing deficiency of adenosine deaminase 2, mimicking antiphospholipid syndrome. Rheumatology (Oxford) 2019;58:181-2.  Back to cited text no. 11
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]



 

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