Session Type: Abstract Submissions (ACR)
Background/Purpose: As a referral clinic for children with periodic fevers, we see a wide variety of clinical presentations. While genetic testing is usually helpful in determining clinical course and possible treatment options, we have seen a wide variation in clinical presentation in those patients found to have a genetic mutation in one of the genes linked to periodic fever syndromes. Familial Mediterranean fever (FMF) is usually regarded as an autosomal recessive inherited disorder due to mutations in the MEFV gene; however we have seen a number of symptomatic children who carry only one identifiable mutation in MEFV. In this study, we aim to characterize the clinical presentations of children with a variety of mutations in MEFV.
Methods: Patients were evaluated at the National Institutes of Health. Clinical and laboratory information were collected at each visit. Genetic testing for mutations in MEFV was performed by GeneDx. Genomic DNA was PCR-amplified for analysis of exons 2, 3, and 10 of the MEFV gene. Patients were evaluated for age at onset (months), duration of episode (days), frequency (weeks), and presence or absence of fever, abdominal pain, chest pain, rash, adenopathy, oral ulcers, or sore throat associated with flares. Patients were considered as meeting the criteria for PFAPA (Periodic Fever with Aphthous Ulcers, Pharyngitis, and Adenopathy) Syndrome if they had a history of periodic fever and 2 of the following: adenopathy, oral ulcers or sore throat.
Results: 82 children with mutations in MEFV were evaluated: 14 had 2 exon 10 mutations, 7 had 2 exon 10 mutations + E148Q, 18 had a single exon 10 mutation, 7 had a single exon 10 mutation + E148Q, 12 had a single E148Q mutation, 9 had a single K695R mutation, and 15 had P369S/R408Q ± E148Q.
We found no significant difference in any of the factors when children with one exon 10 mutation were compared with children with two exon 10 mutations. Children heterozygous for only E148Q were similar to those with a single exon 10 mutation with the exception that a higher percentage of E148Q heterozygotes met criteria for PFAPA (42% vs. 6%, P=.015). Similarly, children heterozygous for K695R had a significantly longer duration of episode (4 days vs. 2.6, P=.01) and higher frequency of adenopathy (89% vs. 39%, P=.014), oral ulcers (67% vs. 17%, P=.009), sore throat (56% vs. 11%), and meeting criteria for PFAPA (78% vs. 6%, P<.009) when compared to children with one mutation in exon 10. Children with P369S/R408Q ± E148Q were similar to those heterozygous for an exon 10 mutation, with the exception of longer duration of episode (4 vs. 2.6 days, P=.027). While most children with one or two exon 10 mutations responded to therapy with colchicine, there was a trend for need for additional treatment options in patients with E148Q, K695R or P369S/R408Q heterozygosity.
Conclusion: A clinical presentation similar to that of PFAPA was more common in patients heterozygous for either E148Q or K695R mutations of MEFV. While this is not an unexpected finding in patients with E148Q, it is surprising that patients with mutations in amino acid 695 do not follow the pattern of severe disease seen historically in patients with mutations in amino acid 694.
A. K. Ombrello,
D. L. Kastner,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/clinical-variation-in-children-with-mutations-in-mefv/