Mutation in MMP2 gene may result in scleroderma-like skin thickening

Abstract

We read with interest the paper by Banka et al 1 who identify microduplications of chromosome 8q22 as the cause of Leri's pleonostosis, a disease belonging to the 'transforming growth factor beta (TGF-beta)-pathies' group of musculoskeletal disorders. We have been involved in the identification of rare monogenic systemic lupus erythematosus (SLE), especially inherited interferonopathies, 2 3 and we agree with the authors that the common phenotype of autoimmune diseases, such as SLE and systemic sclerosis (SSc), could be explained by involvement of different disease-associated genes in related physiological pathways. Herein we aim to report for the first time that mutation in matrix metalloproteinase-2 (MMP-2) may result in scleroderma-like skin thickening.A 12-year-old girl was referred because of distal osteoporosis revealed by several pathological appendicular fractures since the age of 8 years. There was no family history. Physical evaluation revealed mildly coarse face, hypertrophic scars and keloids, gum hypertrophy, nodules on the soles, painless contractures of small joints and diffuse skin thickening. Figure 1 Wrist MRI: small erosive changes of the carpal and proximal metacarpals and enhancement of the synovial were detected.

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

“…Notably, Mmp2 KO was found to impair osteoblast and osteoclast proliferation in vitro , but osteoblast activity intensified in Mmp2 KO mice at later age which could, at least in part, explain the observed calvarial BMD increase (Inoue et al, ; Mosig et al, ). Similar to the pathological fractures in several patients with an MMP2 mutation, the observed osteopenia in Mmp2 KO mice is accompanied by spontaneous tibia fractures (Bader‐Meunier et al, ; Inoue et al, ; Jeong et al, ; Pichler et al, ). Finally, adult Mmp2 KO mice have bone erosion underlying articular cartilage destruction of the knee (Mosig et al, ).…”

“…In doing so, MMP2 directly cooperates with MMP14 and augments its collagenolytic activity (Ohuchi et al, ; Sato et al, ; Takino et al, ). The relevance of MMP2 activity is reflected by the overlap between the MMP14 and MMP2‐related human phenotypes, as outlined above (Al Aqeel et al, ; Al Kaissi et al, ; Azzollini et al, ; Bader‐Meunier et al, ; Bhavani et al, ; Castberg et al, ; De Vos et al, ; Eisenstein et al, ; Ekbote et al, ; Gok et al, ; Jeong et al, ; Martignetti et al, ; Phadke & Dalal, ; Pichler et al, ; Rouzier et al, ; Temtamy et al, ; Tuysuz et al, ; Vanatka et al, ; Zankl et al, , ).…”

“…Most examined individuals with an SH3PXD2B or MMP14 mutation had a broad mouth, as well as one third of examined patients with an MMP2 mutation. Finally, thick lips and either a small or heavy mandible have been reported in most examined patients with an SH3PXD2B , MMP14 , or MMP2 mutation (Al Aqeel et al, ; Al Kaissi et al, ; Azzollini et al, ; Bader‐Meunier et al, ; Bendon et al, ; Bhavani et al, ; Borrone et al, ; Castberg et al, ; Chang et al, ; Eisenstein et al, ; Ekbote et al, ; Gok et al, ; Hamel et al, ; Iqbal et al, ; Jeong et al, ; Maas et al, ; Martignetti et al, ; Mégarbané et al, ; Phadke & Dalal, ; Pichler et al, ; Prapanpoch et al, ; Rouzier et al, ; Temtamy et al, ; Ter Haar et al, ; Tuysuz et al, ; Vanatka et al, ; Van Steensel et al, ; Wilson et al, ; Winchester et al, ; Zankl et al, ; Zankl et al, ; Zrhidri et al, ).…”

“…Gingival hypertrophy has been reported in ≥50% of examined individuals with an SH3PXD2B , MMP14 , or MMP2 mutation (Table ). Delayed dentition, attributed to gingival hypertrophy, was less frequently reported (Al Aqeel et al, ; Bader‐Meunier et al, ; Bhavani et al, ; Borrone et al, ; Chang et al, ; Eisenstein et al, ; Ekbote et al, ; Martignetti et al, ; Mégarbané et al, ; Phadke & Dalal, ; Prapanpoch et al, ; Temtamy et al, ; Tuysuz et al, ; Van Steensel et al, ; Wilson et al, ; Winchester et al, ; Zankl et al, ).…”

Response to: ‘Mutation in MMP2 gene may result in scleroderma-like skin thickening’ by Bader-Meunieret al

“…In this context, this report from Bader-Meunier et al 4 of a patient with biallelic MMP2 mutation and scleroderma-like skin thickening in addition to the other known features of MONA syndrome is instructive. Notably, most previous reports of individuals with MMP2 mutations are of young children and skin thickening can be a progressive feature.…”