Key PointsQuestion
Is pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) genetically heterogeneous and is colchicine an efficient treatment for PAAND associated with a MEFV gene variation?
Findings
This case series study reports an autosomal recessive form of PAAND with a biallelic homozygous p.Ser242Gly variation in the MEFV gene in a consanguineous family. The study provides evidence for the efficacy of colchicine when combined with low-dose prednisolone for the treatment of patients with PAAND.
Meaning
The findings of this case series study describe a novel genetic variant of PAAND and demonstrate successful genotype-guided treatment with colchicine when combined with low-dose prednisolone, a low-cost therapeutic option with minimal adverse effects.
Importance
Pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) is a monogenic autoinflammatory disorder with autosomal dominant inheritance and has been associated with monoallelic p.Ser242Arg and p.Glu244Lys variations in the MEFV gene. This dermatosis shares clinical features and pathogenesis with familial Mediterranean fever, although it is a clinically distinct entity.
Objective
To identify the genetic basis of PAAND in a consanguineous family with 2 affected children and to prescribe an effective genotype-guided treatment.
Design, Setting, and Participants
This case series study examined 2 siblings who presented with clinical features of PAAND. We sought the genetic basis of this disease with trio whole exome sequencing (trio-WES). Genome-wide homozygosity mapping provided additional evidence for causality of a sequence variant identified by trio-WES.
Main Outcomes and Measures
Association of a biallelic MEFV variation with a new form of autosomal recessive PAAND was documented by genetic analysis. Response to treatment with colchicine and a low-dose steroid was assessed clinically and experimentally.
Results
Two siblings, a girl (proband; age 5 years) and a boy (age 2.5 years) of Iranian-Azeri ancestry born to first-cousin consanguineous parents presented with clinical features of PAAND—recurrent episodes of maculopapular and pustular rash, gastrointestinal involvement resembling inflammatory bowel disease, and intussusception with generalized mesenteric lymphadenitis. A trio-WES test detected a previously unreported homozygous missense variation, p.Ser242Gly, in both patients’ MEFV gene. Genome-wide homozygosity mapping revealed shared regions of homozygosity in the patients’ DNA, including 1 on chromosome 16 harboring MEFV. Whole transcriptome sequencing by RNA-sequencing revealed that the variant MEFV transcript, among the inflammasome-associated transcripts, was most upregulated, and the cell-cell receptor interaction and innate immune system pathways were most positively enriched. Under the guidance of MEFV genotype, treatment with colchicine (1 mg/d) and low-dose prednisolone (2.5 mg every other day) was started, and the patients responded well.
Conclusions and Relevance
This case series study demonstrated successful genotype-guided treatment with colchicine and low-dose prednisolone, a low-cost therapeutic option with minimal adverse effects, in patients with a novel form of autosomal recessive PAAND.This case report examines the genetic basis of PAAND in a consanguineous family with 2 affected children and seeks to prescribe an effective genotype-guided treatment.