Osteochondrodysplasias are a heterogenous group of > 350 disorders associated with skeletal maldevelopment and varying degrees of dwarfism or short stature. Diagnosis is by radiography and, in some cases, genetic testing. Treatment is sometimes with vosoritide or surgery.Osteochondrodysplasias are a heterogenous group of > 350 disorders associated with skeletal maldevelopment and varying degrees of dwarfism or short stature. Diagnosis is by radiography and, in some cases, genetic testing. Treatment is sometimes with vosoritide or surgery.
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 Selected Types of Osteochondrodysplasias).
Osteochondrodysplasias are classified based on the causative gene defect, biochemical pathway, or clinical and radiographic features (1). See table Selected Types of Osteochondrodysplasias.
Dwarfism is markedly short stature (adult height < 147 cm [4 ft 10 in]) that is 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 (2). 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 typically during the neonatal period.
Selected Types of Osteochondrodysplasias
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 Radiographs 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 first 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 flat facies Heterogeneous | AD, AR, or XL recessive | Type II collagen (COL2A1), tracking protein particle complex, subunit 2 (TRAPPC2, also known as SEDL) |
Thanatophoric dwarfism | Severe limb shortening Chest wall deformity Respiratory insufficiency | AD (but most cases result from de novo mutations) | FGFR3 |
* 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. | |||
General references
1. Mortier GR, Cohn DH, Cormier-Daire V, et al. Nosology and classification of genetic skeletal disorders: 2019 revision. Am J Med Genet A. 2019;179(12):2393-2419. doi:10.1002/ajmg.a.61366
2. Krakow D, Rimoin DL. The skeletal dysplasias. Genet Med. 2010;12(6):327-341. doi:10.1097/GIM.0b013e3181daae9b
Diagnosis of Osteochondrodysplasias
Radiographs
Sometimes genetic testing
Characteristic changes on radiographs may be diagnostic. A whole-body radiograph of every affected neonate, even if stillborn, should be taken because diagnostic precision is essential for predicting prognosis as well as for genetic counseling regarding future pregnancies.
Prenatal diagnosis by ultrasound is possible in some cases (eg, when fetal limb shortening is severe).
Standard laboratory tests do not help, but molecular diagnosis may be diagnostic for osteochondrodysplasias 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 of Osteochondrodysplasias
Sometimes surgical limb-lengthening, surgical correction of genu varum, or joint replacement
Sometimes vosoritideSometimes vosoritide
In achondroplasia, treatment with human growth hormone is generally not effective.
An increase in adult height may be achieved by surgical limb-lengthening. Genu varum (bowlegs) can be corrected surgically. In achondroplasia and other nonlethal osteochondrodysplasias, surgery (eg, hip replacement) can help improve joint function (1).
Hypoplasia of the odontoid process can predispose to subluxation of the first and second 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 for reproductive purposes can be important.
Vosoritide (a C-type natriuretic peptide analog) improves linear bone growth in pediatric patients with achondroplasia who have open epiphyses (Vosoritide (a C-type natriuretic peptide analog) improves linear bone growth in pediatric patients with achondroplasia who have open epiphyses (2, 3, 4). Whether final adult height will also increase and the adverse effects of long-term therapy are not known.
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 references
1. Krakow D, Rimoin DL. The skeletal dysplasias. Genet Med. 2010;12(6):327-341. doi:10.1097/GIM.0b013e3181daae9b
2. Savarirayan R, Irving M, Bacino CA, et al. C-type natriuretic peptide analogue therapy in children with achondroplasia. N Engl J Med. 2019;381(1):25–35. doi:10.1056/NEJMoa1813446
3. Savarirayan R, Tofts L, Irving M, et al. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial [published correction appears in Lancet. 2020 Oct 10;396(10257):1070. doi: 10.1016/S0140-6736(20)32074-2.]. Lancet. 2020;396(10252):684-692. doi:10.1016/S0140-6736(20)31541-5
4. Cormier-Daire V, Edouard T, Isidor B, et al. Real-World Safety and Effectiveness of Vosoritide in Children with Achondroplasia: French Early Access Program. Horm Res Paediatr. Published online January 25, 2025. doi:10.1159/000543743
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 cause, course, and prognosis, but all cause markedly short stature and often disproportionate growth of the trunk and extremities.
Diagnosis is by genetic testing, clinical manifestations, and identification of characteristic changes on radiographs.
Growth hormone treatments are typically ineffective.
Vosoritide may be used to increase linear bone growth in patients with achondroplasia whose epiphyses are still open.Vosoritide may be used to increase linear bone growth in patients with achondroplasia whose epiphyses are still open.
More Information
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