Recurrent fever no diagnosis

Understanding recurrent fever in children

Recurrent fever in children is a common clinical challenge.

While most cases begin in childhood, similar diagnostic challenges may also arise in adults.

In most cases, episodes are linked to infections.
However, when fever recurs over time without a clear explanation, the situation changes.

At this stage, genetic conditions should be taken into account, including periodic fever syndromes such as PFAPA, familial Mediterranean fever (FMF), TRAPS, or other autoinflammatory diseases.

Genomic analysis may become relevant in this context.

Targeted genetic panels are often used when a specific condition is suspected.
However, in more complex cases, a broader approach may be considered.

→ Clinical Whole Exome Sequencing or → Clinical Whole Genome Sequencing allows the analysis of all coding genes, making it possible to identify genetic conditions even when the presentation is incomplete, atypical, or still evolving.

Causes of recurrent fever in children

Recurrent fever in children may arise from different underlying mechanisms.

These can be broadly grouped into three categories:

• • Infectious causes – the most common, typically self-limited and resolving over time

• • Autoinflammatory conditions – characterized by recurrent episodes of inflammation without a clear infectious trigger

• • Other systemic or genetic conditions – less common, often associated with additional clinical features beyond fever

In clinical practice, the distinction between these categories is not always clear, especially when symptoms evolve over time.

Periodic fever syndromes

Some forms of recurrent fever fall within what are commonly referred to as periodic fever syndromes — a group of conditions, often genetic, characterized by recurrent episodes of inflammation.

These are conditions in which episodes of inflammation recur over time, often without a clear infectious trigger, and with patterns that may appear similar across different patients, at least in the early stages.

Among the conditions most frequently considered:

• • PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) – usually seen in early childhood, with recurrent fever episodes often accompanied by pharyngitis or cervical adenitis

• • Familial Mediterranean Fever (FMF) – a genetic condition characterized by recurrent inflammatory attacks, sometimes involving abdominal pain or serosal inflammation

• • TRAPS (TNF Receptor-Associated Periodic Syndrome) – typically associated with longer and less predictable fever episodes

• • Mevalonate Kinase Deficiency (MKD) – a rarer condition, often with early onset and variable inflammatory manifestations

However, beyond the best-known periodic fever syndromes, many additional genetic entities have been described in association with recurrent fever or fever-like inflammatory episodes.

Some examples include:

• • Autoinflammation with episodic fever and immune dysregulation — SHARPIN

• • Autoinflammation with episodic fever and lymphadenopathy — RIPK1

• • Pelger-Huët–like anomaly and episodic fever with abdominal pain — candidate gene CEBPE

• • Periodic fever, immunodeficiency, and thrombocytopenia syndrome — WDR1

• • Hyper-IgE syndromes with recurrent infections and inflammatory manifestations — genes including STAT3, DOCK8, ZNF341, IL6ST, IL6R, and STAT6

This list is not intended to replace clinical evaluation.
It reflects how broad the genetic landscape can become when recurrent fever does not follow a classic pattern.

In practice, these conditions do not always present in a clear or textbook form.
Features may overlap, evolve, or remain only partially expressed for years, making a definitive diagnosis difficult in many cases.main only partially expressed for years, making a definitive diagnosis difficult in many cases.

When recurrent fever is not a classic periodic fever syndrome

Some monogenic disorders do not initially present with a recognizable syndrome. Recurrent fever may coexist with arthritis, sterile bone inflammation, rash, mouth ulcers, inflammatory bowel disease or recurrent infections. In these cases, genes involved in autoinflammation, innate immunity and primary immunodeficiency may need to be considered together.

Here below selected genes associated with conditions which are not classic periodic fevers:

• LPIN2 – recurrent fever, sterile osteomyelitis, inflammatory bone disease and arthritis.
• IL1RN – autoinflammatory disease with recurrent fever, skin inflammation and sterile osteitis.
• NOD2 – recurrent fever associated with granulomatous inflammation, arthritis, uveitis and inflammatory bowel disease.
• LACC1 – juvenile arthritis, inflammatory bowel disease and recurrent inflammatory episodes.
• MYD88 – primary immunodeficiency with recurrent bacterial infections that may initially mimic recurrent fever syndromes.
• CYBC1 – chronic granulomatous disease with recurrent infections and inflammatory manifestations.
• C1QB – complement deficiency associated with recurrent infections and autoimmune manifestations.
• LPIN1 – recurrent episodes of rhabdomyolysis, often triggered by febrile illnesses.
• CBLB – immune dysregulation with susceptibility to recurrent infections and inflammatory disease.
• TBK1 – rare immune dysregulation syndromes with recurrent inflammatory or infectious presentations.
• PSMB4 – proteasome-associated autoinflammatory disease with recurrent systemic inflammation.

Clinical features and course

Genetic forms of recurrent fever are typically characterized by episodes of inflammation occurring in the absence of identifiable infections or autoantibody production.

Diagnosis is often based on clinical evaluation, supported when necessary by genetic testing.

During febrile episodes, patients may present with associated signs and symptoms such as pharyngitis, lymphadenopathy, rash, abdominal pain, or systemic inflammation.
These features may overlap across different conditions and are not always specific to a single syndrome.

Onset is frequently in childhood, although adult presentations are also recognized.

These conditions may require careful clinical evaluation not only because of their impact on quality of life, but also due to potential long-term complications, including amyloidosis in some forms.

Several therapeutic approaches are currently used, depending on the underlying condition and clinical context.
These include colchicine, IL-1 inhibitors, anti-TNF therapies, and, in selected cases, targeted biological agents such as canakinumab.

When recurrent fever has no diagnosis

A clear diagnosis is not always reached because these conditions often do not present in a complete or recognizable form.

Clinical features may be incomplete, overlapping, or evolving over time, making interpretation difficult.

In infantile forms, understandably concerned parents may begin to add increasingly detailed observations over time.
Some of these can be helpful. Others may unintentionally complicate the diagnostic process — for example, attributing specific patterns to fever episodes (such as “no drug can lower the fever, only a cold towel on the forehead”).

As a result, the diagnostic process may remain inconclusive — not because the condition is absent, but because it is not yet fully interpretable as a whole. explanation.

FLOWCHART – How recurrent fever is usually evaluated

The diagnostic evaluation of recurrent fever aims to distinguish
common infections from autoinflammatory diseases,
primary immunodeficiencies and other rare genetic disorders.

The simplified flowchart below summarizes the typical diagnostic pathway.