Congenital anomalies can result from localized abnormalities in the migration and condensation of mesenchyme (dysostosis) or global disorganization of bone and/ or cartilage (dysplasia). Dysostoses result from defects in the formation of mesenchymal condensations and their differentiation into the cartilage anlage. The most common forms include the complete absence of a bone or a digit (aplasia), extra bones or digits (supernumerary digit), and abnormal fusion of bones (e.g., syndactyly, craniosynostosis). Genetic alterations that affect homeobox genes, cytokines, and cytokine receptors are especially common among the dysostoses. In contrast, dysplasias arise from mutations in genes that control development or remodeling of the entire skeleton. It is important to note that, as for developmental anomalies in other tissues, the term dysplasia implies abnormal growth rather than a premalignant lesion as used in the context of neoplasia (Chapter 6).
More than 350 skeletal dysostoses and dysplasias, most of them extremely rare, have been described. Examples of diseases with defined genetic abnormalities are discussed below. Note that various point mutations in a single gene (e.g., COL2A1) can result in different phenotypes, whereas mutations in diverse genes (e.g., LRP5, RANKL) can give rise to similar clinical phenotypes.
Achondroplasia, the most common skeletal dysplasia and a major cause of dwarfism, is an autosomal dominant disorder resulting from retarded cartilage growth. The disease is caused by gain-of-function mutations in fibroblast growth factor receptor 3 (FGFR3). Normally, FGF inhibits endochondral growth. FGFR3 mutation results in a constitutively active receptor, thereby exaggerating this effect and suppressing growth. Approximately 90% of cases stem from new mutations, almost all of which occur in the paternal allele. Affected individuals have shortened proximal extremities, a trunk of relatively normal length, and an enlarged head with bulging forehead and conspicuous depression of the root of the nose. The skeletal abnormalities are usually not associated with changes in longevity, intelligence, or reproductive status.
Thanatophoric dysplasia, the most common lethal form of dwarfism, results from diminished proliferation of chondrocytes and disorganization in the zone of proliferation. It also is caused by gain-of-function mutations in FGFR3, albeit ones that are distinct from those that cause achondroplasia. It occurs in about 1 of every 20,000 live births. Affected individuals have micromelic shortening of the limbs, frontal bossing, relative macrocephaly, a small chest cavity, and a bell-shaped abdomen. The underdeveloped thoracic cavity leads to respiratory insufficiency, and these individuals usually die at birth or soon thereafter.
Osteogenesis imperfecta (OI), the most common inherited disorder of connective tissue, is a phenotypically diverse disorder caused by deficiencies in the synthesis of type I collagen. OI principally affects bone and other tissues rich in type I collagen (joints, eyes, ears, skin, and teeth). It usually results from autosomal dominant mutations in the genes that encode the α1 and α2 chains of type I collagen. These defects cause misfolding of the mutated collagen polypeptides, and they interfere with the proper assembly of wild-type collagen chains (a dominant negative loss of function).