The basic genetic defects have been identified in most of the osteochondrodysplasias. The mutations typically cause perturbation of function in proteins involved in growth and development of connective tissue, bone, or cartilage (see Table: Types of Osteochondrodysplastic Dwarfism).
Dwarfism is markedly short stature (adult height < 4 ft 10 in) frequently associated with disproportionate growth of the trunk and extremities. Achondroplasia is the most common and best-known type of short-limbed dwarfism, but there are many other distinct types, which differ widely in genetic background, course, and prognosis (see Table: Types of Osteochondrodysplastic Dwarfism). Lethal short-limbed dwarfism (thanatophoric dysplasia, caused by mutations in the same gene as achondroplasia) causes severe chest wall deformities and respiratory failure in neonates, resulting in death.
Types of Osteochondrodysplastic Dwarfism
|
Disorder |
Symptoms and Signs |
Usual Mode of Inheritance |
Defective Gene Product |
|
Achondroplasia |
Bulky forehead, saddle nose, lumbar lordosis, bowlegs |
Fibroblast growth factor receptor 3 (FGFR) |
|
|
Chondrodysplasia punctata |
Variable extraskeletal manifestations X-rays show epiphyseal stippling in infancy due to calcifications |
See below |
See below |
|
Chondrodysplasia punctata (rhizomelic form) |
Marked proximal limb shortening Death during infancy |
Peroxisomal type 2 targeting signal receptor (PTS2) |
|
|
Chondrodysplasia punctata (Conradi-Hünermann form) |
Mild, asymmetric limb shortening Benign |
AD or XL dominant |
Delta(8)-delta(7)-sterol isomerase emopamil-binding protein (EBP) |
|
Chondroectodermal dysplasia (Ellis-van Creveld [EVC] syndrome) |
Distal limb shortening, postaxial polydactyly, structural cardiac defects |
EVC, EVC2 |
|
|
Diastrophic dysplasia |
Severe dwarfism with rigid hitchhiker thumb and fixed talipes equinovarum |
Solute carrier family 26 (sulfate transporter), member 2 (SLC26A2) |
|
|
Hypochondroplasia |
Symptoms of achondroplasia but milder |
Fibroblast growth factor receptor 3 (FGFR3—not all patients) |
|
|
Mesomelic dysplasia* (Langer type) |
Predominantly, shortening of the forearms and shanks Normal facies and spine |
Short stature homeobox (SHOX), short stature homeobox Y-linked (SHOXY) |
|
|
Metaphyseal chondrodysplasia† |
In some forms, malabsorption, neutropenia, thymolymphopenia |
Parathyroid hormone receptor (PTHR), type X collagen (COL10A1) |
|
|
Multiple epiphyseal dysplasia |
Mild dwarfism, normal spine and facies, sometimes stubby digits, hip dysplasia (often as 1st symptom) Very heterogeneous |
Solute carrier family 26 (sulfate transporter), member 2 (SLC26A2; AR form) |
|
|
Pseudoachondroplasia |
Normal facies, various degrees of dwarfism and kyphoscoliosis Heterogeneous |
Cartilage oligomeric matrix protein (COMP) |
|
|
Spondyloepiphyseal dysplasia |
Predominantly, kyphoscoliosis Sometimes myopia and a flat facies Heterogeneous |
AD, AR, or XL recessive |
Type II collagen (COL2A1), tracking protein particle complex, subunit 2 (TRAPPC2, also known as SEDL) |
|
* There are several eponymous forms (eg, Nievergelt, Langer). |
|||
|
† There are many different eponymous forms (eg, Jansen, Schmid, McKusick). |
|||
|
AD = autosomal dominant; AR = autosomal recessive; XL = X-linked. |
|||
Diagnosis
Characteristic x-ray changes may be diagnostic. A whole-body x-ray of every affected neonate, even if stillborn, should be taken because diagnostic precision is essential for predicting prognosis.
Prenatal diagnosis by fetoscopy or ultrasonography is possible in some cases (eg, when fetal limb shortening is severe).
Standard laboratory tests do not help, but molecular diagnosis is feasible for chondrodysplasias with known molecular defects. Genetic testing is advised if a diagnosis cannot be made based on clinical grounds or if genetic counseling is desired.
Treatment
In achondroplasia, treatment with human growth hormone is generally not effective. However, treatment with vosoritide (a C-type natriuretic peptide analog) has shown encouraging preliminary results (1) in facilitating bone growth.
An increase in adult height may be achieved by surgical limb-lengthening. Bowlegs can be corrected surgically In achondroplasia and other nonlethal osteochondrodysplasias, surgery (eg, hip replacement) can help improve joint function.
Hypoplasia of the odontoid process can predispose to subluxation of the 1st and 2nd cervical vertebrae and compression of the spinal cord. Therefore, the odontoid process should be evaluated preoperatively and, if it is abnormal, the patient’s head should be carefully supported when hyperextended for endotracheal intubation during anesthesia.
Because the inheritance pattern and gene mutations in most types are known, genetic counseling can be effective. Organizations such as Little People of America provide resources for affected people and act as advocates on their behalf. Similar societies are active in other countries.
Treatment reference
-
1. Savarirayan R, Irving M, Bacino CA, et al: C-type natriuretic peptide analogue therapy in children with achondroplasia. N Engl J Med 381(1):25–35, 2019. doi: 10.1056/NEJMoa1813446
Key Points
-
Osteochondrodysplasias are inherited abnormalities of growth and development of connective tissue, bone, and/or cartilage.
-
There are many types, which differ widely in genetic background, course, and prognosis, but all cause markedly short stature and often disproportionate growth of the trunk and extremities.
-
Diagnosis is by clinical manifestations and identification of characteristic x-ray changes.
-
Growth hormone treatments are typically ineffective.
More Information
The following is an English-language resource that may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
-
Little People of America: An organization providing community resources and medical support and information to people of short stature
