Segmentation anomalies of the vertebras and ribs: One expression of the primary developmental field

Segmentation anomalies of the axial skeleton have been described with terms such as ‘‘spondylocostal dysostosis (SCD),’’ ‘‘spondylothoracic dysostosis (STD),’’ ‘‘Jarcho–Levin syndrome (JLS),’’ ‘‘spondylothoracic dysplasia,’’ and ‘‘spondylocostal dysplasia’’ [Jarcho and Levin, 1938; Rimoin et al., 1968; Castroviejo et al., 1973; Gellis and Feingold, 1976; Casamassima et al., 1981; Aymé and Preus, 1986; Roberts et al., 1988; Floor et al., 1989; Lorenz and Rupprecht, 1990; Karnes et al., 1991; Turnpenny et al., 1991; Simpson et al., 1995; Aurora et al., 1996; Mortier et al., 1996; Duran et al., 2001; Santiago-Cornier et al., 2001]. But this nomenclature has become very confusing because of the inconsistent way in which these terms have been used. Moreover, some authors, as Cornier et al. [2004], postulate that it is not clear whether the intrinsic pathology of these anomalies is related to the embryonic sclerotomes that form bone tissue (dysplasia) or to the mesoderm itself, in which case the term ‘‘dysostosis’’ would be more appropriate. In recent years, a large body of knowledge has emerged from evolutionary developmental biology, epidemiology, and animal and human molecular genetics that may help to identify the different entities and, consequently, should not be ignored in clinical studies [Opitz and Gilbert, 1982; Davidson, 1991; Opitz, 1993, 2002; Wallin et al., 1993; Martı́nez-Frı́as and Urioste, 1994; Martı́nez-Frı́as et al., 1994, 1998a; Martı́nez-Frı́as, 1994a, 1995, 1996a; Davidson et al., 1995; Gilbert et al., 1996; Wei and Sulik, 1996; Dunwoodie et al., 1997; Tribioli and Lufkin, 1999; Turnpenny et al., 1999, 2003; Brand-Saberi and Christ, 2000; Bulman et al., 2000; Bannykh et al., 2003; Wellik and Capecchi, 2003]. In addition, as the vertebral column represents the characteristic skeletal structure of vertebrates, its development has been highly conserved during evolution. In fact, the great majority of vertebral anomalies observed in humans are also observed in other vertebrate species [Morcuende and Weinstein, 2003]. The development of the axial skeleton starts during blastogenesis (gastrulation) and requires different steps, including mesoderm formation, axial patterning, notochordmesoderm induction, sclerotome condensation, neural tube closure, somite formation, and axial identity specification. Thus, anomalies of the vertebrae and ribs could be the result of perturbations in the patterning of the axial skeleton occurring from the very early stages of development. It follows, then, that alterations in different steps of the process of development of the axial skeleton will produce different clinical anomalies. For instance, alterations of mesenchymal condensation will modify skeletal morphology; abnormal allocation of the mesodermal cells during blastogenesis will block the formation of the whole vertebral column; anomalies of pattern formation will alter vertebral morphology. Moreover, as the other two germ layers are also generated during the early stages of gastrulation, the embryo could also have multiple congenital anomalies beyond those of the axial skeleton. The mechanism for the establishment of the rostral-caudal axis is nowadays better understood, and continued advances in molecular embryology and human molecular genetics are increasing our understanding of the pathogenetic and molecular mechanisms of the alterations of normal and abnormal development of the human axial skeleton [Wei and Sulik, 1996; Dunwoodie et al., 1997; Turnpenny et al., 1999, 2003; Brand-Saberi and Christ, 2000; Bulman et al., 2000; Bannykh et al., 2003; Wellik and Capecchi, 2003]. Thus, from an embryological point of view, we could consider that some of the axial skeletal defects may result from alterations of the embryonic sclerotome (dysplasia), while others may be due to mesoderm anomalies (dysostosis), among other intrinsic pathologies. All of the above support the concept that errors of morphogenesis of the vertebrae and ribs occur during the stage of blastogenesis, when the whole embryo constitutes the ‘‘primary field,’’ and during the process of pattern formation that gradually merges into the component ‘‘progenitor fields’’ that give rise to the secondary developmental fields during organogenesis (5–8 weeks of development). These developmental fields constitute the fundamental units of evolution and development. Evolutionary changes of form reflect permanent modifications of morphogenetic events that confer three essential attributes to the developmental field: heterogeneity, homology, and phylogeneity [Opitz, 1993, 2002; Davidson et al., 1995; Gilbert et al., 1996; Martı́nez-Frı́as and Frı́as, 1997; Martı́nez-Frı́as et al., 1998a; Opitz et al., 2002]. From a clinical point of view, heterogeneity of the developmental fields is one of the most useful characteristics. If we can demonstrate that all parts of an abnormal organ or structure became malformed together in the same manner and in response to different causal agents, it is reasonable to postulate that these parts constitute a morphogenetic unit in normal development and that those alterations constitute a developmental field defect (DFD) [Opitz, 1993, 2002; Gilbert et al., 1996; Martı́nez-Frı́as, 1996b; Martı́nez-Frı́as et al., 1998a; Martı́nez-Frı́as and Frı́as, 1999; Opitz et al., 2002]. The three attributes of developmental fields, including the axial skeleton, are now being documented by an increasing number of experimental studies as well as by animal and human molecular genetics investigations. For example, an evolutionary and conserved mechanism in metazoans to control specification of cell fate through local interaction between cells is Notch signaling [Artavanis-Tsakonas et al., 1999]. This pathway involves a great variety of developmental processes at multiple levels; one of them is the mechanism by which the embryo is divided into segments that will form the axial skeleton (somitogenesis) [Kusumi et al., 1998; Dunwoodie et al., 2002]. In consequence, mutations on the components of this pathway could cause a great variety of genetic disorders. Homologues for each of the core elements of Notch signaling have been identified in mammalians, including Delta-like 1 (Dll1), Dll3, and Dll4. Grant sponsor: Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo of Spain.