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.