Achondroplasia

Achondroplasia
Jason "Wee Man" Acuña, an American actor and stunt performer with achondroplasia
Pronunciation	/eɪˌkɒndrəˈpleɪziə, ə-, -ˈpleɪʒ(i)ə/[1][2]
Specialty	Medical genetics
Symptoms	Short arms and legs, enlarged head, prominent forehead[3]
Complications	Ear infections, hyperlordosis, back pain, spinal stenosis, hydrocephalus[3]
Causes	Genetic (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]
Frequency	1 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.

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.