- Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Luis O Rohena, MD more...
Dwarfism is a commonly used term for disproportionately short stature, although a more medically appropriate term for this disorder is skeletal dysplasia. Short stature is defined as height that is 3 or more standard deviations below the mean height for age. If short stature is proportional, the condition may be due to endocrine or metabolic disorders or chromosomal or nonskeletal dysplasia genetic defects.
In general, patients with disproportionately short stature have skeletal dysplasia (osteochondrodysplasia). Skeletal dysplasias are a heterogeneous group of more than 200 disorders characterized by abnormalities of cartilage and bone growth, resulting in abnormal shape and size of the skeleton and disproportion of the long bones, spine, and head. See the images below.
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- Skeletal dysplasias differ in natural histories, prognoses, inheritance patterns, and etiopathogenetic mechanisms. During the 1950s and 1970s, many new bone dysplasias were identified based on clinical manifestations, radiographic findings, inheritance patterns, and morphology of the growth plate. In the 1980s, research focused on defining the natural history and variability of the disorders. In the 1990s, the focus shifted toward elucidating the responsible mutations and characterizing the pathogenetic mechanisms by which the mutations disrupt bone growth.
- In 1997, the International Working Group on Bone Dysplasias proposed a newly revised "International Nomenclature and Classification of the Osteochondrodysplasias." In the revised nomenclature, families of disorders were rearranged based on recent etiopathogenetic information concerning the gene and/or protein defect involved. Disorders for which the basic defect was well documented were regrouped into distinct families in which component disorders result from mutations of the identical gene. Several new groups of disorders were added, and other families were renamed. Despite this update, the basic defect remains unrecognized in many disorders. With increasing molecular discoveries, classification and nomenclature must be constantly updated. However, over the past decades, substantial advances have been made in understanding the underlying genetic abnormalities responsible for most skeletal dysplasias.
- Based on the underlying molecular genetic cause, the dysplasias can be broadly grouped by the function of the protein product of the causative gene. This type of classification is clinically useful because many of the disorders caused by genes whose protein products have similar functions also share clinical characteristics.
- Until skeletal maturity, cartilage persists at the ends of bone in the growth plate, which is responsible for longitudinal bone growth. The cartilaginous template is eventually replaced by bone. Many of the genes mutated in skeletal dysplasias encode proteins that play critical roles in the growth plate. An understanding of the role in growth plate function gives important clues into the molecular pathology of the skeletal dysplasia and makes it easy to understand how a certain mutation causes a particular phenotype. Examples of genes that play a role in growth plate chondrocytes and skeletal dysplasia include the following:
- Resting zone of the growth plate: SOX9 gene mutation causes camptomelic dysplasia, which is characterized by short and curved bone and is associated with sex reversal in which the female external genitalia does not match the male genotype. A heterozygous mutation is sufficient to cause the disease making this a dominant mutation, despite earlier reports suggesting that camptomelic dysplasia is a recessive disorder.
- Proliferation zone of the growth plate: FGFR3 gene mutation causes achondroplasia, hypochondroplasia, and thanatophoric dysplasia, despite the variability in severity.
- Hypertrophic zone of the growth plate: PTHR1 gene mutation causes metaphyseal dysplasia. Activating mutations of the receptor causes the Jansen form, whereas inactivating mutations causes the Blomstrand form.[7, 8, 9, 10]
- Zone of terminal differentiation of the growth plate: RUNX2 gene mutation causes cleidocranial dysplasia.
- Mutations in type II collagen cause a large number of disorders classified as spondyloepiphyseal dysplasia (ie, spondyloepiphyseal dysplasia congenita, Kniest dysplasia, Stickler syndrome, and achondrogenesis). Mutations in the smaller matrix components, such as type IX collagen and cartilage oligomeric protein, cause multiple epiphyseal dysplasia.
- The overall incidence of skeletal dysplasias is approximately 1 case per 4000-5000 births. The true incidence may be twice as high because many skeletal dysplasias do not manifest until short stature, joint symptoms, or other complications arise during childhood.
- Lethal skeletal dysplasias are estimated to occur in 0.95 per 10,000 deliveries.
- Achondroplasia is the most common nonlethal skeletal dysplasia.
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- Among infants with skeletal dysplasias detected at birth, approximately 13% are stillborn, and 44% die during the perinatal period.
- The overall frequency of skeletal dysplasias in infants who die perinatally is 9.1 per 1000.
See the list below:
- No racial predilections are described.
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- Males are primarily affected in X-linked recessive disorders. X-linked dominant disorders may be lethal in males.
- Otherwise, males and females are usually equally affected by skeletal dysplasias.
See the list below:
- Skeletal dysplasias are usually detected in the newborn period or during infancy.
- Some disorders may not manifest until later in childhood.
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