Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.
Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, Roma, Italy.
Eur J Hum Genet. 2019 Sep;27(9):1361-1368. doi: 10.1038/s41431-019-0421-6. Epub 2019 May 3.
PFAPA is an autoinflammatory syndrome characterized by periodic fever, aphthous stomatitis, sterile pharingitis, and adenitis, with an onset usually before the age of five. While the condition is most commonly sporadic, a few cases are familial and are usually compatible with an autosomal dominant (AD) transmission pattern, with reduced penetrance in some pedigrees. We performed exome analysis in a family where PFAPA was present in three relatives in two generations showing apparent AD segregation, identifying several rare and/or novel heterozygous variants in genes involved in the autoinflammatory pathway. Following segregation analysis of candidate variants, only one, c. 2770T>C p.(S924P) in the ALPK1 gene, was found to be consistently present in affected family members. ALPK1 is broadly expressed in different tissues and its protein is the intracellular kinase activated by the bacterial ADP-heptose bisphosphate that phosphorylates and activates TRAF-Interacting protein with Forkhead-Associated domain (TIFA) and triggers the immediate response to Gram-negative bacterial invasion. Sequencing analysis of 13 additional sporadic cases and 10 familial PFAPA cases identified two additional heterozygous missense variants c.1024G>C p.(D342H) and c.710C>T p.(T237M) in two sporadic patients, suggesting that rare variants in ALPK1 may represent a predisposing factor for recurrent periodic fever in a pediatric population.
周期性发热、口疮性口炎、无菌性咽炎和淋巴结炎（PFAPA）是一种自身炎症综合征，其特征为周期性发热、口疮性口炎、无菌性咽炎和淋巴结炎，发病通常在五岁之前。虽然这种情况最常见于散发病例，但少数病例为家族性，通常与常染色体显性（AD）遗传模式一致，在一些家系中表现出低外显率。我们对一个三代中出现了三个 PFAPA 患者的家系进行了外显子组分析，该家系中存在明显的 AD 分离，在自身炎症途径相关基因中发现了几个罕见的/或新的杂合变异。候选变异的分离分析后，仅在受影响的家族成员中发现了一个一致存在的变异 c.2770T>C p.(S924P)，该变异位于 ALPK1 基因中。ALPK1 在不同组织中广泛表达，其蛋白是由细菌 ADP-庚糖双磷酸激活的细胞内激酶，该激酶磷酸化并激活 TRAF 相互作用蛋白与 Forkhead 相关结构域（TIFA），并触发对革兰氏阴性细菌入侵的即刻反应。对 13 例散发性病例和 10 例家族性 PFAPA 病例的测序分析，在 2 例散发性患者中发现了另外两个杂合错义变异 c.1024G>C p.(D342H)和 c.710C>T p.(T237M)，这表明 ALPK1 中的罕见变异可能是儿科人群反复周期性发热的一个易感因素。
