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Clinical characteristics in subjects with NLRP3 V198M diagnosed at a single UK center and a review of the literature.

Rowczenio DM, Trojer H, Russell T, Baginska A, Lane T, Stewart NM, Gillmore JD, Hawkins PN, Woo P, Mikoluc B, Lachmann HJ - Arthritis Res. Ther. (2013)

Bottom Line: The NLRP3 V198M variant shows variable expressivity and reduced penetrance.The factors that influence the pathogenic consequences of this variant remain unknown.However, the remarkable response to interleukin 1 (IL-1) blockade in all but one individual in our series confirms that their clinical features are indeed mediated by IL-1.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Mutations in the NLRP3 gene are associated with the dominantly inherited cryopyrin-associated periodic syndrome (CAPS). The significance of the V198M variant is unclear; it has been reported in association with various CAPS phenotypes and as a variant of uncertain consequence. The aim of this study was to characterize the clinical phenotypes and treatments in individuals with V198M assessed in a single UK center.

Methods: DNA samples from 830 subjects with fever syndromes or a family history of CAPS were screened for mutations in the NLRP3 gene with polymerase chain reaction (PCR) and sequencing. A detailed medical history was available in all cases. Inflammatory disease activity was monitored monthly with measurements of serum amyloid A protein (SAA) and C-reactive protein (CRP) in symptomatic individuals.

Results: NLRP3 V198M was identified in 19 subjects. It was found in association with CAPS in five cases, in one patient with Schnitzler syndrome, in three patients who also had a nucleotide alteration in another fever gene, and in three other patients with evidence of an autoinflammatory phenotype. Seven asymptomatic individuals were detected during screening of family members.

Conclusions: The NLRP3 V198M variant shows variable expressivity and reduced penetrance. It may be associated with classical inherited or apparently sporadic CAPS and with atypical autoinflammatory disease of varying severity, intriguingly including Schnitzler syndrome. The factors that influence the pathogenic consequences of this variant remain unknown. However, the remarkable response to interleukin 1 (IL-1) blockade in all but one individual in our series confirms that their clinical features are indeed mediated by IL-1.

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Pedigrees of four families with NLRP3 V198M. Family 1 with three members affected by MWS/FCAS/CINCA, family 2 with a proband diagnosed with familial cold autoinflammatory syndrome (FCAS), family 3 with a proband affected by Schnitzler syndrome and family 4 with a proband affected by uncharacterized long-standing systemic inflammatory disorder. Open shapes represent healthy individuals, solid shapes represent affected individuals, and shaded shapes represent asymptomatic carriers; each proband is indicated by an arrow.
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Figure 1: Pedigrees of four families with NLRP3 V198M. Family 1 with three members affected by MWS/FCAS/CINCA, family 2 with a proband diagnosed with familial cold autoinflammatory syndrome (FCAS), family 3 with a proband affected by Schnitzler syndrome and family 4 with a proband affected by uncharacterized long-standing systemic inflammatory disorder. Open shapes represent healthy individuals, solid shapes represent affected individuals, and shaded shapes represent asymptomatic carriers; each proband is indicated by an arrow.

Mentions: The V198M variant was identified in a Caucasian family with Muckle-Wells syndrome but with features overlapping both with FCAS and CINCA/NOMID (Family 1). The proband (subject 1) presented neonatally with a widespread urticarial rash affecting the entire body, particularly the trunk and distal limbs. The rash occurred on a daily basis and worsened with stress or after exposure to damp or cold. Other symptoms included swollen joints and severe ankle pain, generalized arthralgia, and hearing impairment, which was first noticed at age 5 years. Because of progressive hearing loss, hearing aids were required from the age of 27. Two of the proband's children (subjects 2 and 3) have the same syndrome, and both developed sensory neural deafness in late childhood. All three subjects displayed mildly dysmorphic features characteristic of CINCA/NOMID, including short stature, frontal bossing of the skull, and flattening of the nasal bridge. The one unaffected child does not carry the V198M variant (Figure 1).


Clinical characteristics in subjects with NLRP3 V198M diagnosed at a single UK center and a review of the literature.

Rowczenio DM, Trojer H, Russell T, Baginska A, Lane T, Stewart NM, Gillmore JD, Hawkins PN, Woo P, Mikoluc B, Lachmann HJ - Arthritis Res. Ther. (2013)

Pedigrees of four families with NLRP3 V198M. Family 1 with three members affected by MWS/FCAS/CINCA, family 2 with a proband diagnosed with familial cold autoinflammatory syndrome (FCAS), family 3 with a proband affected by Schnitzler syndrome and family 4 with a proband affected by uncharacterized long-standing systemic inflammatory disorder. Open shapes represent healthy individuals, solid shapes represent affected individuals, and shaded shapes represent asymptomatic carriers; each proband is indicated by an arrow.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672677&req=5

Figure 1: Pedigrees of four families with NLRP3 V198M. Family 1 with three members affected by MWS/FCAS/CINCA, family 2 with a proband diagnosed with familial cold autoinflammatory syndrome (FCAS), family 3 with a proband affected by Schnitzler syndrome and family 4 with a proband affected by uncharacterized long-standing systemic inflammatory disorder. Open shapes represent healthy individuals, solid shapes represent affected individuals, and shaded shapes represent asymptomatic carriers; each proband is indicated by an arrow.
Mentions: The V198M variant was identified in a Caucasian family with Muckle-Wells syndrome but with features overlapping both with FCAS and CINCA/NOMID (Family 1). The proband (subject 1) presented neonatally with a widespread urticarial rash affecting the entire body, particularly the trunk and distal limbs. The rash occurred on a daily basis and worsened with stress or after exposure to damp or cold. Other symptoms included swollen joints and severe ankle pain, generalized arthralgia, and hearing impairment, which was first noticed at age 5 years. Because of progressive hearing loss, hearing aids were required from the age of 27. Two of the proband's children (subjects 2 and 3) have the same syndrome, and both developed sensory neural deafness in late childhood. All three subjects displayed mildly dysmorphic features characteristic of CINCA/NOMID, including short stature, frontal bossing of the skull, and flattening of the nasal bridge. The one unaffected child does not carry the V198M variant (Figure 1).

Bottom Line: The NLRP3 V198M variant shows variable expressivity and reduced penetrance.The factors that influence the pathogenic consequences of this variant remain unknown.However, the remarkable response to interleukin 1 (IL-1) blockade in all but one individual in our series confirms that their clinical features are indeed mediated by IL-1.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Mutations in the NLRP3 gene are associated with the dominantly inherited cryopyrin-associated periodic syndrome (CAPS). The significance of the V198M variant is unclear; it has been reported in association with various CAPS phenotypes and as a variant of uncertain consequence. The aim of this study was to characterize the clinical phenotypes and treatments in individuals with V198M assessed in a single UK center.

Methods: DNA samples from 830 subjects with fever syndromes or a family history of CAPS were screened for mutations in the NLRP3 gene with polymerase chain reaction (PCR) and sequencing. A detailed medical history was available in all cases. Inflammatory disease activity was monitored monthly with measurements of serum amyloid A protein (SAA) and C-reactive protein (CRP) in symptomatic individuals.

Results: NLRP3 V198M was identified in 19 subjects. It was found in association with CAPS in five cases, in one patient with Schnitzler syndrome, in three patients who also had a nucleotide alteration in another fever gene, and in three other patients with evidence of an autoinflammatory phenotype. Seven asymptomatic individuals were detected during screening of family members.

Conclusions: The NLRP3 V198M variant shows variable expressivity and reduced penetrance. It may be associated with classical inherited or apparently sporadic CAPS and with atypical autoinflammatory disease of varying severity, intriguingly including Schnitzler syndrome. The factors that influence the pathogenic consequences of this variant remain unknown. However, the remarkable response to interleukin 1 (IL-1) blockade in all but one individual in our series confirms that their clinical features are indeed mediated by IL-1.

Show MeSH
Related in: MedlinePlus