cryopyrin - associated periodic syndrome ( caps ) or cryopyrinopathy constitutes three different entities that often overlap : familial cold auto - inflammatory syndrome ( fcas ) , muckle  wells syndrome ( mws ; mim no 191900 ) , and neonatal onset multi - system inflammatory disease ( nomid ) . cutaneous , neurological , ophthalmologic and rheumatologic manifestations may help in the differentiation of the cryopyrinopathies . mws is characterized by recurrent fever and urticarial rash , progressive sensorineural deafness and the development of secondary amyloidosis . approximately 100 different mutations , mostly missense mutations in exon 3 of this gene have been identified . these are autosomal dominant disorders with varying penetrance , which may also present de novo . the proband was a 27-year - old indian male , born of a non - consanguineous marriage , with normal developmental milestones . he was admitted with recurrent attacks of high grade intermittent fever , associated with occipital headache , conjunctival congestion and rash for 17 years . the rash was migratory , non - pruritic , maculopapular , mainly over the chest , abdomen , and extensor aspect of limbs with exacerbation on exposure to cold . he had 3 - 4 episodes per month , each lasting for 2 - 3 days . he had recurrent episodes of asymmetric non - deforming polyarthritis involving the axial and appendicular joints for 17 years . clinically he had short stature [ figure 1 ] , short neck , conjunctival congestion , diffuse urticarial rash , clubbing [ figure 1 ] and bilateral papilledema . clinical photographs of patients showing short stature and clubbing his hemoglobin was 12.8 g / dl , total wbc count 43900/l ( n 88% , l 06% , e 1% , m 05% ) , platelet count 4.4  10/l and esr 9 mm in 1 hour . pure tone audiometry showed bilateral severe sensorineural hearing loss with an average frequency loss of 65 db in the right ear and 55 db in the left ear . cerebrospinal fluid analysis showed 11 wbcs ( all lymphocytes ) , protein of 98 mg / dl and sugar 54 mg / dl . histopathological examination of urticarial lesions of skin showed normal epidermis , dermal inflammation with perivascular neutrophilic infiltration [ figure 2 ] . 10 micrograph of skin biopsy showing peri - skin appendageal inflammation with hematoxylin and eosin staining the proband 's elder brother , who was 40 years old , had recurrent high grade fever , rashes and polyarthritis from the age of 5 years and progressive hearing loss from the age of 15 years . he had short stature , short neck , urticarial rash , conjunctival congestion , clubbing , bilateral papilledema and bilateral sensorineural hearing loss . exon 3 of nlrp3 was amplified in three fragments with the following primers : forward : 5-gttaccactcgcttccgatg-3and reverse : 5-cctcgttctcctgaatcagac-3 ; forward : 5-catgtggagatcctgggttt-3 ; reverse : ggccaaagaggaaacgtaca-3 ; forward : 5-actacctgctggaagaggaa-3 and reverse : 5-gctgtggcaacagtatttgga-3. negative and positive controls were included in each run . pcr was validated with gel electrophoresis , and pcr products were purified with a qiaquick pcr purification kit ( qiagen , venlo , the netherlands ) according to the manufacturer 's protocol . sequencing reaction was performed with big dye terminator v. 3.1 ready reaction cycle sequencing kit ( applied biosystems , warrington , uk ) . the electrophoretic profiles of nlrp3 sequences were analyzed on the abi 3130xl genetic analyzer by using sequencing analysis software version 5.4 . the analysis revealed the presence of a c.907 g > a ( heterozygous state ) mutation in exon 3 on chromosome 1 [ figure 3 ] . genetic tests were not done for the other members of the family . on the basis of clinical features and molecular analysis , partial dna sequence of the nlrp3 gene showing ( a ) substitution c.907 g > a resulting in d303n variant ; ( b ) corresponding sequence of a negative control sample financial constraints and non - availability of medications in india prevented the initiation of these patients on anti - il-1 therapy . the family has been counseled that this is a genetic condition with autosomal dominant inheritance . additional family members can be tested for the mutation in a cost  effective way by targeted mutation analysis . prenatal diagnosis was possible in at - risk pregnancies by fetal mutation analysis to enable informed reproductive decisions . the proband was a 27-year - old indian male , born of a non - consanguineous marriage , with normal developmental milestones . he was admitted with recurrent attacks of high grade intermittent fever , associated with occipital headache , conjunctival congestion and rash for 17 years . the rash was migratory , non - pruritic , maculopapular , mainly over the chest , abdomen , and extensor aspect of limbs with exacerbation on exposure to cold . he had 3 - 4 episodes per month , each lasting for 2 - 3 days . he had recurrent episodes of asymmetric non - deforming polyarthritis involving the axial and appendicular joints for 17 years . clinically he had short stature [ figure 1 ] , short neck , conjunctival congestion , diffuse urticarial rash , clubbing [ figure 1 ] and bilateral papilledema . clinical photographs of patients showing short stature and clubbing his hemoglobin was 12.8 g / dl , total wbc count 43900/l ( n 88% , l 06% , e 1% , m 05% ) , platelet count 4.4  10/l and esr 9 mm in 1 hour . pure tone audiometry showed bilateral severe sensorineural hearing loss with an average frequency loss of 65 db in the right ear and 55 db in the left ear . cerebrospinal fluid analysis showed 11 wbcs ( all lymphocytes ) , protein of 98 mg / dl and sugar 54 mg / dl . histopathological examination of urticarial lesions of skin showed normal epidermis , dermal inflammation with perivascular neutrophilic infiltration [ figure 2 ] . 10 micrograph of skin biopsy showing peri - skin appendageal inflammation with hematoxylin and eosin staining the proband 's elder brother , who was 40 years old , had recurrent high grade fever , rashes and polyarthritis from the age of 5 years and progressive hearing loss from the age of 15 years . he had short stature , short neck , urticarial rash , conjunctival congestion , clubbing , bilateral papilledema and bilateral sensorineural hearing loss . exon 3 of nlrp3 was amplified in three fragments with the following primers : forward : 5-gttaccactcgcttccgatg-3and reverse : 5-cctcgttctcctgaatcagac-3 ; forward : 5-catgtggagatcctgggttt-3 ; reverse : ggccaaagaggaaacgtaca-3 ; forward : 5-actacctgctggaagaggaa-3 and reverse : 5-gctgtggcaacagtatttgga-3. negative and positive controls were included in each run . pcr was validated with gel electrophoresis , and pcr products were purified with a qiaquick pcr purification kit ( qiagen , venlo , the netherlands ) according to the manufacturer 's protocol . sequencing reaction was performed with big dye terminator v. 3.1 ready reaction cycle sequencing kit ( applied biosystems , warrington , uk ) . the electrophoretic profiles of nlrp3 sequences were analyzed on the abi 3130xl genetic analyzer by using sequencing analysis software version 5.4 . the analysis revealed the presence of a c.907 g > a ( heterozygous state ) mutation in exon 3 on chromosome 1 [ figure 3 ] . genetic tests were not done for the other members of the family . on the basis of clinical features and molecular analysis , partial dna sequence of the nlrp3 gene showing ( a ) substitution c.907 g > a resulting in d303n variant ; ( b ) corresponding sequence of a negative control sample financial constraints and non - availability of medications in india prevented the initiation of these patients on anti - il-1 therapy . the family has been counseled that this is a genetic condition with autosomal dominant inheritance . additional family members can be tested for the mutation in a cost  effective way by targeted mutation analysis . prenatal diagnosis was possible in at - risk pregnancies by fetal mutation analysis to enable informed reproductive decisions . the clinical manifestations of caps are a continuum of disease severity with overlapping phenotypic features , but can be separated on the basis of their organ manifestations and the disease triggers . fcas is the mildest form , and nomid is the most severe form of caps , the latter has the worse prognosis . mws is the intermediate form , characterized by recurrent and self - limiting episodes of fever , urticaria , arthralgia , myalgia and conjunctivitis since childhood . cutaneous eruption is the first symptom to be noticed and is characterized by migratory non - pruritic maculopapular rashes . skin biopsy shows perivascular dermal inflammatory infiltrate mainly consisting of polymorphonuclear cells in contrast to the typical infiltrate of eosinophils and lymphocytes seen in classical urticaria . the term  pseudo - urticaria  is used by some authors , to describe the eruption of mws . in our family , the two patients also exhibited overlapping features with fcas as shown by exacerbation of symptoms upon exposure to cold and nomid like papilledema , chronic aseptic meningitis , and headache . the proband 's father had died of chronic kidney disease . though he had no aforementioned features of mws the three diseases are related to mutations in the nlrp3 gene located in the chromosome1q44 . various mutations , mostly missense , in exon 3 of this gene have been identified . genetic analysis of our family showed c.907 g > a , ( p.asp303asn ) mutation in the nlrp3 gene . c.907 g > a mutation was previously described in patients from various ethnicities . to the best of our knowledge , the correlation of nlrp3 genotype and phenotype is broad in terms of disease characteristics , penetrance and severity . reported the first autosomal dominant periodic fever in patients from the indian subcontinent ; later aganna et al . identified the r260w mutation in them . p.f309s mutation causing nomid in a 7-year - old girl was reported by khemani et al . from india . cryopyrinopathies have been reported in the european population but few such cases have been reported from the indian subcontinent . we report this rare syndrome in two members of a family to highlight awareness of this condition while investigating those with recurrent fever from childhood especially in those with a positive family history . the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s ) has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal . the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed . the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s ) has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal . the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed .
muckle  wells syndrome ( mws ) is a rare autosomal dominant disease that belongs to a group of hereditary periodic fever syndromes . 
 it is part of the wider spectrum of the cryopyrin - associated periodic syndrome ( caps ) which has only rarely been described in non - caucasian individuals . 
 it is characterized by recurrent self - limiting episodes of fever , urticaria , arthralgia , myalgia and conjunctivitis from childhood . 
 progressive sensorineural hearing loss and amyloidosis are two late complications . 
 mws is caused by gain of function mutations in the nlrp3 gene , which encodes cryopyrin , a protein involved in regulating the production of proinflammatory cytokines . 
 we report two patients with mws in an indian family associated with the p.d303n mutation in the nlrp3 gene . 
 these findings promote awareness of these hereditary periodic fever syndromes as a cause for recurrent fevers from childhood in the indian population .