Achondroplasia

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Achondroplasia_table_infobox_0

AchondroplasiaAchondroplasia_header_cell_0_0_0
PronunciationAchondroplasia_header_cell_0_1_0 Achondroplasia_cell_0_1_1
SpecialtyAchondroplasia_header_cell_0_2_0 Medical geneticsAchondroplasia_cell_0_2_1
SymptomsAchondroplasia_header_cell_0_3_0 Short arms and legs, enlarged head, prominent foreheadAchondroplasia_cell_0_3_1
ComplicationsAchondroplasia_header_cell_0_4_0 Ear infections, hyperlordosis, back pain, spinal stenosis, hydrocephalusAchondroplasia_cell_0_4_1
CausesAchondroplasia_header_cell_0_5_0 Genetic (autosomal dominant mutation in the FGFR3 gene)Achondroplasia_cell_0_5_1
Risk factorsAchondroplasia_header_cell_0_6_0 Paternal ageAchondroplasia_cell_0_6_1
Diagnostic methodAchondroplasia_header_cell_0_7_0 Based on symptoms, genetic testing if uncertainAchondroplasia_cell_0_7_1
Differential diagnosisAchondroplasia_header_cell_0_8_0 Hypochondroplasia, thanatophoric dysplasia, cartilage-hair hypoplasia, pseudoachondroplasiaAchondroplasia_cell_0_8_1
TreatmentAchondroplasia_header_cell_0_9_0 Support groups, growth hormone therapy, treatment of complicationsAchondroplasia_cell_0_9_1
PrognosisAchondroplasia_header_cell_0_10_0 10 year shorter life expectancyAchondroplasia_cell_0_10_1
FrequencyAchondroplasia_header_cell_0_11_0 1 in 27,500 peopleAchondroplasia_cell_0_11_1

Achondroplasia is a genetic disorder whose primary feature is dwarfism. Achondroplasia_sentence_0

In those with the condition, the arms and legs are short, while the torso is typically of normal length. Achondroplasia_sentence_1

Those affected have an average adult height of 131 centimetres (4 ft 4 in) for males and 123 centimetres (4 ft) for females. Achondroplasia_sentence_2

Other features include an enlarged head and prominent forehead. Achondroplasia_sentence_3

Complications can include sleep apnea or recurrent ear infections. Achondroplasia_sentence_4

The disorder does not generally affect intelligence. Achondroplasia_sentence_5

Achondroplasia is caused by a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene that results in its protein being overactive. Achondroplasia_sentence_6

The disorder has an autosomal dominant mode of inheritance, meaning only one mutated copy of the gene is required for the condition to occur. Achondroplasia_sentence_7

About 80% of cases result from a new mutation, which originates in the father's sperm. Achondroplasia_sentence_8

The rest are inherited from a parent with the condition. Achondroplasia_sentence_9

The risk of a new mutation increases with the age of the father. Achondroplasia_sentence_10

In families with two affected parents, children who inherit both affected genes typically die before birth or in early infancy from breathing difficulties. Achondroplasia_sentence_11

The condition is generally diagnosed based on the symptoms but may be confirmed by genetic testing. Achondroplasia_sentence_12

Treatments may include support groups and growth hormone therapy. Achondroplasia_sentence_13

Efforts to treat or prevent complications such as obesity, hydrocephalus, obstructive sleep apnea, middle ear infections or spinal stenosis may be required. Achondroplasia_sentence_14

Life expectancy of those affected is about 10 years less than average. Achondroplasia_sentence_15

Achondroplasia is the most common cause of dwarfism and affects about 1 in 27,500 people. Achondroplasia_sentence_16

The shortest known adult with the condition is Jyoti Amge, at 62.8 centimetres (2 ft 0.7 in). Achondroplasia_sentence_17

Signs and symptoms Achondroplasia_section_0

Achondroplasia_unordered_list_0

  • Disproportionate dwarfismAchondroplasia_item_0_0
  • Shortening of the proximal limbs (called rhizomelic shortening)Achondroplasia_item_0_1
  • Short fingers and toes with trident handsAchondroplasia_item_0_2
  • Large head with prominent forehead frontal bossingAchondroplasia_item_0_3
  • Small midface with a flattened nasal bridgeAchondroplasia_item_0_4
  • Spinal kyphosis (convex curvature) or lordosis (concave curvature)Achondroplasia_item_0_5
  • Varus (bowleg) or valgus (knock knee) deformitiesAchondroplasia_item_0_6
  • Frequent ear infections (due to Eustachian tube blockages), sleep apnea (which can be central or obstructive), and hydrocephalusAchondroplasia_item_0_7

Causes Achondroplasia_section_1

Achondroplasia is caused by a mutation in fibroblast growth factor receptor 3 (FGFR3) gene. Achondroplasia_sentence_18

This gene is mainly responsible for making the protein, fibroblast growth factor receptor 3. Achondroplasia_sentence_19

This protein contributes to the production of collagen and other structural components in tissues and bones. Achondroplasia_sentence_20

When the FGFR3 gene is mutated it interferes with how this protein interacts with growth factors leading to complications with bone production. Achondroplasia_sentence_21

Cartilage is not able to fully develop into bone, causing the individual to be disproportionately shorter in height. Achondroplasia_sentence_22

In normal development FGFR3 has a negative regulatory effect on bone growth. Achondroplasia_sentence_23

In achondroplasia, the mutated form of the receptor is constitutively active and this leads to severely shortened bones. Achondroplasia_sentence_24

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). Achondroplasia_sentence_25

This occurs due to respiratory failure from an underdeveloped ribcage. Achondroplasia_sentence_26

A person with achondroplasia thus has a 50% chance of passing dwarfism to each of their offspring. Achondroplasia_sentence_27

People with achondroplasia can be born to parents that do not have the condition due to spontaneous mutation. Achondroplasia_sentence_28

Achondroplasia can be inherited through autosomal dominance. Achondroplasia_sentence_29

In couples where one partner has achondroplasia there is a 50% chance of passing the disorder onto their child every pregnancy. Achondroplasia_sentence_30

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. Achondroplasia_sentence_31

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. Achondroplasia_sentence_32

The frequency of mutations in sperm leading to achondroplasia increase in proportion to paternal age, as well as in proportion to exposure to ionizing radiation. Achondroplasia_sentence_33

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. Achondroplasia_sentence_34

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. Achondroplasia_sentence_35

There are two other syndromes with a genetic basis similar to achondroplasia: hypochondroplasia and thanatophoric dysplasia. Achondroplasia_sentence_36

Diagnosis Achondroplasia_section_2

Achondroplasia can be detected before birth by prenatal ultrasound. Achondroplasia_sentence_37

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. Achondroplasia_sentence_38

Clinical features include megalocephaly, short limbs, prominent forehead, thoracolumbar kyphosis and mid-face hypoplasia. Achondroplasia_sentence_39

Complications like dental malocclusion, hydrocephalus and repeated otitis media can be observed. Achondroplasia_sentence_40

The risk of death in infancy is increased due to the likelihood of compression of the spinal cord with or without upper airway obstruction. Achondroplasia_sentence_41

Radiologic findings Achondroplasia_section_3

A skeletal survey is useful to confirm the diagnosis of achondroplasia. Achondroplasia_sentence_42

The skull is large, with a narrow foramen magnum, and relatively small skull base. Achondroplasia_sentence_43

The vertebral bodies are short and flattened with relatively large intervertebral disk height, and there is congenitally narrowed spinal canal. Achondroplasia_sentence_44

The iliac wings are small and squared, with a narrow sciatic notch and horizontal acetabular roof. Achondroplasia_sentence_45

The tubular bones are short and thick with metaphyseal cupping and flaring and irregular growth plates. Achondroplasia_sentence_46

Fibular overgrowth is present. Achondroplasia_sentence_47

The hand is broad with short metacarpals and phalanges, and a trident configuration. Achondroplasia_sentence_48

The ribs are short with cupped anterior ends. Achondroplasia_sentence_49

If the radiographic features are not classic, a search for a different diagnosis should be entertained. Achondroplasia_sentence_50

Because of the extremely deformed bone structure, people with achondroplasia are often "double jointed". Achondroplasia_sentence_51

The diagnosis can be made by fetal ultrasound by progressive discordance between the femur length and biparietal diameter by age. Achondroplasia_sentence_52

The trident hand configuration can be seen if the fingers are fully extended. Achondroplasia_sentence_53

Another distinct characteristic of the syndrome is thoracolumbar gibbus in infancy. Achondroplasia_sentence_54

Treatment Achondroplasia_section_4

There is no known cure for achondroplasia even though the cause of the mutation in the growth factor receptor has been found. Achondroplasia_sentence_55

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. Achondroplasia_sentence_56

Usually, the best results appear within the first and second year of therapy. Achondroplasia_sentence_57

After the second year of growth hormone therapy, beneficial bone growth decreases, so the therapy is not a satisfactory long-term treatment. Achondroplasia_sentence_58

An experimental drug called Vosoritide has shown promise in stage 3 human trials, although its long-term effects are unknown. Achondroplasia_sentence_59

The controversial surgery of limb-lengthening will increase the length of the legs and arms of someone with achondroplasia. Achondroplasia_sentence_60

Complications Achondroplasia_section_5

Children Achondroplasia_section_6

Children with achondroplasia often have less muscle tone; because of this it is common for them to have delayed walking and motor skills. Achondroplasia_sentence_61

It is also common for children to have bowed legs, scoliosis, lordosis, arthritis, issues with joint flexibility, breathing problems, ear infections, and crowded teeth. Achondroplasia_sentence_62

These issues can be treated with surgery, braces, or physical therapy. Achondroplasia_sentence_63

Hydrocephalus is a severe effect associated with achondroplasia in children. Achondroplasia_sentence_64

This condition occurs when cerebrospinal fluid is not able to flow in and out of the skull because of how the spine narrows. Achondroplasia_sentence_65

This fluid build up is associated with an enlarged head, vomiting, lethargy, headaches, and irritability. Achondroplasia_sentence_66

A shunt surgery is commonly performed to treat this condition, but an endoscopic third ventriculostomy can also be done. Achondroplasia_sentence_67

Adults Achondroplasia_section_7

Adults with achondroplasia often face issues with obesity and sleep apnea. Achondroplasia_sentence_68

It is also typical for adults to suffer from numbness or tingling in their legs because of nerve compression. Achondroplasia_sentence_69

Pregnancy in women with achondroplasia is considered higher risk. Achondroplasia_sentence_70

Women with achondroplasia generally have their babies delivered through C-sections to prevent complications that could occur with a natural birth. Achondroplasia_sentence_71

Epidemiology Achondroplasia_section_8

Achondroplasia is one of several congenital conditions with similar presentations, such as osteogenesis imperfecta, multiple epiphyseal dysplasia tarda, achondrogenesis, osteopetrosis, and thanatophoric dysplasia. Achondroplasia_sentence_72

This makes estimates of prevalence difficult, with changing and subjective diagnostic criteria over time. Achondroplasia_sentence_73

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. Achondroplasia_sentence_74

Another study at the same time found a rate of 1 per 10,000. Achondroplasia_sentence_75

Other animals Achondroplasia_section_9

Based on their disproportionate dwarfism, some dog breeds traditionally have been classified as "achondroplastic". Achondroplasia_sentence_76

This is the case for the dachshund, basset hound, corgi and bulldog breeds. Achondroplasia_sentence_77

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). Achondroplasia_sentence_78

Therefore, it seems unlikely that dogs and humans are achondroplastic for the same reasons. Achondroplasia_sentence_79

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. Achondroplasia_sentence_80

A similar form of achondroplasia was found in a litter of piglets from a phenotypically normal Danish sow. Achondroplasia_sentence_81

The dwarfism was inherited dominant in the offspring from this litter. Achondroplasia_sentence_82

The piglets were born phenotypically normal, but became more and more symptomatic as they reached maturity. Achondroplasia_sentence_83

This involved a mutation of the protein collagen, type X, alpha 1, encoded by the COL10A1 gene. Achondroplasia_sentence_84

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. Achondroplasia_sentence_85

The now-extinct Ancon sheep was created by humans through the selective breeding of common domestic sheep with achondroplasia. Achondroplasia_sentence_86

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. Achondroplasia_sentence_87

Research Achondroplasia_section_10

As of 2019, tentative evidence has found that the experimental peptide drug vosoritide increases growth velocity in those with achondroplasia. Achondroplasia_sentence_88

The drug inhibits the activity of FGFR3. Achondroplasia_sentence_89

See also Achondroplasia_section_11

Achondroplasia_unordered_list_1


Credits to the contents of this page go to the authors of the corresponding Wikipedia page: en.wikipedia.org/wiki/Achondroplasia.