Dwarfism, is defined as a condition of being short in stature, reaching an adult height of 4 feet 10 inches or less and can have many causes.
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Achondroplasia is the most common form of dwarfism. People with achondroplasia have disproportionate bone growth, resulting in the development of disproportionately short limbs, a large head, and small fingers. Around a quarter of a million people around the world are diagnosed with achondroplasia, with roughly 1 child in 25,000 live births affected.
The impact of the disorder can be significant. In addition to being short-statured, people with achondroplasia may suffer from a range of health problems including; limited mobility at the elbows, recurrent ear infections, apnea, which causes interruptions to breathing, and lordosis, which is the result of the spine curving inwards.
They may also suffer from more severe problems including a narrowing of the spinal canal that compresses the upper part of the spinal cord, leading to a buildup of fluid in the brain known as hydrocephalus. In some cases, achondroplasia causes delayed motor development however, cognition and intelligence are unaffected.
The genetics underlying achondroplasia
Studies have shown that 95% of people with achondroplasia have a point mutation of the fibroblast growth factor receptor 3 (FGRF3) gene and 80% of these mutations are of de novo origin as it is autosomal dominant in inheritance.
Research has revealed two specific mutations of the FGFR3 gene that underly almost 100% of cases of achondroplasia.
The FGFR3 gene plays a vital role in bone growth and maintenance and in achondroplasia, mutations lead to a gain in function within the FGFR3 gene, causing overactivity. As a result, the normal processes of the growing skeleton and other tissues are inhibited causing complications in bone formation.
Currently, research is investigating the mechanisms of disease such as the pathogenic pathways to elucidate possible treatments for children born with achondroplasia.
Historically, research into the disorder has focused on how it progresses in childhood and adolescence, researchers are now seeking to define it fully in adults and develop prevention therapies that could be used early on, improving the progression of the disorder.
Possible future treatments of achondroplasia
While achondroplasia is not generally considered to be life-threatening, numerous studies have investigated mortality rates in the disorder. Findings highlighted the prevalence of cases of sudden death and elevated mortality rates in achondroplasia, especially in children.
It is now accepted that achondroplasia has an increased mortality rate and research has investigated the cause. The data demonstrated that children with achondroplasia who are under four years of age are more likely to suffer from acute brainstem compression, which is the leading cause of mortality in this age group, whereas adults are at greater risk of cardiovascular deaths.
As knowledge of achondroplasia has advanced over the past few decades, the causes of death have changed. Previously, pneumonia or hydrocephalus were more prevalent causes of sudden death, whereas now, cardiovascular, cerebrovascular, and accidental deaths are more common. Interestingly, vehicular accidents pose a more significant risk to adults with achondroplasia.
These findings lead to the development of effective new preventions and treatments of the disorder. Most current research focuses on establishing new treatments such as chemical inhibition of receptor signaling, modulating the downstream propagation of FGFR3 signals, and antibody blockade of receptor activation.
References:
- Baujat, G., Legeai-Mallet, L., Finidori, G., Cormier-Daire, V., & Le Merrer, M. (2008). Achondroplasia. Best Practice & Research Clinical Rheumatology, 22(1), 3-18.
- Hashmi, S., Gamble, C., Hoover-Fong, J., Alade, A., Pauli, R., Modaff, P., Carney, M., Brown, C., Bober, M. and Hecht, J. (2018). Multicenter study of mortality in achondroplasia. American Journal of Medical Genetics Part A, 176(11), pp.2359-2364.
- Horton, W., Hall, J., and Hecht, J. (2007). Achondroplasia. The Lancet, 370(9582), pp.162-172.
- Langer Jr, L. O., Baumann, P. A., & Gorlin, R. J. (1967). Achondroplasia. American Journal of Roentgenology, 100(1), 12-26.
- Shiang, R., Thompson, L., Zhu, Y., Church, D., Fielder, T., Bocian, M., Winokur, S. and Wasmuth, J. (1994). Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell, 78(2), pp.335-342.
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