Agostino Gemelli University Polyclinic

Description of a Large Family with Periodic Fever Carrying a Variant in Gene: A Possible Novel Modulator of Inflammation in Autoinflammatory Diseases.

Autoinflammatory diseases involve recurrent systemic inflammation caused by dysregulated innate immunity, arising from genetic or multifactorial mechanisms, as seen in periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. About 10% of PFAPA patients show autosomal dominant inheritance. We describe a three-generation family with a PFAPA-like recurrent fever syndrome displaying clear autosomal dominant transmission. All affected individuals tested negative on a diagnostic panel of 13 known autoinflammatory genes. Whole-exome sequencing was performed in two distantly related affected members, followed by variant filtering, segregation analysis, and phenotype-based prioritization. A single heterozygous missense variant in , c.154G>A p.(Asp52Asn), co-segregated with disease in all affected relatives. This variant is extremely rare in population databases, absent from ClinVar, present in COSMIC, and predicted as damaging by REVEL and CADD. RXFP1, not previously implicated in autoinflammatory or innate immune disorders, encodes the relaxin family peptide receptor 1, a G protein-coupled receptor involved in extracellular matrix regulation, anti-fibrotic pathways, and modulation of inflammatory cytokine production. Protein network analysis showed interactions with RLXN1-3, inflammatory mediators, PTGDR, ADORA2B, and C1QTNF8, supporting an immunomodulatory function. This is the first report linking variation to a hereditary recurrent fever syndrome, identifying relaxin signalling as a potential immune regulatory pathway.

Exploring the significance of vitamin D insufficiency in the periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: a single-center retrospective assessment during the decade 2014-2024.

The underlying mechanisms responsible for the periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome are unknown. The main purpose of this study was to retrospectively assess different characteristics and lab-work investigations including serum 25(OH)-vitamin D levels in patients with PFAPA syndrome evaluated at our University hospital during the decade 2014-2024. The medical charts of 151 children with diagnosis of PFAPA syndrome were retrospectively evaluated: for each patient demographic data, clinical manifestations during acute episodes, and laboratory analyses during a well-being phase within the trimester following PFAPA diagnosis were examined. A focus was given to serum 25-hydroxyvitamin D [25(OH)-vitamin D] concentration, recognized as the functional status indicator for vitamin D. Based on the reference values for normal serum 25(OH)-vitamin D, patients were divided into two groups (inadequate versus normal vitamin D levels); the groups were compared to identify if hypovitaminosis D could have any relationship with the evolution of PFAPA syndrome over time. Forty-five PFAPA patients (30% of the whole cohort) had serum 25(OH)-vitamin D below the normal reference (< 30 ng/mL), and inadequate vitamin D serum levels were associated with a persistent pattern of PFAPA syndrome, also showing an inverse correlation with age at disease onset. This study offers a static snapshot of vitamin D status in children with PFAPA syndrome, without accounting for specific time points, and suggests that serum 25(OH)-vitamin D levels might contribute to a longer duration of the recurring PFAPA symptoms.

A Potential Link Between Outcome of Periodic Fever, Aphthous Stomatitis, Pharyngitis, Cervical Adenitis (PFAPA) Syndrome in Children and Breastfeeding: A Retrospective Single-Center Cohort Snapshot.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome, often referred to as PFAPA syndrome, may enigmatically recur for an undetermined time in affected children: a potential reason to explain its recurring pattern for an unpredictable period or its self-limitation is currently unknown. We explored the relationship between different general, demographic, clinical, and laboratory features of PFAPA children and disease evolution over the course of a decade. We have retrospectively screened 150 Italian children with a history of PFAPA syndrome attending the Outpatients Clinic of Pediatric Rheumatology in our Institution during the period 2014-2024, all without any recognized chronic diseases: 88 males, 62 females, mean age at onset of 2.5 ± 1.7 years, age range of 0.3-9.4 years, and mean age at diagnosis of 4.5 ± 2.0 years. The whole cohort of PFAPA patients had been followed up for a median period of 5 years (IQR: 4-7). After dividing patients into two groups based on either the disappearance or persistence of PFAPA symptoms during follow-up, we found that positive family history of recurring fevers, cervical lymphadenopathy, arthralgia, myalgia, and breastfeeding for more than 6 months were associated with the disappearance of febrile attacks for at least six months. Performing a multivariate analysis adjusted for sex and age, we found that only breastfeeding duration longer than 6 months and higher education level of PFAPA patients' mothers were independently associated with the resolution of PFAPA symptoms.

A Potential Partnership between Genetics and the Oral Microbiome in Children Displaying Periodic Fever/Aphthosis/Pharyngitis/Adenitis Syndrome.

Periodic fever/aphthosis/pharyngitis/adenitis (PFAPA) syndrome was initially described in a small cohort of American children [...].

Current Evidence on Vaccinations in Pediatric and Adult Patients with Systemic Autoinflammatory Diseases.

Systemic autoinflammatory diseases (SAIDs) are defined by recurrent febrile attacks associated with protean manifestations involving joints, the gastrointestinal tract, skin, and the central nervous system, combined with elevated inflammatory markers, and are caused by a dysregulation of the innate immune system. From a clinical standpoint, the most known SAIDs are familial Mediterranean fever (FMF); cryopyrin-associated periodic syndrome (CAPS); mevalonate kinase deficiency (MKD); and periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) syndrome. Current guidelines recommend the regular sequential administration of vaccines for all individuals with SAIDs. However, these patients have a much lower vaccination coverage rates in 'real-world' epidemiological studies than the general population. The main purpose of this review was to evaluate the scientific evidence available on both the efficacy and safety of vaccines in patients with SAIDs. From this analysis, neither serious adverse effects nor poorer antibody responses have been observed after vaccination in patients with SAIDs on treatment with biologic agents. More specifically, no new-onset immune-mediated complications have been observed following immunizations. Post-vaccination acute flares were significantly less frequent in FMF patients treated with colchicine alone than in those treated with both colchicine and canakinumab. Conversely, a decreased risk of SARS-CoV-2 infection has been proved for patients with FMF after vaccination with the mRNA-based BNT162b2 vaccine. Canakinumab did not appear to affect the ability to produce antibodies against non-live vaccines in patients with CAPS, especially if administered with a time lag from the vaccination. On the other hand, our analysis has shown that immunization against , specifically with the pneumococcal polysaccharide vaccine, was associated with a higher incidence of adverse reactions in CAPS patients. In addition, disease flares might be elicited by vaccinations in children with MKD, though no adverse events have been noted despite concurrent treatment with either anakinra or canakinumab. PFAPA patients seem to be less responsive to measles, mumps, and rubella-vaccine, but have shown higher antibody response than healthy controls following vaccination against hepatitis A. In consideration of the clinical frailty of both children and adults with SAIDs, all vaccinations remain 'highly' recommended in this category of patients despite the paucity of data available.

Febrile children with breaches in the responses of innate immunity.

Preliminary data revealing efficacy of K12 (SSK12) in Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome: A multicenter study from the AIDA Network PFAPA syndrome registry.

To evaluate the potential role of K12 (SSK12) in controlling febrile flares in patients with Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome. Further aims were to assess the impact of SSK12 on (i) flare duration, (ii) variation in the degree of the highest body temperature during flares, (iii) steroid-sparing effect, and (iv) change of PFAPA accompanying symptoms before and after SSK12 introduction. The medical charts from 85 pediatric patients with PFAPA syndrome (49 males and 36 females) enrolled in the AIDA registry and treated with SSK12 for a median period of 6.00 ± 7.00 months in the period between September 2017 and May 2022 were examined. Children recruited had a median time of disease duration of 19.00 ± 28.00 months. The number of febrile flares significantly decreased comparing the 12 months before [median (IQR), 13.00 (6.00)] and after SSK12 initiation [median (IQR), 5.50 (8.00), < 0.001]. The duration of fever was significantly reduced from 4.00 (2.00) days to 2.00 (2.00) days [ < 0.001]. Similarly, the highest temperature in°C was found significantly lower in the last follow-up assessment [median (IQR), 39.00 (1.00)] compared to the period prior to SSK12 start [median (IQR), 40.00 (1.00), < 0.001]. Steroid load (mg/year) of betamethasone (or any equivalent steroid) significantly decreased between 12 months before treatment with SSK12 [median (IQR), 5.00 (8.00) mg/year] and the last follow-up visit [median (IQR), 2.00 (4.00) mg/year, < 0.001]. The number of patients experiencing symptoms including pharyngitis/tonsillitis ( < 0.001), oral aphthae ( < 0.001) and cervical lymphadenopathy ( < 0.001) significantly decreased following SSK12. SSK12 prophylaxis given for at least 6.00 months was found to reduce febrile flares of PFAPA syndrome: in particular, it halved the total number per year of fever flares, shortened the duration of the single febrile episode, lowered body temperature by 1°C in the febrile flare, provided a steroid-sparing effect, and significantly reduced the accompanying symptoms related to the syndrome.

The Clinical Chameleon of Autoinflammatory Diseases in Children.

The very first line of defense in humans is innate immunity, serving as a critical strongpoint in the regulation of inflammation. Abnormalities of the innate immunity machinery make up a motley group of rare diseases, named 'autoinflammatory', which are caused by mutations in genes involved in different immune pathways. Self-limited inflammatory bouts involving skin, serosal membranes, joints, gut and other districts of the human body burst and recur with variable periodicity in most autoinflammatory diseases (ADs), often leading to secondary amyloidosis as a long-term complication. Dysregulated inflammasome activity, overproduction of interleukin (IL)-1 or other IL-1-related cytokines and delayed shutdown of inflammation are pivotal keys in the majority of ADs. The recent progress of cellular biology has clarified many molecular mechanisms behind monogenic ADs, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome (or 'autosomal dominant familial periodic fever'), cryopyrin-associated periodic syndrome, mevalonate kinase deficiency, hereditary pyogenic diseases, idiopathic granulomatous diseases and defects of the ubiquitin-proteasome pathway. A long-lasting history of recurrent fevers should require the ruling out of chronic infections and malignancies before considering ADs in children. Little is known about the potential origin of polygenic ADs, in which sterile cytokine-mediated inflammation results from the activation of the innate immunity network, without familial recurrency, such as periodic fever/aphthous stomatitis/pharyngitis/cervical adenopathy (PFAPA) syndrome. The puzzle of febrile attacks recurring over time with chameleonic multi-inflammatory symptoms in children demands the inspection of the mixture of clinical data, inflammation parameters in the different disease phases, assessment of therapeutic efficacy of a handful of drugs such as corticosteroids, colchicine or IL-1 antagonists, and genotype analysis to exclude or confirm a monogenic origin.

Development and implementation of the AIDA International Registry for patients with Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis syndrome.

Aim of this paper is to illustrate the methodology, design, and development of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to patients with the Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome. This is a physician-driven, non-population- and electronic-based registry proposed to gather real-world demographics, clinical, laboratory, instrumental and socioeconomic data from PFAPA patients. Data recruitment is realized through the on-line Research Electronic Data Capture (REDCap) tool. This registry is thought to collect standardized information for clinical research leading to solid real-life evidence. The international scope and the flexibility of the registry will facilitate the realization of cutting-edge study projects through the constant updating of variables and the possible merging and transfer of data between current and future PFAPA registries. A total of 112 centers have already been involved from 23 countries and 4 continents starting from August 24th, 2021, to April 6th, 2022. In total 56/112 have already obtained the formal approval from their local Ethics Committees. The platform counts 321 users (113 principal investigators, 203 site investigators, two lead investigators, and three data managers). The registry collects retrospective and prospective data using 3,856 fields organized into 25 instruments, including PFAPA patient's demographics, medical histories, symptoms, triggers/risk factors, therapies, and impact on the healthcare systems. The development of the AIDA International Registry for PFAPA patients will enable the on-line collection of standardized data prompting real-life studies through the connection of worldwide groups of physicians and researchers. This project can be found on https://clinicaltrials.gov NCT05200715.

Assessment of Congenital Neutropenia in Children: Common Clinical Sceneries and Clues for Management.

A disparate group of rare hematological diseases characterized by impaired maturation of neutrophil granulocytes defines congenital neutropenias. Neutropenic patients are prone to recurrent infections beginning in the first months of life. Of interest is "cyclic neutropenia," an ultra-rare disorder revealed by sinusoidal variations in the neutrophil count and recurring infections every 21 days. Diagnosis of these disorders is frequently obscured by the multiple causes of recurrent fevers in children. The aim of this overview is to outline the physical assessment of children presenting with early-onset symptomatic neutropenia, identify the disease between the many medical conditions and even emergencies which should enter in differential diagnosis, hint at the potential management with granulocyte-colony stimulating factor, define the risk of evolution to hematologic malignancy, and summarize inter-professional team strategies for improving care coordination and outcomes of patients.

Children and Adults with PFAPA Syndrome: Similarities and Divergences in a Real-Life Clinical Setting.

Analogies or differences of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome in children and adults are barely known. The aim of our study was to compare the overall characteristics of a large cohort of patients, both children and adults, diagnosed with PFAPA syndrome. In the last decade, we identified 120 children and 63 adults with periodically recurring fevers, who fulfilled the criteria for PFAPA diagnosis. The two subcohorts were analyzed according to demographic features, clinical manifestations, laboratory data, and responses to therapies. The mean age of onset was 2.4 ± 1.5 and 19.7 ± 10.3 years, respectively, in children and adults, while attacks occurred every 3.8 ± 0.8 and every 4.3 ± 2.3 weeks, respectively, in children and adults. A higher prevalence of exudative pharyngitis was observed in children (58.8%), and the majority of children had only two cardinal signs during flares. In adults, there was a higher interpersonal variability of the intercritical periods. Inflammatory markers measured during non-febrile periods were normal in children but altered in the totality of adults during febrile periods. A strong efficacy of corticosteroids in controlling the pediatric syndrome was observed, but response rates to steroids were less brilliant in adults. Colchicine and interleukin-1 inhibitors were used in the management of the steroid-resistant adult syndrome. Conversely, tonsillectomy was performed in a very low number of children, but was effective in 60.7% of adults when treated after 16 years. The mean age of disappearance of PFAPA symptoms has been 6.4 ± 2.4 years in children, while only 27% of adults have shown a complete drug-free symptom regression. A linear conformity of the PFAPA syndrome has been observed between pediatric and adult patients. PFAPA symptoms tended to disappear with no sequelae in 94.1% of children, while the disease was still active in almost 3/4 of adults at the time of our assessment.

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome: A debate about diagnosis and treatment in children continues.

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

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.

Treatment options for periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome in children and adults: a narrative review.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most frequent non-hereditary autoinflammatory disorder in childhood: Its onset is usually observed before 5 years, though reports regarding adulthood are increasing. The pathogenesis of the syndrome is not completely understood, but a multifactorial origin, probably based on a polygenic pattern of susceptibility, is the most probable rational pathogenetic hypothesis. Treatment of PFAPA syndrome relies on the administration of low-dose corticosteroids, which promptly abort flares but cannot prevent subsequent disease episodes over time. Tonsillectomy with or without adenoidectomy has proved to be successful in some pediatric patients, as proven by different studies. On the other hand, colchicine, cimetidine, nonsteroidal anti-inflammatory drugs, and interleukin-1 inhibitors have shown efficacy, which require further definite confirmations. This review is aimed at summarizing all the recent evidence about treatment options available for PFAPA syndrome both in pediatric and adult patients.

The Broad-Ranging Panorama of Systemic Autoinflammatory Disorders with Specific Focus on Acute Painful Symptoms and Hematologic Manifestations in Children.

Systemic autoinflammatory disorders (SAIDs) are inherited defects of innate immunity characterized by recurrent sterile inflammatory attacks involving skin, joints, serosal membranes, gastrointestinal tube, and other tissues, which recur with variable rhythmicity and display reactive amyloidosis as a potential long-term complication. Dysregulated inflammasome activity leading to overproduction of many proinflammatory cytokines, such as interleukin-1 (IL-1), and delayed shutdown of inflammation are considered crucial pathogenic keys in the vast majority of SAIDs. Progress of cellular biology has partially clarified the mechanisms behind monogenic SAIDs, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndrome, mevalonate kinase deficiency, hereditary pyogenic diseases, idiopathic granulomatous diseases and defects of the ubiquitin-proteasome pathway. Whereas, little is clarified for the polygenic SAIDs, such as periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) syndrome. The puzzle of symptomatic febrile attacks recurring over time in children requires evaluating the mixture of clinical data, inflammatory parameters in different disease phases, the therapeutic efficacy of specific drugs such as colchicine, corticosteroids or IL-1 antagonists, and genotype analysis in selected cases. The long-term history of periodic fevers should also need to rule out chronic infections and malignancies. This review is conceived as a practical template for proper classification of children with recurring fevers and includes tips useful for the diagnostic approach to SAIDs, focusing on the specific acute painful symptoms and hematologic manifestations encountered in childhood.

PFAPA syndrome and Behçet's disease: a comparison of two medical entities based on the clinical interviews performed by three different specialists.

The pediatric syndrome characterized by periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) and adult Behçet's disease share some clinical manifestations and are both polygenic autoinflammatory disorders with interleukin-1β showing to play a pivotal role. However, the diagnosis is mostly clinical and we hypothesize that specific criteria may be addressed differently by different physicians. To determine the diagnostic variability, we compared the answers of 80 patients with a definite diagnosis of Behçet's disease (age 42.1 ± 13.7 years) obtained by separate telephone interviews conducted by a rheumatologist, a pediatrician, and an internist working largely in the field of autoinflammatory disorders. Questions were related to the age of symptom onset, the occurrence of recurrent fevers during childhood, and the association with oral aphthosis, cervical adenitis and/or pharyngitis, previous treatments, possible growth impairment, the time lapse between PFAPA-like symptoms and the onset of Behçet's disease, and the occurrence of Behçet-related manifestation during childhood. The rheumatologist identified 30 % of patients with Behçet's disease fulfilling PFAPA syndrome diagnostic criteria, compared to the pediatrician and the internist identifying 10 and 7.5 %, respectively. Most of the patients suffered from recurrent oral aphthosis in childhood also without fever (50, 39, and 48 % with each interviewer), yet no patient fulfilled the Behçet's disease diagnostic criteria. Our data suggest that physician awareness and expertise are central to the diagnosis of autoinflammatory disorders through an accurate collection of the medical history.