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

Area of Science:

• Genetics and Molecular Biology
• Rare Disease Research
• Biochemistry

Background:

• Frank-Ter Haar syndrome (FTHS), Winchester syndrome (WS), and multicentric osteolysis, nodulosis, and arthropathy (MONA) are ultra-rare multisystem disorders with overlapping clinical features.
• These syndromes result from mutations in SH3PXD2B, MMP14, or MMP2, genes encoding proteins involved in extracellular matrix remodeling.

Purpose of the Study:

• To review and consolidate the clinical features of patients with SH3PXD2B, MMP14, or MMP2 mutations.
• To propose a revised nosology based on the central role of defective collagen remodeling in these disorders.

Main Methods:

• Clinical data compilation from 63 previously reported patients.
• Review of existing animal models for SH3PXD2B, MMP14, and MMP2 related disorders.
• Analysis of the functional relationship between SH3PXD2B, MMP14, and MMP2 proteins in collagen remodeling.

Main Results:

• Significant clinical overlap exists between FTHS, WS, and MONA.
• SH3PXD2B, MMP14, and MMP2 proteins directly cooperate in collagen remodeling.
• Animal models confirm shared pathologies and highlight defective collagen remodeling as a core mechanism.

Conclusions:

• The SH3PXD2B, MMP14, and MMP2 related syndromes represent a spectrum of defective collagen remodeling.
• A new nosological classification, "defective collagen-remodelling spectrum (DECORS)", is proposed.
• Impaired collagen remodeling is a potential therapeutic target for these rare diseases.