What is the significance of family history in patients with prolonged fever?

Family History in Prolonged Fever: Critical Diagnostic Clues

Family history is essential in evaluating prolonged fever because it identifies hereditary recurrent fever syndromes (HRFs), particularly when a positive family history of similar symptoms, specific ethnic backgrounds (Mediterranean, Middle Eastern, Armenian, Turkish), or family history of amyloidosis is present—all of which should prompt genetic testing. 1

Key Elements to Obtain in Family History

Ethnic and Geographic Origin

• Document specific ethnic background, as familial Mediterranean fever (FMF) clusters in non-Ashkenazi Jews, Arabs, Armenians, Turks, and increasingly recognized in Ashkenazi Jewish and Italian populations. 2
• Ethnicity is a critical predictor for finding known MEFV mutations and guides which HRF genes to test first. 1, 2

Family Members with Similar Symptoms

• Ask specifically about relatives with recurrent fever episodes, as 23% of PFAPA patients have at least one family member with the same condition. 3
• Inquire about recurrent pharyngitis and aphthous stomatitis in first-degree relatives (parents and siblings), as these represent reduced penetrance phenotypes of PFAPA syndrome—parents of PFAPA patients have significantly higher rates of recurrent pharyngitis (36% vs 16%) and aphthous stomatitis (46% vs 28%) compared to controls. 3
• Document siblings with similar periodic fever patterns, as they have 5-fold higher prevalence of PFAPA (10% vs 2%) and significantly higher rates of recurrent pharyngitis and aphthous stomatitis. 3

Family History of Amyloidosis

• A family history of amyloidosis is a critical red flag that warrants presymptomatic genetic testing in asymptomatic family members, as this life-threatening complication can be prevented with early monitoring and intervention. 1
• Presymptomatic testing should be offered after genetic counseling when severe genotypes are identified in relatives with overt disease or when amyloidosis has occurred in the family. 1

Inheritance Patterns to Recognize

Recessive Inheritance (FMF and MKD)

• FMF and mevalonate kinase deficiency (MKD) follow autosomal recessive patterns, requiring mutations on both chromosomes for disease manifestation. 1
• Carrier parents are typically asymptomatic, but obtaining parental testing helps phase mutations and determine if variants are on the same chromosome (complex allele) or different chromosomes (compound heterozygote). 1

Dominant Inheritance (TRAPS and CAPS)

• TRAPS and cryopyrin-associated periodic syndrome (CAPS) follow autosomal dominant patterns, meaning a single pathogenic variant causes disease. 1
• Parental testing and familial segregation analysis help determine clinical significance of novel or uncertain variants in these dominant conditions. 1

When Family History Triggers Genetic Testing

Positive Family History Scenarios

• Genetic testing is indicated when family history reveals similar periodic fever patterns, even in patients with atypical or partial clinical symptoms. 1
• Testing asymptomatic family members is recommended when a severe genotype is identified in a symptomatic relative or when family history includes amyloidosis, to enable monitoring of acute phase reactants (CRP, SAA) and kidney function. 1

Sporadic Cases Without Family History

• Absence of family history does not exclude HRFs, as incomplete penetrance, de novo mutations (especially in severe CAPS/CINCA), and unrecognized mild phenotypes in relatives are common. 1, 2
• Most severe CINCA-associated mutations occur de novo, so negative family history is expected in these cases. 1

Common Pitfalls to Avoid

• Do not dismiss HRF diagnosis based solely on negative family history, as many patients present with sporadic disease due to incomplete penetrance or unrecognized symptoms in relatives. 1, 2
• Do not assume all family members with recurrent symptoms have the same condition—recurrent pharyngitis and aphthous stomatitis in relatives may represent reduced penetrance rather than full PFAPA syndrome. 3
• Avoid ruling out FMF in patients from high-risk ethnic backgrounds with atypical features, as MEFV mutations are demonstrable even in clinically atypical presentations. 2
• Do not perform presymptomatic testing without genetic counseling, particularly given the complexity of incomplete penetrance and uncertain clinical significance of some variants. 1