Achondroplasia is a

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

with an autosomal dominant pattern of inheritance whose primary feature is dwarfism. In those with the condition, the arms and legs are short, while the

torso The torso or trunk is an anatomical term for the central part, or the core, of the body of many animals (including humans), from which the head, neck, limbs, tail and other appendages extend. The tetrapod torso — including that of a huma ...

is typically of normal length. Those affected have an average adult height of for males and for females. Other features can include an enlarged head and prominent forehead. Complications can include

sleep apnea Sleep apnea, also spelled sleep apnoea, is a sleep disorder in which pauses in breathing or periods of shallow breathing during sleep occur more often than normal. Each pause can last for a few seconds to a few minutes and they happen many tim ...

or recurrent ear infections. Achondroplasia includes

short-limb skeletal dysplasia with severe combined immunodeficiency Short-limb skeletal dysplasia with severe combined immunodeficiency is an extremely rare autosomal recessive type of achondroplasia which is characterized by short stature, bowing of the long bones, and generalized metaphyseal abnormalities alon ...

. Achondroplasia is caused by a mutation in the

fibroblast growth factor receptor 3 Fibroblast growth factor receptor 3 is a protein that in humans is encoded by the ''FGFR3'' gene. FGFR3 has also been designated as CD333 (cluster of differentiation 333). The gene, which is located on chromosome 4, location q16.3, is expressed in ...

(''FGFR3'')

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

that results in its

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

being overactive. Achondroplasia results in impaired endochondral bone growth (bone growth within cartilage). The disorder has an autosomal dominant mode of inheritance, meaning only one mutated copy of the gene is required for the condition to occur. About 80% of cases occur in children of parents of average stature and result from a new mutation, which most commonly originates as a spontaneous change during spermatogenesis. The rest are inherited from a parent with the condition. The risk of a new mutation increases with the age of the father. In families with two affected parents, children who inherit both affected genes typically die before birth or in early infancy from breathing difficulties. The condition is generally diagnosed based on the clinical features but may be confirmed by genetic testing. Treatments may include support groups and

growth hormone therapy Growth hormone therapy refers to the use of growth hormone (GH) as a prescription medication—it is one form of hormone therapy. Growth hormone is a peptide hormone secreted by the pituitary gland that stimulates growth and cell reproduction. I ...

. Efforts to treat or prevent complications such as

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

hydrocephalus Hydrocephalus is a condition in which an accumulation of cerebrospinal fluid (CSF) occurs within the brain. This typically causes increased pressure inside the skull. Older people may have headaches, double vision, poor balance, urinary inc ...

, obstructive sleep apnea, middle ear infections or

spinal stenosis Spinal stenosis is an abnormal narrowing of the spinal canal or neural foramen that results in pressure on the spinal cord or nerve roots. Symptoms may include pain, numbness, or weakness in the arms or legs. Symptoms are typically gradual i ...

may be required. Achondroplasia is the most common cause of dwarfism and affects about 1 in 27,500 people.

Signs and symptoms

* Disproportionate dwarfism * Shortening of the proximal limbs (called

rhizomelic Rhizomelia refers to either a disproportion of the length of the proximal limb, such as the shortened limbs of achondroplasia, or some other disorder of the hip or shoulder. According to Stedman's medical dictionary "rhizomelic" means "relating to ...

shortening) * 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 ) * Large head with prominent forehead

frontal bossing Skull bossing is a descriptive term in medical physical examination indicating a protuberance of the skull, most often in the frontal bones of the forehead ("frontal bossing"). Although prominence of the skull bones may be normal, skull bossing m ...

* Small midface with a flattened nasal bridge * Spinal

kyphosis Kyphosis is an abnormally excessive convex curvature of the spine as it occurs in the thoracic and sacral regions. Abnormal inward concave ''lordotic'' curving of the cervical and lumbar regions of the spine is called lordosis. It can result ...

(convex curvature) or

lordosis Lordosis is historically defined as an ''abnormal'' inward curvature of the lumbar spine. However, the terms ''lordosis'' and ''lordotic'' are also used to refer to the normal inward curvature of the lumbar and cervical regions of the human spin ...

(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

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. 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. This fluid build up is associated with an enlarged head, vomiting, lethargy, headaches, and irritability. A shunt surgery is commonly performed to treat this condition, but an endoscopic third ventriculostomy can also be done.

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 The psychosocial approach looks at individuals in the context of the combined influence that psychological factors and the surrounding social environment have on their physical and mental wellness and their ability to function. This approach is ...

complications, usually associated with short stature. 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. The life expectancy of people with achondroplasia is approximately 10 years less than average.

Causes

Achondroplasia is caused by a mutation in

(''FGFR3'') gene. 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. 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. 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. The effect is genetically dominant, with one mutant copy 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 (known as a

lethal allele Lethal alleles (also referred to as lethal genes or lethals) are alleles that cause the death of the organism that carries them. They are usually a result of mutations in genes that are essential for growth or development. Lethal alleles may be rec ...

). This occurs due to respiratory failure from an underdeveloped ribcage. A person with achondroplasia thus has a 50% chance of passing dwarfism to each of their offspring. People with achondroplasia are often born to parents that do not have the condition due to

spontaneous mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

. Achondroplasia can be inherited through autosomal dominance. 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 severe or lethal bone

dysplasia Dysplasia is any of various types of abnormal growth or development of cells (microscopic scale) or organs ( macroscopic scale), and the abnormal histology or anatomical structure(s) resulting from such growth. Dysplasias on a mainly microscopi ...

. 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. 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. 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. Research by

urologist Urology (from Greek οὖρον ''ouron'' "urine" and '' -logia'' "study of"), also known as genitourinary surgery, is the branch of medicine that focuses on surgical and medical diseases of the urinary-tract system and the reproductive org ...

Harry Fisch of the Male Reproductive Center at

Columbia Presbyterian Hospital The NewYork-Presbyterian Hospital is a nonprofit academic medical center in New York City affiliated with two Ivy League medical schools, Cornell University and Columbia University. The hospital comprises seven distinct campuses located in the New Y ...

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. There are two other syndromes with a genetic basis similar to achondroplasia:

hypochondroplasia 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, micromeliaupdate 2013 and a head ...

and

thanatophoric dysplasia 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. Symptoms and signs Infants with this condition have disproportionately ...

Diagnosis

Achondroplasia can be detected before birth by

prenatal Prenatal development () includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal devel ...

ultrasound Ultrasound is sound waves with frequencies higher than the upper audible limit of human hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hear it. This limit varies ...

, although signs are often subtle and not apparent before the 24th week of pregnancy. A DNA test can be performed before birth to detect

homozygosity Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. ...

, wherein two copies of the mutant gene are inherited, a lethal condition leading to

stillbirths Stillbirth is typically defined as fetal death at or after 20 or 28 weeks of pregnancy, depending on the source. It results in a baby born without signs of life. A stillbirth can result in the feeling of guilt or grief in the mother. The term ...

. Postnatal diagnosis of achondroplasia is typically uncomplicated, involving an assessment of physical and radiographic features. Clinical features include megalocephaly, short limbs, prominent forehead,

thoracolumbar The vertebral column, also known as the backbone or spine, is part of the axial skeleton. The vertebral column is the defining characteristic of a vertebrate in which the notochord (a flexible rod of uniform composition) found in all chordates ...

kyphosis and mid-face hypoplasia. Complications like dental malocclusion, hydrocephalus and repeated otitis media can be observed. The risk of death in infancy is increased due to the likelihood of compression of the spinal cord with or without upper airway obstruction.

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 spinal canal (or vertebral canal or spinal cavity) is the canal that contains the spinal cord within the vertebral column. The spinal canal is formed by the vertebrae through which the spinal cord passes. It is a process of the dorsal body ca ...

. The iliac wings are small and squared, with a narrow sciatic notch and horizontal acetabular roof. The tubular bones are short and thick with metaphyseal cupping and flaring and irregular growth plates.

Fibular The fibula or calf bone is a leg bone on the lateral side of the tibia, to which it is connected above and below. It is the smaller of the two bones and, in proportion to its length, the most slender of all the long bones. Its upper extremity is ...

overgrowth is present. The hand is broad with short

metacarpals In human anatomy, the metacarpal bones or metacarpus form the intermediate part of the skeletal hand located between the phalanges of the fingers and the carpal bones of the wrist, which forms the connection to the forearm. The metacarpal bones ar ...

and phalanges, and a trident configuration. The ribs are short with cupped anterior ends. If the

radiographic Radiography is an imaging technique using X-rays, gamma rays, or similar ionizing radiation and non-ionizing radiation to view the internal form of an object. Applications of radiography include medical radiography ("diagnostic" and "therapeut ...

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 Hypermobility, also known as double-jointedness, describes joints that stretch farther than normal. For example, some hypermobile people can bend their thumbs backwards to their wrists, bend their knee joints backwards, put their leg behind the h ...

". The diagnosis can be made by fetal

by progressive discordance between the short

femur The femur (; ), or thigh bone, is the proximal bone of the hindlimb in tetrapod vertebrates. The head of the femur articulates with the acetabulum in the pelvic bone forming the hip joint, while the distal part of the femur articulates wit ...

length and biparietal diameter by age. The trident hand configuration can be seen if the fingers are fully extended. Another common characteristic of the syndrome is thoracolumbar gibbus in infancy.

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. After the second year of growth hormone therapy, beneficial bone growth decreases, so the therapy is not a satisfactory long-term treatment. As of December 2020, the treatment of achondroplasia with human growth hormone was approved only in Japan. An experimental drug called

vosoritide Vosoritide, sold under the brand name Voxzogo, is a medication used for the treatment of achondroplasia. The most common side effects include injection site reactions (such as swelling, redness, itching, or pain), vomiting, and decreased blood p ...

has shown promise in stage 3 human trials, although its long-term effects are unknown. Limb-lengthening will increase the length of the legs and arms of someone with achondroplasia, but little medical consensus exists regarding this practice. The age of surgery can vary from early childhood to adulthood. Research has also shown that introducing parents of children with achondroplasia to support and advocacy groups at the time of diagnosis can improve outcomes. Several patient advocacy groups exist to support people with achondroplasia and their families.

Epidemiology

Achondroplasia is one of several congenital conditions with similar presentations, such as

osteogenesis imperfecta Osteogenesis imperfecta (; OI), colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that break easily. The range of symptoms—on the skeleton as well as on the body's other organs—may b ...

, multiple epiphyseal dysplasia tarda,

achondrogenesis Achondrogenesis is a number of disorders that are the most severe form of congenital chondrodysplasia (malformation of bones and cartilage). These conditions are characterized by a small body, short limbs, and other skeletal abnormalities. As a re ...

osteopetrosis 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 ...

, and

. 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. Another study at the same time found a rate of 1 per 10,000. A 2020 review and meta-analysis estimated a worldwide prevalence of 4.6 per 100,000.

Research

, tentative evidence has found that the experimental

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

drug

increases growth velocity in those with achondroplasia. The drug inhibits the activity of ''FGFR3''.

Animals

Based on their disproportionate dwarfism, some dog breeds traditionally have been classified as "achondroplastic". This is the case for the dachshund,

basset hound The Basset Hound is a short-legged breed of dog in the hound family. The Basset is a scent hound that was originally bred for the purpose of hunting hare. Their sense of smell and ability to ''ground-scent'' is second only to the Bloodhound.Har ...

corgi The Welsh Corgi ( or Corgi, plural Corgis, or occasionally the etymologically consistent Corgwn; ) is a small type of herding dog that originated in Wales. The name ''corgi'' is derived from the Welsh words and (which is mutated to ), mean ...

and

bulldog The Bulldog is a British breed of dog of mastiff type. It may also be known as the English Bulldog or British Bulldog. It is of medium size, a muscular, hefty dog with a wrinkled face and a distinctive pushed-in nose.FGF4). 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. 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. 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. 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.

References

External links

* * {{Receptor deficiencies Cell surface receptor deficiencies Connective tissue diseases Growth disorders Rare diseases Dwarfism Wikipedia medicine articles ready to translate