A 9-year-old boy born to non-consanguineous parents was admitted with fever, abdominal pain, poor intake, oral ulcers, cervical lymphadenopathy, loose stools and skin rash. Recurrent attacks of high fever were reported since infancy. During each attack, high grade fever, anorexia, loose stools with mucus and/ or blood, and tender lymphadenopathy of the neck, axillae and groins were present. Inconsistently, findings included abdominal pain, oral ulcers, blanching maculopapular rash, arthralgias or arthritis involving large joints, and eye congestion. Symptoms would resolve in 15-20 days, and then recur following an asymptomatic interval of 20 days to several months. There was no history of malar rash, photosensitivity, Raynaud’s phenomenon, morning stiffness or muscle weakness, and no family history of similar complaints. On admission, the child was cachexic and febrile. Examination revealed maculopapular rash all over the body, with generalized tender lymphadenopathy, aphthous oral ulcers, hepatosplenomegaly (3 cm each), and bilateral few rhonchi. There was no uveitis or arthritis.

Differential diagnoses included immunodeficiency, juvenile rheumatoid arthritis, periodic fever, and connective tissue disorder. Therapy with intravenous antibiotics and paracetamol was started, and one dose of intravenous hydrocortisone administered for wheezing. Hepatosplenomegaly, rash, rhonchi and lymphadeno-pathy resolved in 48 hours. By day 7 all symptoms and signs had disappeared.

During this admission, serum IgD was assayed and found to be polyclonal and increased, at 157 IU/mL (normal <100 IU/mL). Serum IgD remained elevated (287 IU/ml) while the child was asymptomatic. With the clinical suspicion of HIDS, sequencing of the exons and flanking intronic sequences of the mevalonate kinase (MVK) was performed. Sequencing revealed heterozygosity for two mutations, namely c.62C>T (p.Ala21Val) and c.372-6T>C. Both mutations are novel, not described as known polymorphisms, and were absent on screening of 100 control subjects. While the alanine at position 21 is highly conserved across species, c.372-6T>C is expected to cause incorrect splicing. To determine their functional consequences, MVK enzyme activity was measured in cultured primary skin fibroblasts. Mevalonate kinase activity in patient’s fibroblasts was 8 pmol/min/mg, compared to 467 pmol/min/mg in control fibroblasts. Based on these findings, a diagnosis of HIDS was made.

The child did not respond to therapy with prednisolone or non steroidal anti inflammatory drugs (NSAIDS), and developed severe rash when simvastatin was administered. Due to lack of affordability and unclear efficacy, etanercept or anakinra was not administered. The child continues to have recurrent symptoms, and has been re-admitted twice with hyperpyrexia and once with hip joint arthritis.

HIDS belongs to the group of hereditary periodic fevers, rare auto-inflammatory disorders characterized by intermittent self-limited inflammatory episodes with recurrent fever, synovial or serosal inflammation, rashes, uveitis or conjunctivitis, and, in some, amyloidosis [1]. HIDS is a rare autosomal recessive condition due to mutations in the MVK gene on chromosome 12q24 [1]. Only over 170 cases are known, mainly reported from Dutch or French kindreds [1, 2]. HIDS was secondary to different mutations in the only other report from India [3].

The diagnosis of HIDS can be confirmed by demonstrating low activity of MVK enzyme and/or disease-causing mutations in the MVK gene [2]. Most patients are compound heterozygotes for missense mutations in MVK gene, the most common being V337I, which is seen in >80% of cases [1]. Neither of the two nucleotide changes in the alleles of the MVK gene in our patient has been reported before [2]. Pathogenicity of these mutations was confirmed by the finding of a deficient MVK enzyme activity in cultured skin fibroblasts.

Unlike our patient, some patients with HIDS may develop neurological symptoms such as mental retardation, ataxia, and epilepsy, suggesting that mevalonic aciduria (MA, OMIM 251170) and HIDS form a continuous spectrum of abnormalities mediated by a deficiency of MVK enzyme activity [7]. Unlike in patients with MA, patients with HIDS have residual (1-8%) enzyme activity, as is confirmed in our patient [7, 8].

This report highlights the need to consider familial periodic fevers or auto-inflammatory disorders when evaluating patients with recurrent fever, synovial or serosal inflammation, rash, mucocutaneous manifestations and hepatosplenomegaly. HIDS should be considered as a differential diagnosis irrespective of family history and ethnicity.

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