Rare missense variants in the ALPK1 gene may predispose to periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome

Abstract

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 Gramnegative 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.

IL-1 and autoinflammatory disease: biology, pathogenesis and therapeutic targeting

“… 184 ) , ALPK1 (ref. 185 ) Recurrent fever with regular periodicity, aphthous stomatitis, exudative pharyngitis, cervical adenitis IL-1 Kawasaki disease FCGR2A , BLK , CD40 (refs 186 , 187 ), ITPKC , CASP3 (ref. 188 ) Fever, conjunctivitis, mucositis, rash, cervical lymphadenopathy, coronary artery dilatation TNF, IL-1 Behçet disease IL12A , IL10 , STAT4 , CCR1–CCR3 , IL23R–IL12RB2 , FUT2 (refs 109 , 189 ), HLAB51/B5 (ref.…”

The rs13075270 and rs13092160 polymorphisms of CCR1 and CCR3 genes on oral aphthous-like lesions in PFAPA syndrome

“…The age of onset is usually under five years old and may last into adolescence and eventually subside on its own. PFAPA does not cause any side effects (21). The use of steroids on the first day of fever can improve the patient's symptoms, so diagnosing an unexplained disease may involve an exacerbated inflammatory process.…”

Immune Dysregulation in the Tonsillar Microenvironment of Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome

“…The genetic etiology of PFAPA remains largely undefined [43,44], and diagnosis is limited to clinical features and elimination of other autoinflammatory disorders. The identification of two cytokines (IL-1 and TNF) differentially expressed in the tonsillar cells isolated from PFAPA patients compared to other control tonsils suggests that these may be used as biomarker for the diagnosis of PFAPA.…”