REVIEW The skeletal dysplasias Deborah Krakow, MD1, and David L. Rimoin, MD, PhD2,3 Abstract: The skeletal dysplasias (osteochondrodysplasias) are a het- Embryology erogeneous group of more than 350 disorders frequently associated with The human skeleton (from the greek, skeletos, “dried up”) is orthopedic complications and varying degrees of dwarfism or short a complex organ consisting of 206 bones (126 appendicular, 74 stature. These disorders are diagnosed based on radiographic, clinical, axial, and 6 ossicles). The musculoskeletal system also includes and molecular criteria. The molecular mechanisms have been elucidated tendons, ligaments, and muscles, and, in addition to cartilage in many of these disorders providing for improved clinical diagnosis and bone, is involved in linear growth, mechanical support, and reproductive choices for affected individuals and their families. An movement, a blood cell and mineral reservoir, and protection of increasing variety of medical and surgical treatment options can be vital organs. These tissues and adipocytes all derive from mes- offered to affected individuals to try to improve their quality of life and enchymal precursor cells. lifespan. Genet Med 2010:12(6):327–341. The patterning and architecture of the skeleton during fetal development determine the number, size, and the shape of the future skeletal elements.3 Uncondensed mesenchyme undergoes eneralized disorders of cartilage and bone have been re- cellular condensations at sites of future bones and joints and this Gferred to as skeletal dysplasias, whereas those that affect an occurs by two mechanisms. In the process, mesenchymal cells individual bone or group of bones have been referred to as differentiate into chondrocytes to form the cartilage anlagen and dysostoses; however, these distinctions are blurring as their then, the center of the anlagen degrades, mineralizes, and is basic defects are elucidated. The skeletal dysplasias are associ- removed by osteoclast-like cells.4–8 This process spreads up ated with abnormalities in the patterning, development, main- and down the bones, allowing for vascular invasion and influx tenance, and size of the appendicular and axial skeleton and of osteoprogenitor cells. The periosteum in the midshaft region frequently result in disproportionate short stature. Until the produces osteoblasts, which then synthesize the cortex.9 This is early 1960s, most individuals with short stature were considered known as the primary ossification center. At the end of the to have pituitary dwarfism, achondroplasia (short-limb dwarf- cartilage anlagen, a similar process leading to the removal of ism), or Morquio disease (short-trunked dwarfism). Presently, cartilage, initiation of joint formation and a secondary ossifica- there are more than 350 well-characterized skeletal dysplasias tion center forms, leaving a portion of cartilage model “trapped” that are classified primarily on the basis of clinical, radio- between the expanding primary and secondary ossification cen- 1 graphic, and molecular criteria. They result from mutations in ter. This area is referred to as a cartilage growth plate or physis. various families of genes that encode extracellular matrix pro- There are three chondrocyte cell types in the growth plate: teins, transcription factors, tumor suppressors, signal transduc- reserve/resting, proliferative, and hypertrophic. These growth ers (ligands, receptors, and channel proteins), enzymes, cellular plate chondrocytes undergo a tightly regulated program of pro- transporters, chaperones, intracellular binding proteins, RNA liferation, hypertrophy, degradation, and then replacement by processing molecules, cilia and cytoplasmic proteins, and a bone (primary spongiosa) (Fig. 1, A).4 This is the major mech- number of gene products of currently unknown function. anism of skeletogenesis and is the mechanism by which bones The skeletal dysplasias increase in length and the articular surfaces increase in diame- ter. In contrast, the flat bones of the cranial vault and part of the The skeletal dysplasias are disorders associated with a gen- clavicles and pubis formed by intramembranous ossification, eralized abnormality in the skeleton. Although each skeletal where fibrous tissue, derived from mesenchymal cells, differ- dysplasia is relatively rare, collectively the birth incidence of entiates directly into osteoblasts which then directly lay down these disorders is almost 1/5000.2 These disorders range in bone.10,11 These processes are under specific and direct genetic severity from precocious arthropathy in relatively average stat- control.12 Chondrocytes produce a variety of proteins that com- ure individuals to severe dwarfism with perinatal mortality. pose the extracellular matrix. Some of the most prominent These disorders can be associated with a variety of orthopedic, extracellular structural matrix proteins are the collagens, single neurologic, auditory, visual, pulmonary, cardiac, renal, and psy- molecules that associate into chains to form a triple helical chological complications. structure. In the triple helix, every third amino acid is a glycine residue, and the general chain structure is denoted as Gly-X-Y, From the 1Departments of Orthopaedic Surgery, Human Genetics, and where X and Y are commonly proline and hydroxyproline. The Obstetrics and Gynecology, David Geffen School of Medicine at UCLA; helical structure undergoes numerous posttranslational modifi- 2Medical Genetics Institute at Cedar-Sinai Medical Center; and 3Depart- cations before its localization to the extracellular matrix where ments of Pediatrics, Internal Medicine and Human Genetics, David Geffen multiple triple helical chains become a fibril. The collagen helix School of Medicine at UCLA, Los Angeles, CA. can be composed of identical chains (homotrimeric), as in type Deborah Krakow, MD, UCLA, 615 Charles E. Young Drive, Room 410B, II collagen, or can consist of different collagen chains (hetero- Los Angeles, CA 90095. E-mail: [email protected]. trimeric), as seen in types I, IX, and XI collagen.13 Disclosure: The authors declare no conflicts of interest. Collagens are widely distributed throughout the body and are Submitted for publication January 2, 2010. expressed in a tissue specific manner. Collagens are further classified by the structures they form in the extracellular matrix. Accepted for publication February 22, 2010. The most abundant collagens are the fibrillar types (I, II, III, V, Published online ahead of print April 27, 2010. and XI) and their extensive cross-linking provides mechanical DOI: 10.1097/GIM.0b013e3181daae9b strength that is necessary for high stress tissues such as carti- Genetics IN Medicine • Volume 12, Number 6, June 2010 327 Krakow and Rimoin Genetics IN Medicine • Volume 12, Number 6, June 2010 Fig. 1. A, Normal growth plate morphology. Proliferating chondrocytes undergo hypertrophy, then apoptosis to become the primary spongiosum of bone. B, Abnormal growth plate in a case of metatropic dysplasia. Hypertrophic chondrocytes irregularly extend into the primary spongiosum, disturbing the normal architecture (arrow). C, Growth plate chondrocytes from a patient with diastrophic dysplasia demonstrating characteristic rings around the chondrocytes (arrow). P, proliferating chondrocyte; H, hypertrophic chondrocyte; B, bone; PS, primary spongiosum. lage, bone, and skin. Another group of collagens are the fibril The epiphyseal, metaphyseal, and diaphyseal disorders can be associated collagens with interrupted triple helices and include further differentiated depending on whether the spine is in- collagen types IX, XII, XIV, and XVI. These collagens interact volved (spondyloepiphyseal, spondylometaphyseal dysplasias with fibrillar collagens and other extracellular molecules, in- [SMDs], or spondyloepimetaphyseal dysplasias [SEMDs]). The cluding aggrecan, cartilage oligomeric matrix protein (COMP), skeletal dysplasias can be also be differentiated into distinct decorin, fibulin, and numerous other sulfated proteoglycans.14 disorders based on a variety of other clinical and radiographic Collagen types VIII and X are nonfibrillar, short chain collag- findings. ens; type X collagen is the most abundant extracellular matrix molecule expressed by hypertrophic chondrocytes during endo- chondral ossification.15 Mutations in genes that encode these Clinical evaluation and features in the collagens result in various skeletal dysplasias and highlight the chondrodysplasias importance of these molecules in skeletal development. The skeletal dysplasias are generalized disorders of the skel- In the 1970s, there was increasing recognition of the genetic eton, which usually result in disproportionate short stature. and clinical heterogeneity of these disorders and a new aware- Most individuals with disproportionate short stature have skel- ness of their complexity. There have been multiple attempts to etal dysplasias, and those with proportionate short stature have classify these disorders, so that clinicians and scientists could endocrine, nutritional, or other genetic or teratogenic disorders, effectively diagnose them and determine their pathogenicity although there are exceptions to this generalization. Some forms (International Nomenclature of Constitutional Diseases of of osteogenesis imperfecta (OI) and hypophosphatasia can be Bone, 1970, 1977, 1983, 1992, 2001, 2005, and 2009).1 The associated with relatively normal body proportions. initial categories were purely descriptive and clinically based. A disproportionate