Achondroplasia
Achondroplasia | |
---|---|
Support groups, growth hormone therapy, treatment of complications[5] | |
Frequency | 1 in 27,500 people[3] |
Achondroplasia is a
Achondroplasia is caused by a mutation in the
Treatments include small molecule therapy with a C-natriuretic peptide analog (
Signs and symptoms
- Disproportionate dwarfism
- Shortening of the proximal limbs (called rhizomelicshortening)
- Short fingers and toes, with "trident hands" (short hands with stubby fingers, and a separation between the middle and ring fingers – reminiscent of a trident on fetal ultrasound [11])
- Large head with prominent forehead frontal bossing
- Small midface with a flattened nasal bridge
- Spinal kyphosis (convex curvature) or lordosis (concave curvature)
- Varus (bowleg) or valgus (knock knee) deformities
- Frequent ear infections (due to Eustachian tube blockages), sleep apnea (which can be central or obstructive), and hydrocephalus
Complications
Children
Children with achondroplasia often have less muscle tone; because of this it is common for them to have delayed walking and motor skills. It is also common for children to have bowed legs, scoliosis, lordosis, arthritis, issues with joint flexibility, breathing problems, ear infections, and crowded teeth.[12] These issues can be treated with surgery, braces, or physical therapy.
Hydrocephalus is a severe effect associated with achondroplasia in children. This condition occurs when cerebrospinal fluid is not able to flow in and out of the skull because of how the spine narrows.[13] This fluid build up is associated with an enlarged head, vomiting, lethargy, headaches, and irritability.[14] A shunt surgery is commonly performed to treat this condition, but an endoscopic third ventriculostomy can also be done.[15]
Adults
Adults with achondroplasia often face issues with obesity and sleep apnea. It is also typical for adults to experience numbness or tingling in their legs because of nerve compression.
Some research has found that adults with achondroplasia may also experience psychosocial complications, usually associated with short stature.[16][17]
Pregnancy in women with achondroplasia is considered higher risk. Women with achondroplasia generally have their babies delivered through C-sections to prevent complications that could occur with a natural birth.[18] Intelligence and life span are usually near normal, although craniocervical junction compression increases the risk of death in infancy.[19]
Causes
Achondroplasia is caused by a mutation in fibroblast growth factor receptor 3 (FGFR3) gene.[20] This gene encodes a protein called fibroblast growth factor receptor 3, which contributes to the production of collagen and other structural components in tissues and bones.[21] When the FGFR3 gene is mutated it interferes with how this protein interacts with growth factors leading to complications with bone production. Cartilage is not able to fully develop into bone, causing the individual to be disproportionately shorter in height.[22]
In normal development, FGFR3 has a negative regulatory effect on bone growth. In achondroplasia, the mutated form of the receptor is constitutively active, and this leads to severely shortened bones. This is an example of a
Where achondroplasia is inherited, its pattern is autosomal dominant. In couples where one partner has achondroplasia there is a 50% chance of passing the disorder on to their child every pregnancy. In situations where both parents have achondroplasia there is a 50% chance the child will have achondroplasia, 25% chance the child will not, and a 25% chance that the child will inherit the gene from both parents resulting in double dominance and leading to lethal bone dysplasia.[24]
Studies have demonstrated that new gene mutations for achondroplasia are exclusively inherited from the father and occur during
There are two other syndromes with a genetic basis similar to achondroplasia: hypochondroplasia and thanatophoric dysplasia.
Diagnosis
Achondroplasia can be detected before birth by
Radiologic findings
A skeletal survey is useful to confirm the diagnosis of achondroplasia. The skull is large, with a narrow
Another common characteristic of the syndrome is thoracolumbar gibbus in infancy.[33]
Treatment
There is no known cure for achondroplasia even though the cause of the mutation in the growth factor receptor has been found. Although used by those without achondroplasia to aid in growth,
Small molecule therapy with a C-natriurtic peptide analog (vosoritide) is approved to improve growth velocity in children with achondroplasia based on results in Phase 3 human trials, although its long-term effects are unknown.[10] Vosoritide inhibits the activity of FGFR3.[37] In October 2023, the FDA approved and expanded the use of vosoritide, a once-daily injection for the treatment of children under the age of 5 with achondroplasia. It had previously been approved in 2021 for treating the genetic disorder in children aged five and older under the FDA's accelerated approval pathway.[38]
Research has also shown that introducing parents of children with achondroplasia to support and advocacy groups at the time of diagnosis can improve outcomes.[41] Several patient advocacy groups exist to support people with achondroplasia and their families.[42] Resources are available to support patients and their caregivers with information that they can distribute to their physicians, who may not be familiar with the unique medical requirements of managing achondroplasia. Physician-oriented best practice guidelines are also available to guide physicians managing the spinal disorders,[43] foramen magnum stenosis,[44] craniofacial implications,[45] pregnancy,[46] and peri-operative[47] needs of people with achondroplasia.
Epidemiology
Achondroplasia is one of several congenital conditions with similar presentations, such as osteogenesis imperfecta, multiple epiphyseal dysplasia tarda, achondrogenesis, osteopetrosis, and thanatophoric dysplasia. This makes estimates of prevalence difficult, with changing and subjective diagnostic criteria over time. One detailed and long-running study in the Netherlands found that the prevalence determined at birth was only 1.3 per 100,000 live births.[48] Another study at the same time found a rate of 1 per 10,000.[48] A 2020 review and meta-analysis estimated a worldwide prevalence of 4.6 per 100,000.[49]
Psychological and social aspects
In addition to physical challenges, individuals with achondroplasia may also experience psychological challenges such as fear or negative perception of individuals with achondroplasia. Gollust et al have indicated that adults with achondroplasia tend to have lower self-esteem, annual income, educational attainment, and overall quality of life (QOL) when compared to their unaffected siblings.[50] Interestingly, the Golust study revealed that the subjects were as likely to cite disadvantages relating to social barriers as those relating to health issues and functioning.
On the other hand, other investigators, such as Ancona, state that for many individuals in immediate environments that have natural acceptance of the condition from the beginning, their main challenge lies in adapting to a world designed for those without the condition. However, when society rejects the condition from the start and associates it with destructive anxiety, it significantly damages the individual's self-image and leads to their social exclusion. Thus, the author hypothesizes, an accepting environment is crucial to prevent significant suffering for individuals with achondroplasia and to ensure the best outcomes for corrective interventions, rather than perpetuating rejection. [51]
Similarly, a study conducted in Japan by Nishimura and Hanaki found that children with achondroplasia faced challenges related to their short stature, but there was no indication of psychosocial maladjustment. They hypothesized that focusing on coping strategies and self-efficacy may play a crucial role in promoting psychological well-being among children with achondroplasia.[52]
Social support and peer connections can be important for individuals with achondroplasia. Support groups, online communities, and advocacy organizations can provide a sense of belonging and can help individuals with achondroplasia connect with others who understand their experiences. Additionally, these communities can serve as a resource for information and support for both individuals with achondroplasia and their families. In the United States, The Little People of America (LPA) is a national organization that provides support, resources, and advocacy for individuals with dwarfism, including achondroplasia.[53]
Animals
Based on their disproportionate dwarfism, some dog breeds traditionally have been classified as "achondroplastic". This is the case for the
A similar form of achondroplasia was found in a litter of piglets from a phenotypically normal Danish sow. The dwarfism was inherited dominant in the offspring from this litter. The piglets were born phenotypically normal but became more and more symptomatic as they reached maturity.
The now extinct Ancon sheep was created by humans through the selective breeding of common domestic sheep with achondroplasia. The average-sized torso combined with the relatively smaller legs produced by achondroplasia was valued for making affected sheep less likely to escape without affecting the amount of wool or meat each sheep produced.[60]
See also
References
- ^ "Achondroplasia". Lexico UK English Dictionary. Oxford University Press. Archived from the original on 11 December 2019.
- ^ "Achondroplasia". Merriam-Webster.com Dictionary.
- ^ a b c d e f g h i j k l m n o "Achondroplasia". Genetics Home Reference. May 2012. Retrieved 12 December 2017.
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- ^ "Achondroplasia". Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. 2016. Retrieved 12 December 2017.
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- ^ "Trident hand". Radiopaedia. Retrieved 31 May 2022.
- ^ "Dwarfism". kidshealth.org. Retrieved 26 September 2018.
- ^ "Achondroplasia | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 26 September 2018.
- ^ Kieffer S. "Achondroplasia | Johns Hopkins Pediatric Neurosurgery". Retrieved 26 September 2018.
- ^ "Hydrocephalus – Diagnosis and treatment – Mayo Clinic". mayoclinic.org. Retrieved 26 September 2018.
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- ^ Services Do. "Dwarfism". Retrieved 26 September 2018.
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- ^ "Learning About Achondroplasia". National Human Genome Research Institute (NHGRI). Retrieved 26 September 2018.
- ^ Reference GH. "FGFR3 gene". Genetics Home Reference. Retrieved 26 September 2018.
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Ultrasound findings of achondroplasia are generally not apparent until 24 weeks of gestation and are often quite subtle.
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The postnatal diagnosis of achondroplasia is fairly straightforward. A combination of key clinical (that is, macrocephaly, short limbed-short stature with rhizomelia and redundant skin folds) and radiographic (that is, characteristic pelvis with short and square ilia, narrow sacro-sciatic notches and narrowing interpedicular distances in the lumbar vertebral spine progressing from L1 to L5) features enables accurate diagnosis in most people with achondroplasia.
- ^ ISBN 978-1-901198-99-7.
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- ^ "Achondroplasia Pelvis". Archived from the original on 22 October 2007. Retrieved 28 November 2007.
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Spinal thoracolumbar kyphosis (gibbus) in infants with achondroplasia is common but should resolve when the child begins to mobilize.
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One therapy offered to ACH patients is treatment with recombinant human growth (r-hGH) (approved today only in Japan).
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- ^ Jain P (20 October 2023). "BioMarin's dwarfism therapy gets FDA nod for expanded use". Reuters. Retrieved 24 October 2023.
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Although evidence in this area is scarce, limb lengthening is advised in some countries and not recommended in others. … The timing of limb lengthening varies and has been performed from early childhood to adult life in individuals with achondroplasia.
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Introducing parents to advocacy and support groups has been proven beneficial.
- ^ "Associations". Beyond Achondroplasia. Retrieved 2 January 2022.
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External links
- Achondroplasia at Curlie
- Pauli RM (1998). "Achondroplasia". In Pagon RA, Bird TD, Dolan CR, et al. (eds.). GeneReviews. Seattle WA: University of Washington, Seattle. PMID 20301331. NBK1152.