Dataset Information

Dual Diagnosis of Ellis-van Creveld Syndrome and Hearing Loss in a Consanguineous Family.

ABSTRACT: Multilocus analysis of rare or genetically heterogeneous diseases is a distinct advantage of next-generation sequencing (NGS) over conventional single-gene investigations. Recent studies have begun to uncover an under-recognized prevalence of dual molecular diagnoses in patients with a "blended" phenotype that is the result of 2 clinical diagnoses involving 2 separate genetic loci. This blended phenotype could be mistakenly interpreted as a novel clinical extension of a single-gene disorder. In this study, we ascertained a proband from a large consanguineous Iranian family who manifests postlingual, progressive, moderate hearing loss in addition to suspected Ellis-van Creveld syndrome phenotype. NGS with a customized skeletal dysplasia panel containing over 370 genes and subsequent bioinformatics analysis disclosed 2 homozygous mutations in EVC2 (c.2653C>T; p.Arg885*) and COL11A2 (c.966dup; p.Thr323Hisfs*19), respectively. This study highlights a dual molecular diagnosis in a patient with a blending of 2 distinct phenotypes and illustrates the advantage and importance of this staple technology to facilitate rapid and comprehensive genetic dissection of a heterogeneous phenotype. The differentiation between phenotypic expansion of a genetic disorder and a blended phenotype that is due to more than one distinct genetic aberration is essential in order to reduce the diagnostic odyssey endured by patients.

SUBMITTER: Vona B

PROVIDER: S-EPMC5803684 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Dual Diagnosis of Ellis-van Creveld Syndrome and Hearing Loss in a Consanguineous Family.

Vona Barbara B Maroofian Reza R Mendiratta Geetu G Croken Matthew M Peng Siwu S Ye Xiaoqian X Rezazadeh Jamileh J Bahena Paulina P Lekszas Caroline C Haaf Thomas T Edelmann Lisa L Shi Lisong L

Molecular syndromology 20170922 1

Multilocus analysis of rare or genetically heterogeneous diseases is a distinct advantage of next-generation sequencing (NGS) over conventional single-gene investigations. Recent studies have begun to uncover an under-recognized prevalence of dual molecular diagnoses in patients with a "blended" phenotype that is the result of 2 clinical diagnoses involving 2 separate genetic loci. This blended phenotype could be mistakenly interpreted as a novel clinical extension of a single-gene disorder. In ...[more]

PMID: 29456477

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Project description:Ellis-van Creveld is a dwarfing syndrome transmitted as an autosomal recessive trait. The constant features of the condition include acromelic-micromelic dwarfism, ectodermal dysplasia involving the nails, teeth and gums, postaxial polydactyly of the hands and congenital heart disease. Congenital heart disease affects 50-60 % of all patients and nearly 50 % of patients die by 18 months of age from cardiopulmonary complications. This study is intended to characterise the orthopaedic manifestations of Ellis-van Creveld based on the authors' unique opportunity to interview and examine the largest group of patients to date in the literature.Detailed interviews, physical examinations and/or radiographs were available on 71 cases of Ellis-van Creveld syndrome. Data were collected from physical examinations, radiographs, computed tomography (CT) reconstruction and magnetic resonance imaging (MRI) of the knee. Pathoanatomy of the knee was reinforced by the direct surgical observation of 25 limbs surgically managed during adolescence and puberty.A number of interesting clinical and radiographic abnormalities were noted in the upper extremities and lower extremities, but by far the most significant orthopaedic finding was a severe and relentlessly progressive valgus deformity of the knee. Although many patients had difficulties making a "fist" with the hand, no patient reported any functional disability. The severe valgus deformity of the knee is the result of a combination of profound contractures of the iliotibial band, lateral quadriceps, lateral hamstrings and lateral collateral ligament, leading to lateral patellar subluxation and dislocation. The lateral portion of the upper tibial plateau presents with cupping and progressive depression of the lateral plateau, along with severe valgus angulation of the proximal tibia and fibula. A proximal medial tibial exostosis is seen in nearly all cases.This is the largest group of Ellis-van Creveld syndrome patients identified in the literature. An understanding of the orthopaedic pathoanatomy of the knee deformity is critical to determining the appropriate surgical management. This paper characterises the orthopaedic manifestations of Ellis-van Creveld syndrome and especially identifies the pathoanatomy of the severe and progressive valgus knee deformity.Level II.

Dataset Information

Dual Diagnosis of Ellis-van Creveld Syndrome and Hearing Loss in a Consanguineous Family.

Publications

Dual Diagnosis of Ellis-van Creveld Syndrome and Hearing Loss in a Consanguineous Family.

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