Adenosine Deaminase Two and Immunoglobulin M Accurately Differentiate Adult Sneddon’s Syndrome of Unknown Cause

Abstract

Background: The association that exists between livedo reticularis (LR) and stroke is known as Sneddon’s syndrome (SnS). The disorder is classified as primary SnS (PSnS), if the cause remains unknown and secondary SnS. The condition is rare and it occurs mainly sporadically. In 2014, 2 independent teams described a new genetic disorder with childhood-onset, which was called deficiency of adenosine deaminase 2 (DADA2), characterized by recurrent fevers and vascular pathologic features that included LR and stroke. All the patients carried recessively inherited mutations in cat eye syndrome chromosome region candidate 1 gene (CECR1), encoding the adenosine deaminase 2 (ADA2) protein. Genetic testing is the standard for the diagnosis of DADA2. However, the diagnostic accuracy of more affordable laboratorial analysis in CECR1-mutated individuals remains to be established. We aim to determine whether plasma ADA2 activity and serum immunoglobulin M (IgM) levels can distinguish (1) DADA2 from other adult patients within the SnS spectrum, and (2) healthy CECR1 heterozygous (HHZ) from healthy controls (HC). Methods: ADA2 activity in plasma and serum IgM concentrations was measured in adult patients within the SnS spectrum, healthy first-degree relatives and HC. Genetic results were used as the reference standard. The primary outcome measures were sensitivity and specificity derived from receiver operating curve analysis. Results: A total of 73 participants were included in the study: 26 patients with PSnS with no CECR1 mutation (PSnS), 6 bi-allelic (DADA2 patients) and 7 HHZ CECR1 mutations and 34 HC. Plasma ADA2 activity and serum IgM levels were significantly lower in DADA2 patients than in PSnS. With the use of the best indexes, plasma ADA2 activity differentiated PSnS from DADA2 with a sensitivity and specificity of 100.0% and HHZ from HC with a sensitivity of 97.1% and specificity of 85.7%. Serum IgM levels also differentiated PSnS from DADA2 with a sensitivity of 85.2% and specificity of 83.3%. Conclusion: Serum IgM levels might be used as a triage tool and plasma ADA2 activity performs perfectly as a diagnostic test for DADA2 in adult patients within the SnS spectrum. ADA2 activity in plasma also reliably distinguishes HHZ from HC.

Livedo racemosa in neurological diseases: an update on the differential diagnoses

“…The diagnostic gold standard is the detection of ADA2 gene mutations. Santo and Santana showed that plasma ADA2 activity can distinguish patients with DADA2 from those with primary SS [22].…”

A wide spectrum of phenotype of deficiency of deaminase 2 (DADA2): a systematic literature review

“…The most frequent neurologic manifestation is the stroke that was reported in 165/378 patients (43.6%) [ 1 , 2 , 4 , 5 , 8 , 11 , 12 , 15 , 16 , 22 , 25 , 26 , 28 – 31 , 34 , 37 , 40 , 41 , 43 , 46 , 48 , 56 – 59 , 62 – 66 , 70 , 71 , 73 – 77 , 80 – 82 , 84 , 85 , 87 – 90 ]. In 146 patients showed ischaemic characteristics, while in 46 haemorrhagic.…”

A Case of Deficiency of Adenosine Deaminase 2: 28 years of Diagnostic Challenges

“…The presence of consanguinity and family history plays an important role in the presumptive diagnosis since it's an autosomal recessive disease [ 9 ]. Plasma ADA2 enzyme activity is a well-established test for the diagnosis with 100% sensitivity and 100% specificity in a cohort of Sneddon's syndrome patients [ 20 ]. We did not study MEFV genes or any other genes related to familial fevers [ 21 ].…”