Achondroplasia

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Achondroplasia
Jason Acuna - Wee-Man - Waterfront Marriott, Portland, Oregon - August 15, 2009 - Full Body.jpg
Jason "Wee Man" Acuña, an American actor and stunt performer with achondroplasia
Pronunciation
Specialty Medical genetics
Symptoms Short arms and legs, enlarged head, prominent forehead [3]
Complications Ear infections, hyperlordosis, back pain, spinal stenosis, hydrocephalus [3]
CausesGenetic (autosomal dominant mutation in the FGFR3 gene) [3]
Risk factors Paternal age [4] [3]
Diagnostic method Based on symptoms, genetic testing if uncertain [5]
Differential diagnosis Hypochondroplasia, thanatophoric dysplasia, cartilage-hair hypoplasia, pseudoachondroplasia [5]
Treatment Support groups, growth hormone therapy, treatment of complications [5]
Frequency1 in 27,500 people [3]

Achondroplasia is a genetic disorder with an autosomal dominant pattern of inheritance whose primary feature is dwarfism. [3] It is the most common cause of dwarfism [4] and affects about 1 in 27,500 people. [3] In those with the condition, the arms and legs are short, while the torso is typically of normal length. [3] Those affected have an average adult height of 131 centimetres (4 ft 4 in) for males and 123 centimetres (4 ft) for females. [3] Other features can include an enlarged head with prominent forehead (frontal bossing) [3] and underdevelopment of the midface (midface hypoplasia). [6] Complications can include sleep apnea or recurrent ear infections. [3] Achondroplasia includes the extremely rare short-limb skeletal dysplasia with severe combined immunodeficiency.

Contents

Achondroplasia is caused by a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene that results in its protein being overactive. [3] Achondroplasia results in impaired endochondral bone growth (bone growth within cartilage). [7] The disorder has an autosomal dominant mode of inheritance, meaning only one mutated copy of the gene is required for the condition to occur. [8] About 80% of cases occur in children of parents without the disease, and result from a new (de novo, or sporadic) mutation, which most commonly originates as a spontaneous change during spermatogenesis. [5] The rest are inherited from a parent with the condition. [3] The risk of a new mutation increases with the age of the father. [4] In families with two affected parents, children who inherit both affected genes typically die before birth or in early infancy from breathing difficulties. [3] The condition is generally diagnosed based on the clinical features but may be confirmed by genetic testing. [5] Mutations in FGFR3 also cause achondroplasia related conditions including hypochondroplasia and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans), a rare disorder of bone growth characterized by skeletal, brain, and skin abnormalities resulting in severe short-limb skeletal dysplasia with severe combined immunodeficiency. [9]

Treatments include small molecule therapy with a C-natriuretic peptide analog (vosoritide), 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] Growth hormone therapy may also be used. [5] Efforts to treat or prevent complications such as obesity, hydrocephalus, obstructive sleep apnea, middle ear infections or spinal stenosis may be required. [5] Support groups support people with achondroplasia, including the Little People of America (LPA) and Growing Stronger. Nonprofit physician organizations also exist to disseminate information about treatment and management options, including development of patient resources.

Signs and symptoms

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

Autosomal dominant inheritance Autosomal dominant - en.svg
Autosomal dominant inheritance
Mother and child with achondroplasia with unaffected father, showing inheritance Gould Pyle 161.jpg
Mother and child with achondroplasia with unaffected father, showing inheritance

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 gain of function mutation. The effect is genetically dominant, with one variant of the FGFR3 gene being sufficient to cause achondroplasia, while two copies of the mutant gene are invariably fatal (recessive lethal) before or shortly after birth. This occurs due to respiratory failure from an underdeveloped ribcage. [3] People with achondroplasia are often born to parents that do not have the condition due to spontaneous mutation. [23]

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 spermatogenesis; it has been theorized that sperm carrying the mutation in FGFR3 have a selective advantage over sperm with normal FGFR3. [4] The frequency of mutations in sperm leading to achondroplasia increases in proportion to paternal age, as well as in proportion to exposure to ionizing radiation. [25] The occurrence rate of achondroplasia in the children of fathers over 50 years of age is 1 in 1,875, compared to 1 in 15,000 in the general population. [26] Research by urologist Harry Fisch of the Male Reproductive Center at Columbia Presbyterian Hospital in 2013 indicated that in humans this defect may be exclusively inherited from the father and becomes increasingly probable with paternal age, specifically males reproducing after 35. [27]

There are two other syndromes with a genetic basis similar to achondroplasia: hypochondroplasia and thanatophoric dysplasia.

Diagnosis

Detail of Las Meninas by Diego Velazquez (1656), showing Maribarbola and Nicolasito Pertusato (right), achondroplastic dwarfs in the entourage of Infanta Margarita Las Meninas detail.jpg
Detail of Las Meninas by Diego Velázquez (1656), showing Maribarbola and Nicolasito Pertusato (right), achondroplastic dwarfs in the entourage of Infanta Margarita

Achondroplasia can be detected before birth by prenatal ultrasound, although signs are often subtle and not apparent before the 24th week of pregnancy. [28] A DNA test can be performed before birth to detect homozygosity, wherein two copies of the mutant gene are inherited, a lethal condition leading to stillbirths. Postnatal diagnosis of achondroplasia is typically uncomplicated, involving an assessment of physical and radiographic features. [29] Clinical features include megalocephaly, short limbs, prominent forehead, thoracolumbar kyphosis and mid-face hypoplasia. [30] Complications like dental malocclusion, hydrocephalus and repeated otitis media can be observed. [30] The risk of death in infancy is increased due to the likelihood of compression of the spinal cord with or without upper airway obstruction.[ citation needed ]

Radiologic findings

A skeletal survey is useful to confirm the diagnosis of achondroplasia. The skull is large, with a narrow foramen magnum, and relatively small skull base. The vertebral bodies are short and flattened with relatively large intervertebral disk height, and there is congenitally narrowed spinal canal. The iliac wings are small and squared, with a narrow sciatic notch and horizontal acetabular roof. [31] [32] The tubular bones are short and thick with metaphyseal cupping and flaring and irregular growth plates. [31] Fibular overgrowth is present. The hand is broad with short metacarpals and phalanges, and a trident configuration. The ribs are short with cupped anterior ends. [31] If the radiographic features are not classic, a search for a different diagnosis should be entertained. Because of the extremely deformed bone structure, people with achondroplasia are often "double jointed". The diagnosis can be made by fetal ultrasound by progressive discordance between the short femur length and biparietal diameter by age. The trident hand configuration can be seen if the fingers are fully extended.[ citation needed ]

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, human growth hormone does not help people with achondroplasia, which involve a different hormonal pathway. Usually, the best results appear within the first and second year of therapy. [34] After the second year of growth hormone therapy, beneficial bone growth decreases, [35] so the therapy is not a satisfactory long-term treatment. [34] As of December 2020, the treatment of achondroplasia with human growth hormone was approved only in Japan. [36]

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]

Limb-lengthening will increase the length of the legs and arms of someone with achondroplasia, [39] but little medical consensus exists regarding this practice. The age of surgery can vary from early childhood to adulthood. [40]

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

Munchkin dwarf cat. Munchkin cat grooming.jpg
Munchkin dwarf cat.

Based on their disproportionate dwarfism, some dog breeds traditionally have been classified as "achondroplastic". This is the case for the dachshund, basset hound, corgi and bulldog breeds. [54] [55] [56] Data from whole genome association studies in short-limbed dogs reveal a strong association of this trait with a retro-gene coding for fibroblast growth factor 4 (FGF4). [57] Therefore, it seems unlikely that dogs and humans are achondroplastic for the same reasons. However, histological studies in some achondroplastic dog breeds have shown altered cell patterns in cartilage that are very similar to those observed in humans exhibiting achondroplasia. [58]

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. [59] This involved a mutation of the protein collagen, type X, alpha 1, encoded by the COL10A1 gene. In humans a similar mutation (G595E) has been associated with Schmid metaphyseal chondrodysplasia (SMCD), a relatively mild skeletal disorder that is also associated with dwarfism.[ citation needed ]

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

Related Research Articles

<span class="mw-page-title-main">Dwarfism</span> Small size of an organism, caused by growth deficiency or genetic mutations

Dwarfism is a condition wherein an organism is exceptionally small, and mostly occurs in the animal kingdom. In humans, it is sometimes defined as an adult height of less than 147 centimetres, regardless of sex; the average adult height among people with dwarfism is 120 centimetres (4 ft). Disproportionate dwarfism is characterized by either short limbs or a short torso. In cases of proportionate dwarfism, both the limbs and torso are unusually small. Intelligence is usually normal, and most have a nearly normal life expectancy. People with dwarfism can usually bear children, though there are additional risks to the mother and child depending upon the underlying condition.

<span class="mw-page-title-main">Osteopetrosis</span> Rare disease of the bones

Osteopetrosis, literally "stone bone", also known as marble bone disease or Albers-Schönberg disease, is an extremely rare inherited disorder whereby the bones harden, becoming denser, in contrast to more prevalent conditions like osteoporosis, in which the bones become less dense and more brittle, or osteomalacia, in which the bones soften. Osteopetrosis can cause bones to dissolve and break.

<span class="mw-page-title-main">Thanatophoric dysplasia</span> Severe form of genetic dwarfism that is usually lethal

Thanatophoric dysplasia is a severe skeletal disorder characterized by a disproportionately small ribcage, extremely short limbs and folds of extra skin on the arms and legs.

Short stature refers to a height of a human which is below typical. Whether a person is considered short depends on the context. Because of the lack of preciseness, there is often disagreement about the degree of shortness that should be called short. Dwarfism is the condition of being very short, often caused by a medical condition. In a medical context, short stature is typically defined as an adult height that is more than two standard deviations below a population’s mean for age and sex, which corresponds to the shortest 2.3% of individuals in that population.

<span class="mw-page-title-main">Hypochondroplasia</span> Medical condition

Hypochondroplasia (HCH) is a developmental disorder caused by an autosomal dominant genetic defect in the fibroblast growth factor receptor 3 gene (FGFR3) that results in a disproportionately short stature, micromelia and a head that appears large in comparison with the underdeveloped portions of the body. It is classified as short-limbed dwarfism.

Chondrodystrophy refers to a skeletal disorder caused by one of myriad genetic mutations that can affect the development of cartilage. As a very general term, it is only used in the medical literature when a more precise description of the condition is unavailable.

Crouzonodermoskeletal syndrome is a disorder characterized by the premature joining of certain bones of the skull (craniosynostosis) during development and a skin condition called acanthosis nigricans.

An osteochondrodysplasia, or skeletal dysplasia, is a disorder of the development of bone and cartilage. Osteochondrodysplasias are rare diseases. About 1 in 5,000 babies are born with some type of skeletal dysplasia. Nonetheless, if taken collectively, genetic skeletal dysplasias or osteochondrodysplasias comprise a recognizable group of genetically determined disorders with generalized skeletal affection. These disorders lead to disproportionate short stature and bone abnormalities, particularly in the arms, legs, and spine. Skeletal dysplasia can result in marked functional limitation and even mortality.

<span class="mw-page-title-main">Multiple epiphyseal dysplasia</span> Rare genetic disorder

Multiple epiphyseal dysplasia (MED), also known as Fairbank's disease, is a rare genetic disorder that affects the growing ends of bones. Long bones normally elongate by expansion of cartilage in the growth plate near their ends. As it expands outward from the growth plate, the cartilage mineralizes and hardens to become bone (ossification). In MED, this process is defective.

<span class="mw-page-title-main">Pseudoachondroplasia</span> Inherited disorder of bone growth

Pseudoachondroplasia is an inherited disorder of bone growth. It is a genetic autosomal dominant disorder. It is generally not discovered until 2–3 years of age, since growth is normal at first. Pseudoachondroplasia is usually first detected by a drop of linear growth in contrast to peers, a waddling gait or arising lower limb deformities.

<span class="mw-page-title-main">Fibroblast growth factor receptor 3</span> Gene involved in the most common form of dwarfism

Fibroblast growth factor receptor 3 is a protein that in humans is encoded by the FGFR3 gene. FGFR3 has also been designated as CD333. The gene, which is located on chromosome 4, location p16.3, is expressed in tissues such as the cartilage, brain, intestine, and kidneys.

<span class="mw-page-title-main">Boomerang dysplasia</span> Medical condition

Boomerang dysplasia is a lethal form of osteochondrodysplasia known for a characteristic congenital feature in which bones of the arms and legs are malformed into the shape of a boomerang. Death usually occurs in early infancy due to complications arising from overwhelming systemic bone malformations.

<span class="mw-page-title-main">Parastremmatic dwarfism</span> Medical condition

Parastremmatic dwarfism is a rare bone disease that features severe dwarfism, thoracic kyphosis, a distortion and twisting of the limbs, contractures of the large joints, malformations of the vertebrae and pelvis, and incontinence. The disease was first reported in 1970 by Leonard Langer and associates; they used the term parastremmatic from the Greek parastremma, or distorted limbs, to describe it. On X-rays, the disease is distinguished by a "flocky" or lace-like appearance to the bones. The disease is congenital, which means it is apparent at birth. It is caused by a mutation in the TRPV4 gene, located on chromosome 12 in humans. The disease is inherited in an autosomal dominant manner.

<span class="mw-page-title-main">Eiken syndrome</span> Medical condition

Eiken syndrome, also known as "Eiken skeletal dysplasia", is a rare autosomal bone dysplasia with a skeletal phenotype which has been described in a unique consanguineous family, where it segregates as a recessive trait. First described in 1985, the syndrome primarily affects the development of bones, leading to short stature, long limbs, and joint dislocations. Eiken syndrome is caused by mutations in the PTH1R gene, located on chromosome 3, and is involved in skeletal development.

Langer Mesomelic Dysplasia (LMD) is a rare congenital disorder characterised by altered bone formation, which typically causes affected individuals to experience shortening of the bones of the extremities as well as an abnormally short stature.

Vosoritide, sold under the brand name Voxzogo, is a medication used for the treatment of achondroplasia.

Acromesomelic dysplasia is a rare skeletal disorder that causes abnormal bone and cartilage development, leading to shortening of the forearms, lower legs, hands, feet, fingers, and toes. Five different genetic mutations have been implicated in the disorder. Treatment is individualized but is generally aimed at palliating symptoms, for example, treatment of kyphosis and lumbar hyperlordosis.

<span class="mw-page-title-main">Severe achondroplasia with developmental delay and acanthosis nigricans</span> Medical condition

Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) is a very rare genetic disorder. This disorder is one that affects bone growth and is characterized by skeletal, brain, and skin abnormalities. Those affected by the disorder are severely short in height and commonly possess shorter arms and legs. In addition, the bones of the legs are often bowed and the affected have smaller chests with shorter rib bones, along with curved collarbones. Other symptoms of the disorder include broad fingers and extra folds of skin on the arms and legs. Developmentally, many individuals who suffer from the disorder show a higher level in delays and disability. Seizures are also common due to structural abnormalities of the brain. Those affected may also suffer with apnea, the slowing or loss of breath for short periods of time.

<span class="mw-page-title-main">Schneckenbecken dysplasia</span> Medical condition

Schneckenbecken dysplasia is a rare pre-natally fatal hereditary autosomal recessive condition which affects the bones and pre-natal growth.

<span class="mw-page-title-main">Spondyloenchondrodysplasia</span> Medical condition

Spondyloenchondrodysplasia is the medical term for a rare spectrum of symptoms that are inherited following an autosomal recessive inheritance pattern. Skeletal anomalies are the usual symptoms of the disorder, although its phenotypical nature is highly variable among patients with the condition, including symptoms such as muscle spasticity or thrombocytopenia purpura. It is a type of immunoosseous dysplasia.

References

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  24. ↑ "Achondroplasia" . Retrieved 26 September 2018.
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  26. ↑ Kovac JR, Addai J, Smith RP, Coward RM, Lamb DJ, Lipshultz LI (November 2013). "The effects of advanced paternal age on fertility". Asian Journal of Andrology. 15 (6): 723–728. doi:10.1038/aja.2013.92. PMC   3854059 . PMID   23912310.
  27. ↑ Harry Fisch (24 September 2013). The Male Biological Clock: The Startling News About Aging, Sexuality, and Fertility in Men. Simon and Schuster. pp. 11–. ISBN   978-1-4767-4082-9.
  28. ↑ Savarirayan R, et al. (2021). "International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia". Nature Reviews Endocrinology. 18 (3): 173–189. doi: 10.1038/s41574-021-00595-x . PMID   34837063. S2CID   244638495. Ultrasound findings of achondroplasia are generally not apparent until 24 weeks of gestation and are often quite subtle.
  29. ↑ Savarirayan R, et al. (2021). "International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia". Nature Reviews Endocrinology. 18 (3): 173–189. doi: 10.1038/s41574-021-00595-x . PMID   34837063. S2CID   244638495. 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.
  30. 1 2 Beattie, R.M., Champion, M.P., eds. (2004). Essential questions in paediatrics for MRCPCH (1st ed.). Knutsford, Cheshire: PasTest. ISBN   978-1-901198-99-7.
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