Department of Pediatrics, Medical University, Varna, Bulgaria.
National Human Genome Research Institute, National Institutes of Health, Washington D.C, USA.
Pediatr Rheumatol Online J. 2019 May 2;17(1):19. doi: 10.1186/s12969-019-0322-9.
CANDLE syndrome (an acronym for Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature) is a recently described rare autosomal recessive disorder charaterized by systemic autoinflammation. Clinical manifestations include presentation in the first year of life, episodes of fever accompanied by erythematous skin lesions, progressive lipodystrophy, violaceous periorbital swelling and failure to thrive. This syndrome is caused by loss of function mutations and malfunction of the immunoproteasome complex. Most patients have biallelic mutations in the PSMB8 gene that encodes the β5i catalytic subunit of the immunoproteasome. Examples of digenic inheritance have been also described in CANDLE. CANDLE patients have strong type I interferon gene expression signature and they are responsive to treatment with JAK inhibitors. However, possible serious side-effects remain a concern. Here, we report another patient with CANDLE whose disease activity was well controlled by the treatment with baricitinib.
We report a Bulgarian patient of the Turkish ancestry who carries biallelic mutations in the PSMB8 gene: p.Ala92Val and p.Lys105Gln. The pathogenic variant p.Ala92Val has not been previously described in patients with CANDLE. We also comment on the unusual feature in this patient, nephrolithiasis, that has not been described in other patients, however it might be related to the positive family history for kidney stones. We have treated the patient with the JAK inhibitor baricitinib for the past year and we observed a significant amelioration of his inflammatory episodes, skin and joint manifestations, and improvements in physical activities and growth. The treatment with glucocorticoids (GC) was completely discontinued. No side effects have been observed, however they remain in consideration for a life-long therapy of this disease.
CANDLE should be suspected in patients with early-onset systemic inflammatory disease and prominent skin manifestations. Molecular testing can confirm the clinical diagnosis and is very important in guiding therapies. Treatment with JAK inhibitors is highly efficacious and appears to be safe in children with CANDLE and other intereforonopathies.
CANDLE 综合征（慢性非典型中性粒细胞皮肤病伴脂肪营养不良和发热的缩写）是一种最近描述的罕见常染色体隐性遗传病，其特征为全身自身炎症。临床表现包括在生命的第一年出现、伴有红斑皮损的发热发作、进行性脂肪营养不良、紫蓝色眶周肿胀和生长不良。该综合征是由免疫蛋白酶体复合物的功能丧失突变和功能障碍引起的。大多数患者在 PSMB8 基因中具有双等位基因突变，该基因编码免疫蛋白酶体的β5i 催化亚基。在 CANDLE 中也描述了双基因遗传的例子。CANDLE 患者具有强烈的 I 型干扰素基因表达特征，对 JAK 抑制剂治疗有反应。然而，可能存在严重的副作用仍然是一个问题。在这里，我们报告了另一名患有 CANDLE 的患者，他的疾病活动通过巴瑞替尼治疗得到很好的控制。
我们报告了一名来自保加利亚的土耳其血统患者，他携带 PSMB8 基因的双等位基因突变：p.Ala92Val 和 p.Lys105Gln。p.Ala92Val 这种致病变体以前未在 CANDLE 患者中描述过。我们还对该患者的不寻常特征进行了评论，即肾结石，在其他患者中未描述过，但可能与肾结石的阳性家族史有关。我们用 JAK 抑制剂巴瑞替尼治疗了该患者一年，我们观察到他的炎症发作、皮肤和关节表现以及身体活动和生长的显著改善。糖皮质激素（GC）的治疗已完全停止。未观察到任何副作用，但仍需要考虑这种疾病的终身治疗。
应怀疑患有早期发病的全身性炎症性疾病和突出皮肤表现的患者患有 CANDLE。分子检测可以确认临床诊断，对于指导治疗非常重要。JAK 抑制剂治疗 CANDLE 和其他干扰素相关疾病的儿童具有高度疗效且似乎安全。
