Background/Purpose: HyperIgD syndrome is an autoinflammatory disorder caused by mutations in the MVK gene. While mutations in most patients follow autosomal recessive inheritance, we have identified a cohort of patients with recurrent fevers and only 1 mutation in the MVK gene.  The purpose of this study was to compare clinical features in those with 1 vs. 2 MVK mutations and to report therapeutic responses in all.

Methods: Patients were evaluated at the National Institutes of Health.  Clinical and laboratory information were collected at each visit.

Results: 31 pts with mutations in MVK were evaluated: 22 had 2 mutations (21 with V377I and 1 other mutation; 1 with V203A/H380R), 9 had only 1 mutation after testing the whole gene (8 with V377I, 1 with I268V).  The carrier frequency of V377I in our control Caucasian population is 0.3% (2/739). 

Clinical or laboratory presentation at the time of a flare was compared between the 2 groups.  There was no significant difference with regard to age of onset, duration of flares, frequency of flares, flares after immunization, GI symptoms, oral ulcers, sore throat, arthralgia, or adenopathy associated with flares.  Rash was more common in pts with 2 mutations, 20/22 compared to 4/9 in those with one mutation (p=.01).  Level of IgA was increased in those with 2 mutations (452±230 mg/dl) compared to those with 1 mutation (230±175) (p=.01), as well as level of IgD (95±95, 2 mutations, vs. 8.3±7.4, 1 mutation, p=.01).

Since there was no significant difference in clinical presentation, other than presence of rash and levels of IgA and IgD, pts were considered together to evaluate their therapeutic responses.  Prednisone given at the time of a flare was helpful in 18/25, however one patient developed steroid psychosis.  Colchicine was given to 8 pts and 7 showed no improvement or worsening.  15 pts tried montelukast: 4 reported some improvement, however 11 reported no improvement or worsening.  Intermittent anakinra at the time of a flare was helpful in 14/19 pts, not helpful in 3 and too early to assess in 2 patients.  One patient developed acute renal failure shortly after initiating intermittent anakinra therapy. Of the 9 pts receiving weekly etanercept, 4 showed some improvement and 5 showed no improvement of worsening (with one patient developing massive lymphadenopathy).  3 pts have required daily anakinra and shown a favorable response.

Conclusion: Aside from the presence of rash and higher IgA and IgD levels in those children with 2 MVK mutations, there are no significant clinical differences between those patients with 1 or 2 mutations.  The relatively small number of children with 1 mutation may influence the analyses, but thus far there are no clear trends that allow identification or predictability of the disease course in children with either 1 or 2 mutations. Given the higher frequency of V377I heterozygotes in our patient cohort compared to the general population, our data suggest that under some circumstances this may be associated with recurrent fevers.  Therapeutic options for children with MVK mutations include intermittent prednisone or anakinra, either given intermittently or daily; however, not all patients respond to therapy and there are associated adverse events in some patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/single-mvk-mutation-and-recurrent-fevers/