Centro Malattie Autoinfiammatorie e Immunodeficienze- Clinica Pediatrica e Reumatologia, IRCCS Giannina Gaslini, Via Gaslini 5, 16147, Genova, Italy.
Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università di Genova, Genoa, Italy.
Pediatr Rheumatol Online J. 2019 Jul 8;17(1):38. doi: 10.1186/s12969-019-0336-3.
Autosomal dominant gain of function mutations in caspase recruitment domain family member 14 (CARD14) is a rare condition associated with plaque-type psoriasis, generalized pustular psoriasis, palmoplantar pustular psoriasis and pityriasis rubra pilaris. Recently, a new CARD14 -associated phenotype defined as CAPE (CARD14-associated papulosquamous eruption) with clinical features of both psoriasis and pityriasis rubra pilaris was reported. We describe a family carrying a novel heterozygous mutation in CARD14 gene, with childhood-onset erythrodermic psoriasis requiring an unusual extremely high dose (up to 2 mg/kg every 8 weeks) of ustekinumab to achieve disease remission.
We describe a large family with three pairs of twins presenting a clinical phenotype characterized by childhood-onset erythrodermic psoriasis; in some family members is also reported psoriatic arthritis. The two probands presented poor clinical response to topic and systemic therapy with antihistamine, steroid, retinoids, cyclosporine and etanercept. After exclusion of the most common genes associated to autoinflammatory diseases (IL36RN, IL1RN, MVK, TNFRSF1A, NLRP3, NLRP12, MEFV, NOD2, PSMB8, PSTPIP1, LPIN2) we approached a new gene search by subjecting to Whole Exome Sequencing (WES) analysis five members of the family. A novel heterozygous mutation (c.446 T > G, leading to the missense amino acid substitution p.L149R) in the exon 4 of the CARD14 gene was identified in all affected members. Increasing dosages (up to 2 mg/kg every 8 weeks) of ustekinumab, a human monoclonal antibody targeting interleukin-12 (IL-12) and interleukin-23 (IL-23), allowed the complete control of the clinical manifestations, with an evident reduction of circulating Th17 and Th22 CD4+ T cell subsets.
We describe the association of mutations of the CARD14 gene with an erythrodermic psoriasis pedigree, underlying the necessity to investigate CARD14 mutations in childhood-onset psoriasis cases and confirming the presence of CARD14 causative mutations also in erythrodermic psoriasis form, as recently reported. Also in pediatric age, ustekinumab represents a powerful therapeutic option for this rare condition, that is usually refractory to other treatments. In young children, high and frequent dosages allowed a complete control of the clinical manifestations without any severe side effects, with a long-term follow-up.
半胱氨酸天冬氨酸蛋白酶募集域家族成员 14（CARD14）的常染色体显性获得性功能突变是一种罕见的疾病，与斑块型银屑病、泛发性脓疱型银屑病、掌跖脓疱型银屑病和红皮病性银屑病有关。最近，一种新的 CARD14 相关表型被定义为 CAPE（CARD14 相关丘疹鳞屑疹），其临床表现既有银屑病又有红皮病性银屑病。我们描述了一个携带 CARD14 基因突变的家族，该基因突变是杂合的，患有儿童期发病的红皮病性银屑病，需要使用非常高的剂量（高达每 8 周 2mg/kg）的乌司奴单抗才能使疾病缓解。
我们描述了一个大家庭，有三对双胞胎，临床表现为儿童期发病的红皮病性银屑病；在一些家庭成员中还报告有银屑病关节炎。两个先证者对包括抗组胺药、类固醇、维甲酸、环孢素和依那西普在内的局部和全身治疗的临床反应不佳。在排除了与自身炎症性疾病最常见的相关基因（IL36RN、IL1RN、MVK、TNFRSF1A、NLRP3、NLRP12、MEFV、NOD2、PSMB8、PSTPIP1、LPIN2）之后，我们对家族的五名成员进行了全外显子组测序（WES）分析，以寻找新的基因。在 CARD14 基因的外显子 4 中发现了一个新的杂合突变（c.446T>G，导致氨基酸替换 p.L149R），该突变在所有受影响的成员中均存在。乌司奴单抗是一种针对白细胞介素 12（IL-12）和白细胞介素 23（IL-23）的人源单克隆抗体，增加剂量（高达每 8 周 2mg/kg）可完全控制临床表现，同时明显减少循环 Th17 和 Th22 CD4+T 细胞亚群。
我们描述了 CARD14 基因突变与红斑性银屑病家系的关联，这表明有必要在儿童期发病的银屑病病例中调查 CARD14 突变，并证实 CARD14 致病突变也存在于红斑性银屑病中，这是最近的报道。在儿科年龄，乌司奴单抗是治疗这种罕见疾病的有效治疗选择，因为这种疾病通常对其他治疗方法有抗性。在幼儿中，高剂量和高频度给药可完全控制临床表现，无严重副作用，并进行了长期随访。
