Patients with mutations in the gene for cold‐induced autoinflammatory syndrome (CIAS1; cryopyrin) have a wide range of disease phenotypes including the familial cold autoinflammatory syndrome, Muckle–Wells syndrome and chronic infantile neurologic cutaneous articular syndrome. We recently identified a new mutation in CIAS1 in a 10‐year‐old boy who had lifelong inflammatory episodes characterised by non‐pruritic urticaria, fevers and articular symptoms. His mother had similar symptoms but no other family member could be identified with similar clinical features. The boy's urticarial lesions typically occurred with exposure to cold temperatures. Skin biopsy showed mixed perivascular inflammatory cells in the superficial dermis suggestive of an early‐phase urticarial response. His spiking fevers to 39°C often responded to non‐steroidal anti‐inflammatory drugs, yet after the febrile episodes he frequently experienced discomfort in the feet. Through his first decade his arthralgias and urticarial lesions became more persistent, and he developed lower extremity large‐joint and small‐joint arthritis without radiographic changes, as well as conjunctivitis, mild self‐resolving headaches, poor weight gain and distal cyanosis with cold exposure. Audiology testing was within normal limits. He never had neurological symptoms to warrant central nervous system imaging.
Laboratory evidence of persistent inflammation was present from an early age (table 1).
Table 1 Dose dependent response to Anakinra.
| Age (years) | Anakinra (mg/kg/day) | WBC (103/μl) | Platelets (103/μl) | ESR (mm/h) |
|---|---|---|---|---|
| 1.6 | – | 14 | 17 | |
| 2.9 | – | 18 | 585 | 35 |
| 3.4 | – | 13 | 521 | |
| 4 | – | 8 | 464 | 25 |
| 8.5 | – | 12 | 462 | 73 |
| 9 | – | 10 | 377 | 48 |
| 9.3 | 0.9 | 7 | 363 | 8 |
| 9.8 | 0.3 | 7 | 360 | 31 |
| 10.1 | 1 | 8 | 335 | 22 |
| 10.6 | 1 | 7 | 302 | 9 |
ESR, erythrocyte sedimentation rate; WBC white blood cells.
He did not have proteinuria. Mutational analysis identified a heterozygotic change of A→G in the CIAS gene, which can result in a substitution from threonine to alanine at amino acid position 436 (T436A) in the cryopyrin protein. As expected, confirmatory parental genetic testing identified an identical nucleotide missense substitution in the mother, but not in the father.
Improved clinical symptoms after inhibition of interleukin 1 (IL 1) activity by anakinra was reported in all of the cryopyrin‐associated autoinflammatory syndromes, although treatment failure has also been reported.1,2,3,4 Therapy with IL 1 antagonism was begun in our patient at 9 years and a clinical response was reported within days. On taking Anakinra (∼0.90 mg/kg/day) his energy level improved, his rash appeared less frequently and his arthritis and conjunctivitis were resolved. His erythrocyte sedimentation rate, white cell count and platelet count all improved (table 1). The patient's family temporarily reduced the dose of anankinra to 0.30 mg/kg/day, and he again experienced clinical and laboratory evidence of disease flare, indicating a dose‐dependent response (table 1).
In all, 60 different dominantly inherited missense mutations within exon three of CIAS1 have been associated with the three heterogeneous cryopyrin‐associated autoinflammatory syndromes.5,6 Previous patients described with characteristics of both familial cold‐induced autoinflammatory syndrome and Muckle–Wells syndrome have had other unique cryopyrin mutations that were distinct from the new mutation described here.1,7 It is interesting to note that two other mutations that would cause different amino acid substitutions at this site (Thr436iie; Thr436Asn) were reported in patients with chronic infantile neurological cutaneous articular syndrome. 8 These findings would suggest that specific amino acid substitutions at this site are solely responsible for the clinical phenotype. However, phenotypic heterogeneity, including incomplete penetrance among family members, has been described among individuals carrying identical mutations.7,9,10 Thus there is probably an effect of additional modifier genes or environmental factors in the phenotypic expression of the cryopyrin‐associated autoinflammatory syndromes.8
Acknowledgements
Helpful input and comments from Dr John Carey are appreciated.
Footnotes
Competing interests: None.
References
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