Santo Gustavo C, Baldeiras Inês, Guerreiro Rita, Ribeiro Joana A, Cunha Rosário, Youngstein Taryn, Nanthapisal Sira, Leitão João, Fernandes Carolina, Caramelo Francisco, Almeida Maria do Rosário, Brás José, Santana Isabel
Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal,
Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal.
Cerebrovasc Dis. 2018;46(5-6):257-264. doi: 10.1159/000495794. Epub 2019 Jan 15.
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).
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.
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%.
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.
网状青斑（LR）与中风之间的关联被称为斯内登综合征（SnS）。如果病因不明，该疾病被归类为原发性SnS（PSnS），否则为继发性SnS。这种病症很罕见，主要呈散发性出现。2014年，两个独立的研究团队描述了一种新的儿童期起病的遗传性疾病，称为腺苷脱氨酶2缺乏症（DADA2），其特征为反复发热以及包括LR和中风在内的血管病理特征。所有患者在编码腺苷脱氨酶2（ADA2）蛋白的猫眼综合征染色体区域候选1基因（CECR1）中携带隐性遗传突变。基因检测是诊断DADA2的标准。然而，在CECR1突变个体中，更经济实惠的实验室分析的诊断准确性仍有待确定。我们旨在确定血浆ADA2活性和血清免疫球蛋白M（IgM）水平是否能够区分：（1）SnS范围内的DADA2与其他成年患者，以及（2）健康的CECR1杂合子（HHZ）与健康对照（HC）。
对SnS范围内的成年患者、健康的一级亲属和HC测量血浆ADA2活性和血清IgM浓度。基因检测结果用作参考标准。主要结局指标是通过受试者工作特征曲线分析得出的敏感性和特异性。
共有73名参与者纳入研究：26例无CECR1突变的PSnS患者（PSnS）、6例双等位基因（DADA2患者）和7例CECR1突变的HHZ以及34例HC。DADA2患者的血浆ADA2活性和血清IgM水平显著低于PSnS患者。使用最佳指标时，血浆ADA2活性区分PSnS与DADA2的敏感性和特异性分别为100.0%，区分HHZ与HC的敏感性为97.1%，特异性为85.7%。血清IgM水平区分PSnS与DADA2的敏感性为85.2%，特异性为83.3%。
血清IgM水平可作为一种分诊工具，血浆ADA2活性作为SnS范围内成年患者DADA2的诊断测试表现完美。血浆ADA2活性也能可靠地区分HHZ与HC。
