Hyperimmunoglobulinaemia D syndrome (HIDS) is an autosomal recessive auto‐inflammatory syndrome caused by mutation in the mevalonate kinase (MVK) gene.1 It presents with febrile episodes starting in infancy with increased serum immunoglobulin (Ig)D levels.2 It is mostly described in people of Dutch or North European descent.3 Isolated cases have been reported from Turkey,4 Japan5 and Qatar.6 No case of HIDS has been reported from South Asia.
A 15‐year‐old boy from Kerala, India, presented with history of febrile episodes lasting 3–7 days since the age of 3 months. The episodes of fever were variably associated with polyarthritis, abdominal pain, headache, vomiting, diarrhoea, pleuritic chest pain and erythematous papular rash. The episodes occurred at an interval of 1–6 months. He underwent a laparotomy at the age of 8 years, when peritoneal adhesions were detected. During the few episodes of fever, liver, spleen and lymph node enlargement, raised erythrocyte sedimentation rate and leucocytosis were found. He showed good response to non‐steroidal anti‐inflammatory drugs. His total serum cholesterol was 132 mg/dl. Serum IgG, IgM, IgA and IgD levels were 1465 mg/dl, 58.6 mg/dl, 1166 mg/dl and 938 IU/ml, respectively.
The 11‐year‐old brother of the proband had also suffered similar episodes of fever since the age of 2 months, except that he had arthritis only once. A laparotomy performed at the age of 4 years revealed peritoneal adhesions. Serum IgG, IgM, IgA and IgD levels were 1377 mg/dl, 119.1 mg/dl, 633 mg/dl and 1363 IU/ml, respectively.
The pedigree analysis was compatible with an autosomal recessive pattern of inheritance. The MVK gene analysis showed both sibs to be compound heterozygotes for V377I and IVS2+2delT. The father carried the V377I allele and the mother possessed the IVS2+2delT allele (fig 1).
Figure 1 (A) depicts the family tree of hyperimmunoglobulinaemia D syndrome. Females are indicated by circles and males by squares. Solid symbols denote affected members. The mevalonate kinase (MVK) mutations are listed on the left and right sides of the members. Note that the parents are heterozygotic for MVK mutations whereas both siblings are compound heterozygotic for V377I and IVS2+2 delT. The IgD serum concentrations are listed below the members. The serum concentrations of the affected siblings are grossly increased (normal <100 IU/ml), whereas those of the nonaffected father and mother are normal. (B) shows the electrospherogram with sequence identification of the deletion of a T nucleotide in intron 2. This mutation, IVS2+2 delT, is predicted to affect correct splicing of the exon, resulting in a shift of the reading frame.
The presence of recurrent episodic fever in two siblings with evidence of serositis suggested familial Mediterranean fever or HIDS. The duration of the episodes (3–7 days), prominence of diarrhoea and vomiting along with the early onset in infancy pointed to HIDS. HIDS is associated with increased concentrations of serum IgA and IgD,7 and both our patients had increased concentrations. One patient with proven HIDS has been reported6 from Doha (with Palestinian ancestry). Although there is a report of HIDS from Japan,5 no MVK mutation has been reported. Our patients had increased serum IgD concentrations along with MVK mutation (ancestral 1129G>A(V377I) mutation along with a novel mutation IVS2+2delT). The presence of a mutation on both alleles of MVK confirmed the diagnosis of HIDS.
V377I mutation is seen mostly in patients of Dutch descent.3 The Dutch East India company had a trading relationship with Kerala, India, and the present family hails from Kerala. The gene could have come along with the European traders or through a Mediterranean route with Arab traders. A recent report of a patient with HIDS from Qatar6 with V3771 mutation and absence of any Dutch ancestry in the family supports the second view. The second mutation, IVS2+2delT, is reported for the first time. This mutation probably results in aberrant splicing and shifts the reading frame.
Acknowledgements
We thank Dr Remesh Bhasi, Consultant Rheumatologist at Malabar Institute of Medical Sciences, Kozhikode, for referring the patients to us for evaluation.
Abbreviations
HIDS - hyperimmunoglobulinaemia D syndrome
MVK - mevalonate kinase
Footnotes
Competing interests: None declared.
References
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