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

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

Torg syndrome is caused by inactivating mutations in MMP2 and is allelic to NAO and Winchester syndrome

Torg syndrome is a multicentric osteolysis syndrome of unknown etiology. We identified mutations in the MMP2 gene in a patient with Torg syndrome that resulted in complete loss of MMP2 activity. MMP2 mutations were previously identified in patients with NAO and Winchester syndrome. Our findings suggest that Torg, NAO, and Winchester syndrome are allelic disorders. INTRODUCTION: Torg, nodulosis-arthropathy-osteolysis (NAO), and Winchester syndrome are a group of autosomal recessive osteolysis syndromes with marked clinical and radiological overlap. It has been suggested that the three conditions are causally related, but molecular evidence for this assumption has been lacking. Recently, mutations in the matrix metalloproteinase 2 gene (MMP2) have been reported in patients with NAO and Winchester syndrome. MATERIALS AND METHODS: We sequenced the MMP2 gene in a patient with clinical and radiographic findings of Torg syndrome. MMP2 activity was measured with gelatin zymography. RESULTS: Two mutations in the MMP2 gene were identified in this patient. Gelatin zymography indicated complete loss of MMP2 activity. CONCLUSIONS: Torg, NAO, and Winchester syndrome are allelic disorders. The name Torg-Winchester syndrome is suggested as a common denominator for this group of disorders

Three-dimensional evaluation of root canal morphology in lower second premolars of early and middle pleistocene human populations from atapuerca (Burgos, Spain)

The aim of this study is to describe the morphology of the roots and root canals of permanent lower second premolars (LP4s) with fully developed roots of five hominin groups: Homo sp. (ATE9‐1 specimen) from Atapuerca‐Sima del Elefante locality, H. antecessor (ATD6‐4 and ATD6‐125) from Atapuerca‐Gran Dolina TD6 locality, H. heidelbergensis from Atapuerca‐Sima de los Huesos locality, H. neanderthalensis from Krapina, Regourdou, and Abri Bourgeois‐Delaunay localities, and two contemporary H. sapiens groups. The teeth were scanned by means of microtomography. The roots were divided into three virtual segments by three planes: cemento‐enamel junction (CEJ), mid‐root (MR), and mid‐apex (MA). Volumetric and planar direct measurements of the whole teeth and each segment were taken. Descriptive statistical analyses and nonparametric Mann‐Whiney test were performed to test for significant differences (P < 0.025) between groups. ATE9‐1 and Gran Dolina‐TD6 fossils present intricate radicular complexes that might be transitional between the morphologies of Australopithecus robustus and African early Homo and the derived conditions typically found in later Homo. In H. neanderthalensis and H. heidelbergensis, the root canals are wide, with small apical convergence. This trait is particularly pronounced in the Sima de los Huesos sample which may reflect a particularity of this population. Our study demonstrates the potential of hominin roots and root canals as untapped sources of taxonomic information when the tooth crown is fragmented. Future studies, including more fossil specimens and species will shed light in the polarity of the morphologies observed