TY - JOUR

T1 - Multicentric osteolytic syndromes represent a phenotypic spectrum defined by defective collagen remodeling

AU - de Vos, I.J.H.M.

AU - Wong, A.S.W.

AU - Welting, T.J.M.

AU - Coull, B.J.

AU - van Steensel, M.A.M.

N1 - This is the peer reviewed version of the following article: Vos, IJHM, Wong, ASW, Welting, TJM, Coull, BJ, Steensel, MAM. Multicentric osteolytic syndromes represent a phenotypic spectrum defined by defective collagen remodeling. Am J Med Genet Part A. 2019; 179A: 1652– 1664. https://doi.org/10.1002/ajmg.a.61264 which has been published in final form at https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.a.61264 This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Frank-Ter Haar syndrome (FTHS), Winchester syndrome (WS), and multicentric osteolysis, nodulosis, and arthropathy (MONA) are ultra-rare multisystem disorders characterized by craniofacial malformations, reduced bone density, skeletal and cardiac anomalies, and dermal fibrosis. These autosomal recessive syndromes are caused by homozygous mutation or deletion of respectively SH3PXD2B (SH3 and PX Domains 2B), MMP14 (matrix metalloproteinase 14), or MMP2. Here, we give an overview of the clinical features of 63 previously reported patients with an SH3PXD2B, MMP14, or MMP2 mutation, demonstrating considerable clinical overlap between FTHS, WS, and MONA. Interestingly, the protein products of SH3PXD2B, MMP14, and MMP2 directly cooperate in collagen remodeling. We review animal models for these three disorders that accurately reflect the major clinical features and likewise show significant phenotypical similarity with each other. Furthermore, they demonstrate that defective collagen remodeling is central in the underlying pathology. As such, we propose a nosological revision, placing these SH3PXD2B, MMP14, and MMP2 related syndromes in a novel “defective collagen-remodelling spectrum (DECORS)”. In our opinion, this revised nosology better reflects the central role for impaired collagen remodeling, a potential target for pharmaceutical intervention.

AB - Frank-Ter Haar syndrome (FTHS), Winchester syndrome (WS), and multicentric osteolysis, nodulosis, and arthropathy (MONA) are ultra-rare multisystem disorders characterized by craniofacial malformations, reduced bone density, skeletal and cardiac anomalies, and dermal fibrosis. These autosomal recessive syndromes are caused by homozygous mutation or deletion of respectively SH3PXD2B (SH3 and PX Domains 2B), MMP14 (matrix metalloproteinase 14), or MMP2. Here, we give an overview of the clinical features of 63 previously reported patients with an SH3PXD2B, MMP14, or MMP2 mutation, demonstrating considerable clinical overlap between FTHS, WS, and MONA. Interestingly, the protein products of SH3PXD2B, MMP14, and MMP2 directly cooperate in collagen remodeling. We review animal models for these three disorders that accurately reflect the major clinical features and likewise show significant phenotypical similarity with each other. Furthermore, they demonstrate that defective collagen remodeling is central in the underlying pathology. As such, we propose a nosological revision, placing these SH3PXD2B, MMP14, and MMP2 related syndromes in a novel “defective collagen-remodelling spectrum (DECORS)”. In our opinion, this revised nosology better reflects the central role for impaired collagen remodeling, a potential target for pharmaceutical intervention.

KW - ECM remodeling

KW - MMP14

KW - MMP2

KW - podosomes

KW - SH3PXD2B

U2 - 10.1002/ajmg.a.61264

DO - 10.1002/ajmg.a.61264

M3 - Journal article

VL - 179

SP - 1652

EP - 1664

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

SN - 1552-4825

IS - 8

ER -