Progressive Pseudorheumatoid Dysplasia resolved by whole exome sequencing: a novel mutation in WISP3 and review of the literature

Ben Pode-Shakked,Dina Marek-Yagel,Shiri Shpilman,Friedhelm Hildebrandt,Alvit Veber,Shirlee Shril,Irit Tirosh,Aviva Eliyahu,Yair Anikster,Mordechai Shohat,Shai Padeh,Ortal Barel,Shachar Abudi,Asaf Vivante

doi:10.1186/s12881-019-0787-x

Abstract

BackgroundProgressive pseudorheumatoid dysplasia (PPRD) is a rare autosomal-recessive, non-inflammatory arthropathy, shown to be caused by mutations in the WNT1-inducible signaling pathway protein 3 (WISP3) gene. Although several hundred cases were reported worldwide, the diagnosis remains challenging. Subsequently, the syndrome is often unrecognized and misdiagnosed (for instance, as Juvenile Idiopathic Arthritis), leading to unnecessary procedures and treatments. The objective of the current study was to identify the molecular basis in a family with PPRD and describe their phenotype and course of illness.Patients and methodsWe present here a multiply affected consanguineous family of Iraqi-Jewish descent with PPRD. The proband, a 6.5 years old girl, presented with bilateral symmetric bony enlargements of the 1st interphalangeal joints of the hands, without signs of synovitis. Molecular analysis of the family was pursued using Whole Exome Sequencing (WES) and homozygosity mapping.ResultsWES analysis brought to the identification of a novel homozygous missense mutation (c.257G > T, p.C86F) in the WISP3 gene. Following this diagnosis, an additional 53 years old affected family member was found to harbor the mutation. Two other individuals in the family were reported to have had similar involvement however both had died of unrelated causes.ConclusionThe reported family underscores the importance of recognition of this unique skeletal dysplasia by clinicians, and especially by pediatric rheumatologists and orthopedic surgeons.

Highlights

Progressive pseudorheumatoid dysplasia (PPRD) is a rare autosomal-recessive, non-inflammatory arthropathy, shown to be caused by mutations in the WNT1-inducible signaling pathway protein 3 (WISP3) gene
Whole Exome Sequencing (WES) analysis brought to the identification of a novel homozygous missense mutation (c.257G > T, p.C86F) in the WISP3 gene
Two other individuals in the family were reported to have had similar involvement both had died of unrelated causes

Summary

Introduction

Progressive pseudorheumatoid dysplasia (PPRD) is a rare autosomal-recessive, non-inflammatory arthropathy, shown to be caused by mutations in the WNT1-inducible signaling pathway protein 3 (WISP3) gene. Several hundred cases have been reported in the literature with varied phenotypes, and an array of causative mutations identified throughout the WISP3 gene [2, 3, 6] (For an extensive list of all WISP3 variants reported in patients with PPRD to date, see Additional file 1: Table S1). The diagnosis remains elusive and is often only made years following the onset of symptoms. This can be attributed to several reasons, including the relatively limited joint involvement often characterizing the initial presentation, the nonspecific findings of joint swelling without signs of arthritis, and the fact that the specialist to which the patients present is more often a pediatrician, rheumatologist or orthopedic surgeon, and only rarely a medical geneticist

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