by Robert C. Mellors, M.D., Ph.D.

II. Congenital and Hereditary Bone Disorders

1. Achondroplasia

General Considerations

Achondroplasia is a congenital and often hereditary (autosomal dominant) skeletal disorder characterized by a unique form of dwarfism and bone deformity resulting in a disproportinate shortness of the extremities relative to the trunk.

632: Achondroplasia: note the disproportionate shortness of the extremities to the trunk in this form of dwarfism.

Achondroplasia is caused by a failure of proliferation and column formation of epiphysial cartilage cells, that is, by a defect in endochondral bone formation which impairs the longitudinal growth of the tubular bones. Point mutations in the FGR3 gene (encoding fibroblast growth receptors) on human chromosome 4 p segregate with disease in achondroplasia families (Rousseau, F., et al. Nature 371:252-254, 1994).


Achondroplasia shows various degrees of expression. The severest cases result in fetal or neonatal death, and milder cases survive and comprise the commonest type of adult dwarfism. The adult height in achondroplasia is usually less than four feet. The extremities (legs, arms, fingers, toes) are very short (micromelia) relative to the trunk which is only slightly shortened. Intramembraneous ossification is not affected. The head (cranial vault) is large. The root of the nose is depressed. The skeletal deformities just noted along with normal intelligence and sexual development distinguish achondroplasia from dwarfism resulting from endocrine and nutritional deficiencies and other causes.

The microscopic changes in achondroplasia are best shown by a section of the epiphysis of a long bone during the neonatal period. The epiphysial growth plate is thin. There are few cells in the zone of proliferating cartilage. The hypertrophic cartilage cells form extremely irregular columns, if any, and as a result the zone of provisionally calcified cartilage is small and does not provide an adequate scaffolding for bone matrix deposition by metaphysial osteoblasts. Periosteal new-bone formation by osteoblasts is not impaired.

2. Osteogenesis Imperfecta (Brittle Bones, Fragilitas Ossium)

General Considerations

Osteogenesis imperfecta (OI) is a rare heritable and often congenital disorder of skeletal development characterized by bone fragility which predisposes to fractures and deformity and by connective-tissue abnormalities which may involve the eyes (blue sclerae), ears, teeth, joints, and skin. The underlying cellular defect lies in abnormal collagen synthesis by osteoblasts and fibroblasts. (Collagens are the major protein constituents of connective tissue, and type I collagen is the main collagen of bone, tendon, and skin.) Molecular studies indicate that the primary biochemical defect in OI is defective synthesis and secretion of collagen I caused by mutations (deletions, insertions, substitutions) in the two structural genes which encode the alpha1- and alpha 2- peptides of this triple helix molecule. Many, if not all, of the OI phenotypes are mutants of the two collagen 1 structural genes. Inheritance may be dominant, recessive, or sporadic.


OI is divisible into two main clinical groups based upon the age of onset and the clinical severity: OI congenita with multiple fractures usually present at or before birth and often fatal.

631: Osteogenesis imperfecta congenita with multiple fractures of extremities.

OI tarda in which disease expression is less severe and often not apparent at birth. There is a broad range of disease expression within each group. The chief clinical features are fragility of bones, multiple fractures (of long bones), bone deformities, (caused by fracture healing with poor alignment and weak callus):

655: Osteogenesis imperfecta with tibial deformities.

and shortness of stature or dwarfism (in the congenita group). The bones of the extremities are shorter, smaller, and thinner than normal. A general decrease in bone mass (osteopenia/osteoporosis) is seen radiographically. The teeth may be fragile and discolored as a result of dentin imperfection (dentinogenesis imperfecta). A striking feature is the presence of blue sclerae caused by a thin or defective fibrous layer which is translucent to the underlying choroid and vitreous. Ligamentous laxity of joints and thin fragile skin also reflect a defective fibrous structure. Progressive impairment of hearing, more common in the tarda group, is caused by otosclerosis.

The typical microscopic changes of OI can be seen in a section of a long bone of a severely affected child. The bone cortex is thin and porous. The bone trabeculae are thin, delicate, and widely separated. Many osteoblasts and osteocytes are present, but the formation and organization of osteoid is deficient. There is less bone tissue than normal and most of it is woven or non-lamellar bone with collagen fibers of small size and random distribution. The woven bone has an increase in basophilic ground substance (shown by blue staining in H.&E. sections):

658: Osteogenesis imperfecta congenica: fracture callus. H&E.

Replacement of immature by mature bone with circumferential lamellae and Haversian systems is delayed or incomplete. The woven bone in OI may persist into adolescence, whereas in normal children woven bone usually occurs only in the embryo or early childhood ( or in fracture repair). The proliferation of epiphysial cartilage cells is normal, but the formation of osteoid by osteoblasts is impaired and delays the process of endochondral bone formation.

3. Osteopetrosis (Marble Bone Disease, Osteosclerosis)

General Considerations

Osteopetrosis is a rare hereditary, usually congenital, disorder of skeletal development characterized by massive but fragile bones,

638: Osteopetrosis: characterized by massive but fragile bones with "trumpet-like" expansion and thickening of long bones of the extremities.

with marked thickening of cortical and medullary bone and concomitant reduction of the marrow space, and resulting in some cases in severe, even fatal, anemia and in blindness and deafness. The cause of osteopetrosis is unknown but the pathogenesis appears to be related to a defect in the function of osteoclasts in bone resorption and remodeling. There are two different genetic and clinical forms of the disease. The autosomal recessive form runs a "malignant" course and is fatal in utero, infancy or young adult life as a result of bone marrow obliteration, profound anemia, or other hemopoietic abnormalities. The autosomal dominant form has a more benign course marked by repeated fractures on slight trauma, a near normal normal life expectancy, and the absence of hemopoietic abnormalities.


Radiographically and pathologically, all bones are affected, but the most significant changes in osteopetrosis occur in the bones which are preformed in cartilage. The long bones of the extremities, vertebrae, pelvic bones, and base of the skull show a great increase in the density and thickness of the cortex, an increase in the number and size of bony trabeculae, and a marked reduction or obliteration of the marrow spaces and haversian systems. The reduction in the total amount of bone marrow leads to anemia and extramedullary hemopoiesis, resulting in enlargement of the spleen, liver, and lymph nodes. Bone overgrowth at the base of the cranium causes narrowing of the optic foramina and pressure on the optic nerves, resulting in primary optic atrophy and blindness. Other cranial nerves, such as the auditory nerves, are similarly involved. In addition to the increased density and mass of the long bones, the most characteristic microscopic change in medullary and cortical bone is the presence and persistence into adult life of spicules of calcified cartilage which normally would have been resorbed, replaced, and remodeled preparatory to endochondral ossification. These changes apparently reflect a basic defect in the function of osteoclasts in the resorption and remodeling of mineralized epiphysial cartilage. Osteoclasts and active osteoblasts are few in number. The bone tissue formed is largely woven bone, and very little of it is remodeled and replaced by lamellar bone. Although massive, the bone structure is of poor structure and easily fractured.

4. Hereditary Multiple Exotosis (Osteochondromatosis)

General Considerations

This is an hereditary developmental disorder of the skeleton in which multiple cartilage-capped bony outgrowths (exostoses/osteochondromas) protrude from the bone cortex in the metaphysial region of bones preformed in cartilage, such as the long bones of the extremities particularly in the region of the knee, ankle, or shoulder.

645: Osteochondromatosis: multiple cartilage-capped exostoses of femur and tibia.

The exostoses tend to have a bilateral and symmetrical distribution. The scapulae, ribs, inominate bones, vertebrae, and metacarpal and metatarsal bones may also be involved. Although not common, hereditary multiple exostosis is the most frequently seen systemic disorder of skeletal development. It is apparently inherited as an autosomal dominant, but there is an unexplained 3:1 preponderance of affected males compared to females. The precise origin of the cartilage-capped lesions is uncertain. The usual explanation is that the exostoses arise from foci of misplaced or misdirected epiphysial cartilage which grows outwardly rather than longitudionally, abetted by a lack of normal restraint from the covering perichondrium. The exostoses grow by endochondral ossification of the cartilage cap, and growth of the exostoses ceases at or prior to the skeletal maturation of the individual.


Pathologically and radiographically, the exostoses are seen as sessile or stalked bony protuberances, with various shapes (knobby, hemispherical, conical) and sizes (1-10 cm. in diameter), protruding from the metaphysial region of the involved bones

633: Osteochondromatosis of radius and ulna.

644: Osteochondromatosis of humerus.

The exostoses of long bones characteristically point away from the joint because the epiphysial site of origin of the exostoses lags behind the advancing epiphysial growth plate as the long bones increase in length. Grossly, the exostoses are covered with periosteum and capped with a thin layer of cartilage

627: Cartilage-capped solitary osteochondroma of rib.

Microscopically, the deeper layers of the cartilage cap of an actively growing exostosis contain proliferating and column-forming cartilage cells with underlying endochondral ossification, much as seen in an epiphysial cartilage growth plate.

661: Cartilage-capped solitary osteochondroma, rib, H&E.

In some ( 3-5%) cases of hereditary multiple exostosis, the cartilage cap or remnants of it undergoes malignant transformation to a sarcoma, most often a peripheral chondrosarcoma. Malignant transformation is less often seen in solitary exostosis which, although microscopically similar and much more common than multiple exostosis, does not have an hereditary basis and is not a systemic disorder of skeletal development.

5. Enchondromatosis (Ollier's Disease)

General Considerations

Enchondromatosis is a rare disorder of skeletal development characterized by the presence of multiple circumscribed foci or masses of cartilage in the interior of bones preformed in cartilage, particularly the long and short tubular bones of the extremities. The disorder does not appear to be hereditary. Clinical manifestations of the condition may first appear in early childhood. Swellings of the fingers and toes, bone deformities, leg length discrepancies, and pathological fractures may be caused by the presence of the enchondromas.

662: Enchondromatosis (Ollier's disease) of phalanges of fingers.

Skeletal involvement tends to be greater on one side of the body than the other. Multiple hemangiotama of the soft tissues and muscles is sometimes associated with enchondromatosis (Maffucci syndrome).


The characteristic radiographical appearance of enchondromatosis is that of multiple, central, well circumscribed areas of radiolucency, often striped with calcification, located in the short or long tubular bones, and frequently causing thinning and bulging of the cortex.

659: Enchondromatosis of great toe and metatarsal bone.

Microscopically, the multiple enchondromas are composed of lobules of cartilage cells of benign but richly cellular appearance and forming a hyaline matrix. The morphological appearance is similar to that of solitary enchondroma, a benign cartilage growth that involves only a single bone in an individual ( discussed under Bone Tumors).

653: Solitary enchondroma, femur, composed of lobules of benign cartilage cells and hyaline matrix. H&E.

Nevertheless, compared to the solitary enchondroma, the cartilaginous lesions in enchondromatosis are more cellular histologically and more prone to malignant transformation to chondrosarcoma, which may appear near midlife as a complication of enchondromatosis at a reported incidence, variously, of 5-50%.