Expanding the clinical spectrum of COL2A1 related disorders by a mass like phenotype

Till Joscha Demal,Fabian Speth,Helke Schüler,Christian Kubisch,Georg Rosenberger,Hermann Reichenspurner,Jakob Olfe,Thomas S Mir,Tasja Scholz,Yskert Von Kodolitsch,Anja Fröhlich,Maja Hempel

doi:10.1038/s41598-022-08476-7

Abstract

MASS phenotype is a connective tissue disorder clinically overlapping with Marfan syndrome and caused by pathogenic variants in FBN1. We report four patients from three families presenting with a MASS-like phenotype consisting of tall stature, arachnodactyly, spinal deformations, dural ectasia, pectus and/or feet deformations, osteoarthritis, and/or high arched palate. Gene panel sequencing was negative for FBN1 variants. However, it revealed likely pathogenic missense variants in three individuals [c.3936G > T p.(Lys1312Asn), c.193G > A p.(Asp65Asn)] and a missense variant of unknown significance in the fourth patient [c.4013G > A p.(Ser1338Asn)] in propeptide coding regions of COL2A1. Pathogenic COL2A1 variants are associated with type II collagenopathies comprising a remarkable clinical variablility. Main features include skeletal dysplasia, ocular anomalies, and auditory defects. A MASS-like phenotype has not been associated with COL2A1 variants before. Thus, the identification of likely pathogenic COL2A1 variants in our patients expands the phenotypic spectrum of type II collagenopathies and suggests that a MASS-like phenotype can be assigned to various hereditary disorders of connective tissue. We compare the phenotypes of our patients with related disorders of connective tissue and discuss possible pathomechanisms and genotype–phenotype correlations for the identified COL2A1 variants. Our data recommend COL2A1 sequencing in FBN1-negative patients suggestive for MASS/Marfan-like phenotype (without aortopathy).

Highlights

MASS phenotype is a connective tissue disorder clinically overlapping with Marfan syndrome and caused by pathogenic variants in FBN1
Subsequent standardized clinical examination, 200 patients were included to this study according to following criteria: clinical features were suggestive of Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), Ehlers-Danlos syndrome (EDS), congenital contractural arachnodactyly (CCA), MASS phenotype, syndromic/non-syndromic TAAD, or an unspecified heritable disorder of connective tissue with or without vascular involvement
We report four subjects with a clinical presentation partially overlapping with Marfan syndrome (MFS; MIM #154700) and to a minor extent with Loeys-Dietz syndrome 3 (LDS3; syn. aneurysmsosteoarthritis syndrome; MIM #613795)[23,24] (Table 2) and fulfilling the criteria of MASS-like phenotype diagnosis according to the revised Gent nosology

Summary

Introduction

MASS phenotype is a connective tissue disorder clinically overlapping with Marfan syndrome and caused by pathogenic variants in FBN1. The identification of likely pathogenic COL2A1 variants in our patients expands the phenotypic spectrum of type II collagenopathies and suggests that a MASS-like phenotype can be assigned to various hereditary disorders of connective tissue. Pathogenic sequence variants in the COL2A1 gene cause clinically distinguishable type II collagenopathies with mild to lethal phenotypes, which are usually of dominant inheritance[3,4]. Main known features of COL2A1-associated disorders are skeletal dysplasia, ocular anomalies, and auditory impairment, all with different severities[3]. Most disease-associated COL2A1 variants (i.e. 80–85%) are located in the triple-helical region of the collagen chain (Fig. 1a)[4,11]. We report four patients carrying variants in the propeptide regions of COL2A1 and presenting with tall stature, arachnodactyly, dural ectasia, and varying skeletal manifestations, resembling MASS (mitral valve, myopia, aorta, skeletal and skin features) phenotype

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Results

Discussion

Conclusion