Indian Pediatr 2012;49: 583-585
Novel Mutations causing Hyperimmunoglobulin D
and Periodic Fever Syndrome
Aditi Sinha, *Hans R Waterham, K Vijesh Sreedhar and Vandana Jain
From Department of Pediatrics, All India Institute of
Medical Sciences, New Delhi and *Laboratory Genetic Metabolic Diseases,
Departments of Clinical Chemistry and Pediatrics, Academic Medical
Center, University of Amsterdam, The Netherlands.
Correspondence to: Dr Vandana Jain, Professor,
Department of Pediatrics, All India Institute of Medical Sciences,
New Delhi, India.
Received: February 19, 2011;
Initial review: April 4, 2011;
Accepted: October 27, 2011.
Hyperimmunoglobulin D and periodic fever syndrome (HIDS) is a rare,
hereditary autoinflammatory condition characterized by recurrent
inflammatory episodes. We report a 9-year-old boy, diagnosed with HIDS
due to two novel mutations, c.62C>T (p.Ala21Val) and c.372-6T>C
(probable splicing defect), in the mevalonate kinase (MVK)
gene. The pathogenicity of these mutations was confirmed by measurement
of low MVK enzyme activity in cultured primary skin fibroblasts of the
patient. The symptoms have been refractory to therapy with steroids and
non steroidal anti inflammatory drugs. This report expands the genetic
and ethnic spectrum of HIDS.
Key words: Diagnosis, HIDS, India, Mevalonate kinase,
Hereditary periodic fevers are rare, autosomal
recessive diseases characterized by apparently spontaneous attacks
of inflammation . Hyper IgD syndrome (HIDS, OMIM #260920) is one
such entity caused by mutations in the gene encoding mevalonate
kinase (MVK), an enzyme involved in the isoprenoid and cholesterol
biosynthesis pathway . We report its sporadic occurrence in an
Indian boy in whom two novel MVK gene mutations were
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
At admission, investigations showed neutrophilic
leukocytosis (total count 20,400/mm3,
64% neutrophils), normocytic normochromic anemia, normal renal and
liver function tests, and elevated erythrocyte sedimentation rate
and C reactive protein. Blood and urine cultures were sterile, chest
radiograph showed clear lung fields, while stool and urine
examination were unremarkable. Immunological testing showed normal
C3 complement, absence of rheumatoid factor, antinuclear, anti-dsDNA
and anti neutrophilic cytoplasmic antibodies, negative HIV serology
and normal nitroblue tetrazolium test. Serum IgG (1105 mg/dL, range
600-1236 mg/dL) and IgM (159 mg/dL, range 99-196 mg/dL) levels were
normal, while IgA was increased (417 mg/dL; range 25-154 mg/dL).
Fine needle aspiration and biopsy of cervical lymph node suggested
reactive hyperplasia. Lipid profile was unremarkable except for an
elevated triglyceride level of 840 mg/dL (normal <200 mg/dL).
Repeated extensive microbiological and immunological investigations
during previous admissions were negative or inconclusive. However,
elevated triglyceride (246 mg/dL) and elevated IgA (1005 mg/dL) had
also been documented previously.
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
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 . HIDS is a rare
autosomal recessive condition due to mutations in the MVK
gene on chromosome 12q24 . 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 .
The diagnosis of HIDS can be confirmed by
demonstrating low activity of MVK enzyme and/or
disease-causing mutations in the MVK gene . Most patients
are compound heterozygotes for missense mutations in MVK
gene, the most common being V337I, which is seen in >80% of cases
. Neither of the two nucleotide changes in the alleles of the
MVK gene in our patient has been reported before .
Pathogenicity of these mutations was confirmed by the finding of a
deficient MVK enzyme activity in cultured skin fibroblasts.
The mechanisms by which defects in the MVK
gene cause a periodic inflammatory disease are unclear [4,5].
Abnormalities noted include increased levels of immunoglobulins (IgD,
IgA), cytokines [interleukin (IL)-6, tumor necrosis factor (TNF)-a,
and interferon (IFN)-a],
serum IL-1 receptor antagonist soluble TNF receptor, and urinary
leukotriene E4 excretion . The precise role of IgD in the
pathogenesis has not yet been defined.
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 . Unlike in patients with MA,
patients with HIDS have residual (1-8%) enzyme activity, as is
confirmed in our patient [7, 8].
Consensus is lacking regarding how HIDS should be
managed. Although HIDS is considered to be a benign condition,
treatment is difficult and largely supportive. Anti-inflammatory
drugs have variable efficacy in suppressing febrile attacks;
relapses are unresponsive to steroids and only partially subdued by
NSAIDS. Colchicine is suggested to be effective at prolonging
intercritical remission periods without changing disease severity.
Similarly, beneficial effects have been ascribed to therapy with
simvastatin, an inhibitor of HMG-CoA reductase, anakinra, a
recombinant interleukin-1 receptor antagonist, and etanercept, the
tumour necrosis factor-a
inhibitor [9, 10]. More recently, demonstration of efficacy of
zaragozic acid A suggests a role for modulation of isoprenoid
biosynthesis in treatment of HIDS .
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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