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Brief Report
October 13, 2021

Homozygous MEFV Gene Variant and Pyrin-Associated Autoinflammation With Neutrophilic Dermatosis: A Family With a Novel Autosomal Recessive Mode of Inheritance

Author Affiliations
  • 1Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania
  • 2Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
  • 3Genetics, Genomics, and Cancer Biology PhD Program, Thomas Jefferson University, Philadelphia, Pennsylvania
  • 4Pediatric Rheumatology Research Group, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
  • 5Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran
  • 6Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran
  • 7Research Center for Immunodeficiencies, Tehran University of Medical Sciences, Tehran, Iran
  • 8Division of Allergy and Clinical Immunology, Department of Pediatrics, Children’s Medical Centre, Tehran, Iran
  • 9Department of Pediatric Surgery, Pediatric Center Excellence, Children's Hospital Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  • 10Rowan University School of Osteopathic Medicine, Stratford, New Jersey
  • 11Department of Pathology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran
  • 12Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
  • 13Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  • 14Kawsar Human Genetics Research Center, Tehran, Iran
  • 15Biotechnology Research Center, Department of Molecular Medicine, Pasteur Institute of Iran, Tehran, Iran
JAMA Dermatol. Published online October 13, 2021. doi:10.1001/jamadermatol.2021.3899
Key Points

Question  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.

Abstract

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.

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