Background/Purpose:  Monogenic autoinflammatory diseases are mainly disorders of innate immunity and characterized by unprovoked inflammatory attacks. We studied a consanguineous family with two affected children, with an initial diagnosis of Familial Mediterranean Fever (FMF). While recurrent febrile attacks with serositis, high acute response and parental origin were consistent with FMF, disease onset before age one year, delay in growth, no mutation in MEFV and poor response to colchicine were not typical features of this disease.

Methods:  SNP genotype data for all family members were used for multipoint linkage analysis. Targeted sequencing was performed for MVK residing in one of the linked regions and seven other autoinflammation related genes, IL1RN, LPIN2, MEFV, NLRP12, NLRP3, TNFRSF1A and PSTPIP1. After the identification of the causative mutation, serum IgD and urinary mevalonic acid levels were measured.

Results:  Linkage analysis detected seven candidate regions. The largest candidate region, at 12q24.11-q24.31 (LOD=1.92), contained 191 genes. Novel homozygous c.481T>C (p.Cys161Arg) mutation in MVK, the gene responsible for Hyper IgD Syndrome (HIDS) was identified. At the protein level, cysteine at position 161 is totally conserved in mammals. Urinary mevalonic acid was not detected for either patient, and serum IgD level was slightly elevated for only one patient.

Conclusion:   We identified a novel homozygous MVK mutation in patients with a FMF-like disease but without a typical HIDS phenotype. We hypothesize that this novel mutation underlies the atypical clinical presentation. Phenotypic variability of HIDS is well known, and our findings further expand the MVK mutation phenotype.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-missense-mvk-mutation-in-a-family-with-familial-mediterranean-fever-like-disease/