New topics in the skeletal dysplasias

Abstract

A first glance at the Table of contents of this issue might give the impression that we have chosen a disparate group of conditions to explore. However, we feel that this selection represents several key principles of the field and genetics, as well as medicine in general: these rare disorders need careful delineation and study so as not to be mistakenly lumped and inappropriately treated, molecular origins turn out to be more intricate and beautiful than previously imagined, and only through accurate recording can we move forward. Drs. Terhal and Mortier from the Netherlands and Belgium, together with clinical partners from several countries, have studied a large series of patients with mutations in theCOL2A1 gene and elaborated new growth curves for spondylo-epiphyseal dysplasia congenital (SEDC) and related collagen 2 disorders. Development of these molecularly based growth curves is a major step forward in the nosography of collagen 2-related dysplasias, one of the largest and most important group of patients in a skeletal dysplasia clinic. Although variability remains significant and points to the multifactorial determination of height even in the presence of a single gene with a major influence, the possibility of comparing the growth chart of a single patient with that of a cohort of patients with similar mutations is a significant improvement over the past and projects us towards the future. It is hoped that similar studies will begin as soon as possible for all other major chondrodysplasia genes allowing the creation of a comprehensive database. In the best of worlds, such a database would include also data on morbidity and complications. The data presented by Drs. Terhal, Mortier and coworkers will undoubtedly constitute an important reference for years to come. The so-called enchondromatoses have been difficult to deal with in many a revision of the Nosology. Are they really ‘‘anarchic’’ development of bone or are they a special type of dysplasia? Andwhat about their inheritance, so many cases being sporadic? Drs. SupertiFurga, Nishimura and Spranger have tried to tackle these questions with the help of recent results that have revealed unexpected molecular mechanisms. They suggest that enchondromas are useful but nonspecific findings and that the molecular bases include both homeostatic defects of bone resorption as well as true dysregulation of cell proliferation. In the latter group, the role of somatic mutations gives a novel twist to the story. The newly proposed classification and the presentation of reference images from molecularly proven individuals will prove to be a helpful companion for the clinician and radiologist. The Paris group led by Dr. Valerie Cormier-Daire contributes two articles illustrating the contribution of the study of genetic disorders to our understanding of skeletal biology and of human growth. In the article on ‘‘ciliary’’ disorders, Drs. Huber and Cormier take us into the world of monocilia, fascinating structures that stand like tall poles on the surface ofmost cells, including chondrocytes, receiving and transmitting signals—much like the antennas of cellular phones that today line the highways of modern countries—or, like in photoreceptors, carry large stacks of sensory molecules. The high morphologic and functional specialization of cilia is based on a complex transport and assembly apparatus (the intraflagellary transport system, IFT) and mutations in components of this apparatus affect proliferation and differentiation of cells. Based on the current state of knowledge in the skeletal dysplasias and in other ciliary disorders such as the Bardet–Biedl syndrome and the genetic nephropathies, Le Goff and Cormier predict that mutations in many more ciliary genes will be uncovered, and that genotype– DEDICATION To the memory of