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Rheumatology Advance Access published online on December 18, 2006
Rheumatology, doi:10.1093/rheumatology/kel399
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A cryopyrin-associated periodic syndrome with joint destruction

T. Lequerré1,2, O. Vittecoq1,2, P. Saugier-Veber3, A. Goldenberg3, P. Patoz1, T. Frébourg3 and X. Le Loët1,2

1Rheumatology Department, Rouen University Hospital, 2Inserm U519, IFR 23, Faculté de Médecine-Pharmacie and 3Department of Medical Genetics, Inserm U614, IFR 23, Rouen University Hospital, Rouen, France.

Correspondence to: Dr T. Lequerré, Department of Rheumatology, Rouen University Hospital, 76031 Rouen, Cedex, France. E-mail: thierry.lequerre{at}univ-rouen.fr


   Abstract
Top
 Abstract
Introduction
 Patients
 Methods
 Results
 Discussion
 Acknowledgement
 References
 
Objective. Describe four generations (11 members) of a family with a cryopyrin-associated periodic syndrome (CAPS), including joint destruction, associated with a CIAS1-gene mutation and good responses to anakinra.

Methods. In addition to detailed questioning and physical examination, six family members underwent haematological, immunological and biochemical testing. Exon 3 of the CIAS1 gene was sequenced in search of a mutation in the 1q44 region.

Results. During childhood or adolescence, four family members developed different combinations of the following CAPS manifestations: deafness (3/4); arthritis (4/4) with joint destruction for two of them; nervous (cerebral demyelinization, 2/4), cutaneous (livedo and/or urticaria, 3/4) and eye lesions (episcleritis and/or papilloedema, 4/4); IgA hypergammaglobulinaemia (4/4) and inflammatory syndrome (3/4). Sequencing of six family members’ CIAS1-gene exon 3 identified a heterozygous mutation, c.1043C > T. Pertinently, this CAPS is distinct from chronic infantile neurological cutaneous and arthritis syndrome/neonatal onset multisystemic inflammatory disease syndrome and Muckle–Wells syndrome (MWS), which also result from exon 3 mutations in this gene. Moreover, this family did not have the usual neurological manifestations, typical morphological features and frequent amyloidosis of MWS.

Conclusions. We describe a previously unreported form of CAPS with atypical neurological signs, joint destruction and livedo. This observation extends the clinical spectrum associated with CIAS1 mutations. Anakinra, an interleukin-1-receptor antagonist, prescribed to two family members, was highly effective.

KEY WORDS: CAPS syndrome, Muckle–Wells syndrome, CINCA/NOMID, Autoinflammatory disease, CIAS1, Cryopyrin


   Introduction
Top
 Abstract
 Introduction
Patients
 Methods
 Results
 Discussion
 Acknowledgement
 References
 
Although mutations in a single gene can generate different clinical phenotypes, recent advances in molecular genetics revealed that several clinically distinct syndromes, with some overlapping traits, were associated with mutations in the same gene, thereby assimilating them into the same clinical spectrum [1, 2]. The latter necessitated revisiting the nosological classification of conditions originally described as distinct genetic entities based on clinical criteria.

Cryopyrin-associated periodic syndromes (CAPS) are autosomal-dominant autoinflammatory disorders, including chronic infantile neurological cutaneous articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), Muckle–Wells syndrome (MWS) and familial cold autoinflammatory syndrome (FCAS). They are examples of single-locus allelism, with documented CIAS1-gene mutations [3–7]. CINCA syndrome (MIM 607115 [OMIM] ) is a severe chronic inflammatory disease, characterized by the neonatal onset of cutaneous symptoms, chronic meningitis and joint manifestations, with recurrent fever and inflammation, while MWS (MIM 191900 [OMIM] ) is characterized by the classical triad of deafness, rashes, swollen and painful joints, and FCAS (MIM 120100 [OMIM] ) manifests as skin lesions after exposure to cold [3–9].

We report a previously undescribed CAPS variant with autosomal-dominant inheritance in a French family that is characterized by deafness, arthritis with joint destruction and nervous (cerebral demyelinization), cutaneous (urticaria and/or livedo) and eye lesions (papilloedema, episcleritis, etc). The identification of a familial mutation in the CIAS1 gene, c.1043C > T, demonstrated the allelism of this autoinflammatory syndrome with CINCA/NOMID and MWS. However, its phenotype is distinct from those of CINCA/NOMID and MWS, thereby extending the clinical spectrum associated with CIAS1 mutations. More importantly, the discovery of this mutation and the suspected underlying pathophysiological defect led us to attempt treatment of two family members with anakinra, an interleukin-1-receptor antagonist (IL-1Ra), which proved highly effective against symptoms.


   Patients
Top
 Abstract
 Introduction
 Patients
Methods
 Results
 Discussion
 Acknowledgement
 References
 
This family includes 11 members over four generations (Fig. 1A), seven of whom are still alive. Among the latter, the proband (IV-3) and two (IV-2, IV-4) of her three siblings, and their mother (III-2) are affected.


Figure 1
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  		FIG. 1. Pedigree of this family's CAPS and direct sequencing of exon 3 in the CIAS1 gene showing the c.1043C > T mutation generating p.Thr348Met. (A) The proband, IV-3, is indicated by the arrow. Squares, males; circles, females; WT, wild type; MT, mutant type. (B) CIAS1-gene exon 3 sequences for the proband (bottom) and a control (top) are shown.

 
The proband's (IV-3; Fig. 1) manifestations began in 1979, when she was 14 yrs old, with relapsing winter flares of progressively destructive polyarthritis. They were accompanied by recurrent episodes of painless red eyes due to episcleritis, documented papilloedema and the onset of progressive bilateral deafness, which subsequently required hearing aids. She finally consulted our Rheumatology Department in 1991. X-rays detected knee and metacarpo phalangeal (MCP) joint destruction (Fig. 2A and B). Inflammatory synovial fluid drained from her left knee contained 102 000 cells/mm3 (88% neutrophils) and 48 g/l of protein without crystals or bacteria. Synovium biopsy showed hyperplastic villosities intercalated with fibrin and lymphocyte–plasmocyte infiltrates. Immunofluorescence-labelling studies (IgA, IgM, IgG, C3, C4, C1q and fibrinogen) detected IgA, IgM and fibrinogen deposits around the lymphoid nodules. Cutaneous manifestations (urticaria-like rash without pruritus) on all four limbs and trunk; inflammatory subcutaneous panniculitis; livedo on all limbs accompanied joint flares (Fig. 2C). Biopsies of affected skin showed normal epidermis, with perivascular lymphocyte–plasmocyte infiltrations in the dermis and inflammatory subcutaneous panniculitis with negative immunohistochemistry. The main biological findings were: elevated erythrocyte sedimentation rates (ESR) during flares that declined between them; thrombocytosis; anaemia; serum hyper-IgA and hyper-IgM.


Figure 2
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  		FIG. 2. X-rays documenting joint destruction and cutaneous lesions seen in this family's CAPS. (A) Joint-space narrowing of right 3rd and 4th MTP in IV-3. (B) Joint-space narrowing, osteosclerosis surrounding erosions and osteophytes in the knees of IV-3. (C) The arrows point to patient IV-3's leg livedo and inflammatory panniculitis. (D) Joint destruction with joint-space narrowing of the radiocarpal joint and carpitis in the right wrist of IV-4. (E) The arrows indicate maculopapular-like urticaria on patient III-2's arm.

 
During childhood, her sister (IV-4) suffered from polyarthritis, diagnosed as rheumatic fever in 1978 and developed oligoarthritis at 11. After 2 yrs, polyarthritis recurred. X-rays showed wrist, MCP, ankle and carpal joint destruction (Fig. 2D). Since childhood, she has also had episodes of urticaria without pruritus. Progressive deafness became manifest in 1985, and eventually required hearing aids. During adolescence, she suffered many episcleritis attacks of painless red eyes with papilloedema. In 1987, retrobulbar optic neuritis (RBON) caused loss of visual acuity; it regressed with corticosteroids. During RBON, laboratory analyses found: elevated ESR; leucocytosis, serum hyper-IgA and hyper-IgM.

During childhood, their brother (IV-2) developed bilateral knee arthritis that disappeared spontaneously after adolescence. Arthritis was associated with bilateral deafness requiring hearing aids when he was 15 yrs old (1980); papilloedema when he was 14; inflammatory syndrome; leucocytosis and serum hyper-IgA.

Their older brother (IV-1) never had any symptoms or signs.

Their mother (III-2), born in 1946, experienced functional disabilities during childhood [ankles, metatarsal phalanges (MTP)], which disappeared after her first pregnancy. She reported many episodes of painless red eyes. Physical examination found livedo and urticaria (Fig. 2E); their biopsies showed normal epidermis and perivascular lymphocyte accumulation in the dermis. When she was 42 yrs old, she developed left diplopia and right hemiparesia. While brain computed tomography (CT) scan and Doppler ultrasonography of cervical vessels were normal, magnetic resonance imaging (MRI) T2-weighted sequences showed hypersignals in the periventricular, right temporal, left occipital and centrum semiovale areas compatible with demyelinization. During the same year, her right hemiparesia progressed, with RBON responsible for right diplopia. Cerebral CT scan, auditory (AEP) and somatosensory evoked potentials (SEP) were normal, but visual evoked potential (VEP) revealed an anterior optic nerve lesion. After 2 yrs, right arm hemiparesia recurred with left leg paresthesia, left cerebellar syndrome, nystagmus to the left and bilateral astereognosis. Cerebrospinal fluid was still normal but VEP and motor (M) EP were consistent with RBON and the right pyramidal syndrome, respectively. These neurological signs were associated with episcleritis and a cutaneous rash. All these signs regressed on oral prednisone (20 mg/day). She had a white blood-cell count (WBC) of 12 000/mm3 and hyper IgA.

Interrogation of living family members revealed the onset of clinical manifestations during the childhood/adolescence of generations I and II: joint manifestations disappeared after great-grandmother I-2's first pregnancy without functional disability; grandmother (II-2) had intermittent arthritis associated with livedo and deafness, and maternal uncle (III-1) was deaf.


   Methods
Top
 Abstract
 Introduction
 Patients
 Methods
Results
 Discussion
 Acknowledgement
 References
 
This family included 11 members over four generations (Fig. 1). III-2, III-3, IV-1, IV-2, IV-3 and IV-4, followed in our department since 1989, underwent complete physical examinations. Investigations (joint X-rays, synovium and skin biopsies with immunofluorescence labelling, funduscopy, visual field, audiometry, lumbar puncture with cerebrospinal fluid analysis, skull radiography, cerebral CT scan and MRI, electroencephalogram, and VEP, AEP, SEP and/or MEP) were performed according to their clinical manifestations. Detailed history-taking (I-1, I-2, II-1, II-2 and III-1) was supplemented by analysis of hospital records starting from 1970.

Every examined patient had complete analyses of inflammation markers, humoral, cellular and non-specific immunity, metabolic and enzyme studies, HLA class I and II typing and karyotyping [9].

Treatment with Il-1Ra
After methotrexate failure, the joint symptoms and suspected pathophysiological mechanism underlying this CAPS led us to prescribe subcutaneous IL-1Ra (100 mg/day; anakinra, Amgen, Thousand Oaks, CA, USA) to IV-3 and IV-4, since March 2004 and September 2004, respectively. Clinical, biochemical and haematological parameters have since been monitored every 3 months.

Genetic investigations
Blood samples were drawn after written informed consent was obtained from patients III-2, III-3, IV-1, IV-2, IV-3 and IV-4. Genomic DNA was extracted from peripheral blood lymphocytes (QIAamp DNA Blood Mini Kit, Qiagen, Courtaboeuf, France). The 1753-bp–long CIAS1-gene exon 3 was amplified by polymerase chain reaction (PCR) using six primer pairs (Supplementary Table 1). After electrophoresis in a 2.5% Seakem LE Agarose gel (FMC, Rockland, ME, USA), PCR products were purified using the Qiaquick Gel Extraction Kit (Qiagen). Sequencing reactions used the Big-dye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Courtaboeuf, France) and sequences were analysed on an ABI 3100 automated DNA sequencer (Applied Biosystems).


   Results
Top
 Abstract
 Introduction
 Patients
 Methods
 Results
Discussion
 Acknowledgement
 References
 
At least four patients from two generations of a French family developed, during childhood or adolescence, the following symptoms: deafness (3/4), arthritis (4/4) with joint destruction in two, with nervous (cerebral demyelinization; 2/4), cutaneous (livedo and/or urticaria; 3/4) and eye lesions (episcleritis and/or papilloedema; 4/4), IgA hypergammaglobulinaemia (4/4), inflammatory syndrome (3/4) with winter flares (Table 1). Notably, the proband, IV-3 and III-2 reported that cutaneous signs (livedo, urticaria), arthralgias or arthritis were exacerbated, but not triggered, by exposure to cold. However, concerning the elevated levels of biological markers of inflammation during flares, we cannot confirm a posteriori that the weather was cold when markers were evaluated. Because all the mutations identified in MWS, CINCA/NOMID and FCAS are missense mutations located in CIAS1-gene exon 3, the proband's exon 3 was directly sequenced. A heterozygous c.1043C > T mutation, thought to generate a p.Thr348Met missense mutation in the NACHT [NAIP (neuronal apoptosis inhibitory protein), CIITA (MHC class II transcription activator), HET-E (incompatibility locus protein from podospora anserina) and TP1 (telomerase-associated protein)] domain of the protein, was identified and subsequently found in affected relatives IV-3, IV-4 and III-2, but not in healthy relatives III-3 and IV-1, thereby demonstrating the cosegregation of the c.1043C > T mutation with the phenotype (Fig. 1B).


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  		TABLE 1. CAPS manifestations with concomitant onset during childhood/adolescence, subsequent winter flares and biological responses to treatment

 
Patients IV-3 and IV-4 have received IL-1Ra since March and September 2004, respectively. Rapid regression of most of their clinical manifestations, except episcleritis, was obtained, and has persisted for at least 2 yrs. Hearing did not improve. Treatment is well tolerated. Laboratory findings are summarized in Table 1.


   Discussion
Top
 Abstract
 Introduction
 Patients
 Methods
 Results
 Discussion
Acknowledgement
 References
 
Among these 11 members of one family, six underwent complete examinations and four had developed this new autosomal-dominant CAPS. All their manifestations, particularly deafness, arthritis and urticaria evocative of the MWS or CINCA syndrome spectrum, began during childhood/adolescence with subsequent winter flares in the context of a biological inflammatory syndrome without antibodies.

Identification of the c.1043C > T mutation in CIAS1-gene exon 3 that cosegregated with the disease in the family demonstrated the allelism of this syndrome with CINCA/NOMID and MWS. This mutation, previously described in at least three families with CINCA syndrome, 10 with MWS and 6 with FCUS, can thus be responsible for their overlapping clinical manifestations [10–12]. The latter further highlight the phenotypic heterogeneity of CIAS1-gene–associated syndromes.

Pertinently, this family's syndrome is clinically distinguishable from MWS and CINCA syndrome. MWS is usually characterized by urticaria, deafness, arthralgia, joint effusion or arthritis and frequently amyloid deposits, but not joint destruction and livedo [8]. Our family's destructive arthritis, characterized by bone and cartilage lesions resembling rheumatoid arthritis, caused functional disabilities, and was associated with concomitant livedo and/or urticarial flares in winter.

Although one family member (two, if we consider patient IV-4's RBON) developed multiple-sclerosis–like neurological signs, concomitant with urticaria, arthritis and episcleritis, none had a low IQ, chronic meningitis or other abnormalities (macrosomia, frontal bossing, etc.) typical of CINCA syndrome [13, 14]. The neurological symptoms of III-2 and IV-4 were not compatible with classical multiple sclerosis because their cerebrospinal fluid analyses were normal, and simultaneous neurological attack, episcleritis and urticaria were unusual, leading us to consider the neurological manifestations as an intrinsic part of this syndrome. Central nervous system involvement, such as multiple-sclerosis-like neurological signs, has been reported in other autoinflammatory syndromes, e.g. familial Mediterranean fever (FMF) and tumour necrosis factor-associated periodic syndrome, but not with a CIAS1-gene mutation, hence the originality of this new phenotype [15, 16]. Moreover, in CINCA syndrome, joint X-rays are normal or show periosteal reactions, soft-tissue swelling, epiphyseal overgrowth with premature ossification and only joint destruction with joint-space narrowing. In addition, this syndrome differs from CINCA syndrome by its onset during childhood/adolescence, cerebral demyelinization and destructive arthritis, and the absence of malformations, low IQ and amyloidosis.

Despite the shared cutaneous signs and deafness, we consider it a new CAPS phenotype. Indeed, this phenotype, with joint destruction and neurological manifestations, seems to be intermediate between the most severe MWS and CINCA syndrome, and FCUS at the lower end of a severity scale, and thus broadens the phenotypic spectrum associated with CIAS1 mutations. The clinical spectrum of CIAS1-gene mutations is very large. Pertinently, another mutation (p.Arg554X) of the CIAS1 gene was associated with an original phenotype of FMF with flares triggered by cold [17]. The triggering or exacerbation of these symptoms by cold might be inherent to all syndromes associated with CIAS1-gene mutation and not only FCAS, and thus might be an indication to look for a CIAS1-gene mutation.

The CIAS1 gene, located at chromosome 1q44, encodes the protein cryopyrin, expressed in polymorphonuclear leucocytes and chondrocytes, that binds with an intrinsic inhibitor, thereby controlling the activation of caspase-1 and nuclear factor-{kappa}B (NF-{kappa}B) pathways [7, 13, 18]. Intra- and interfamilial phenotypic variations might be explained by hypothesizing that gene modifiers could act on the NF-{kappa}B pathway, and thereby modulate the phenotype. Feldmann et al. [13] postulated that CIAS1 mutations might perturb the physiological balance between the proinflammatory and proapoptotic NF-{kappa}B functions by favouring the former.

Because of enhanced IL-1ß production in CINCA syndrome and MWS, IL-1Ra was prescribed [19–22] and proved to be highly effective, as for our patients IV-3 and IV-4. Their clinical manifestations regressed or were controlled, except for episcleritis (IV-3); deafness and joint destruction persisted due to irreversible damage. Moreover, joint flares disappeared under IL-1Ra. Biological parameters improved and inflammatory markers returned to normal.

This observation again emphasizes the heterogeneity of diseases associated with CIAS1-gene mutation. This family's CAPS broadens the phenotypic spectrum of CIAS1-gene mutations and differs by the joint destruction, livedo and nervous lesion(s) observed in some patients. The suspected mechanisms responsible, prompted us to prescribe anakinra, which attenuated clinical manifestations and corroborated its efficacy against diseases associated with CIAS1-gene mutations.

Formula


   Acknowledgement
Top
 Abstract
 Introduction
 Patients
 Methods
 Results
 Discussion
 Acknowledgement
References
 
The authors thank Janet Jacobson for her valuable advice in editing the manuscript.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients
 Methods
 Results
 Discussion
 Acknowledgement
 References
 

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Submitted 1 June 2006; revised version accepted 27 October 2006.
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