What is the clinical significance of a heterozygous MEFV (Mediterranean Fever) mutation compared to a homozygous one?

Clinical Significance of Heterozygous vs Homozygous MEFV Mutations

Homozygous or compound heterozygous MEFV mutations confirm the diagnosis of Familial Mediterranean Fever (FMF), while heterozygous mutations represent a susceptibility factor rather than a definitive cause of classical Mendelian FMF, though they can still produce FMF-like symptoms in a subset of patients. 1, 2

Diagnostic Certainty

Homozygous/Compound Heterozygous Mutations:

• Two clearly pathogenic variants (either homozygous or compound heterozygous) provide definitive genetic confirmation of FMF diagnosis 1, 3
• This genotype follows the expected autosomal recessive inheritance pattern for classical FMF 4
• In affected siblings of patients with two MEFV mutations, 92% carry two mutated alleles, confirming the recessive nature of the disease 2

Heterozygous Mutations:

• A single pathogenic variant does NOT confirm FMF diagnosis genetically, though it may be consistent with clinical symptoms 1, 3
• Diagnosis in heterozygotes relies primarily on clinical judgment rather than genetic confirmation 3
• Statistical analysis demonstrates that heterozygosity is not responsible for classical Mendelian FMF per se, but constitutes a susceptibility factor for clinically-similar multifactorial forms 2

Disease Risk and Penetrance

The actual risk for heterozygotes to develop FMF-like symptoms is low but measurable:

• Heterozygotes have an estimated absolute risk of 2.1 × 10⁻³ to 5.8 × 10⁻³ (0.21% to 0.58%) of developing FMF 2
• The relative risk compared to non-carriers is 6.3 to 8.1-fold higher 2
• At the population level, heterozygosity does not contribute significantly to overall FMF disease prevalence 2

Clinical Phenotype Differences

Severity and Presentation:

• Patients with single heterozygous mutations typically have milder disease courses compared to those with two pathogenic variants 5, 6
• Heterozygotes are less prone to developing new clinical signs of FMF during follow-up 6
• In very young heterozygous children (age <6 years at onset), clinical signs may completely disappear by puberty, allowing discontinuation of colchicine in approximately 28% (5 of 18) of cases 6

Symptom Profile:

• Initial presenting symptoms may be indistinguishable between heterozygotes and homozygotes in young children 6
• However, the long-term disease trajectory differs significantly, with heterozygotes showing spontaneous resolution more frequently 6

Critical Amyloidosis Risk

This is a crucial distinction for patient counseling:

• Mutations affecting codons 680 or 694 of the MEFV gene carry critical amyloidosis risk that must be discussed regardless of zygosity status 1
• The guidelines emphasize that comments about amyloidosis risk are "critical" when these specific mutations are present 1
• However, no amyloidosis was observed in patients homozygous for the milder E148Q mutation in one cohort, though family history of amyloidosis was present in some cases 7

Important Clinical Caveats

Diagnostic Pitfalls:

• Finding a single MEFV pathogenic variant in Mediterranean populations does not exclude disease-causing mutations in other hereditary recurrent fever genes 1, 3
• Very young heterozygous children (<6 years) can present with FMF-like disease similar to those with two mutations, but this is not necessarily predictive of lifelong illness 6
• Clinical diagnosis of FMF in very young heterozygous children should be made with caution 6

Triggering Factors:

• Certain immunosuppressants may trigger FMF attacks in asymptomatic heterozygous carriers, as demonstrated in a case during myelodysplastic syndrome treatment 8
• This suggests that environmental or iatrogenic factors can unmask disease in heterozygotes 8

Practical Management Implications

For Homozygous/Compound Heterozygous Patients:

• Genetic confirmation supports lifelong colchicine therapy
• Monitoring for amyloidosis is essential, particularly with high-risk mutations (codons 680,694) 1
• Family screening is indicated 1

For Heterozygous Patients:

• Diagnosis relies on clinical criteria, not genetics alone 3
• Consider trial of colchicine if symptoms are consistent with FMF 6
• In young children, reassess diagnosis during follow-up, particularly around puberty 6
• Consider alternative diagnoses or other hereditary recurrent fever genes 1, 3
• Referral to genetic counseling and clinical reference centers is preferable for discussing prognosis and family risk 1