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INTRODUCTION — Achondroplasia is the most common bone dysplasia in humans, with a prevalence of approximately 1 in 20,000 livebirths. It is an autosomal dominant condition caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. The most salient clinical features include disproportionate short stature (adult height is approximately 4 feet), long bone shortening that predominantly affects the proximal aspects of the upper and lower extremities (rhizomelic shortening), and macrocephaly. Patients with achondroplasia may have delayed motor development early on, but cognition is normal. There are a number of medical issues associated with this disorder.
The clinical findings, diagnosis, treatment options, and anticipatory guidance are discussed in this topic review. An overview of the diagnostic approach to skeletal dysplasias is presented in detail separately. (See "Skeletal dysplasias: Approach to evaluation".)
GENETICS — Patients with achondroplasia have gain-of-function mutation in the fibroblast growth factor receptor 3 (FGFR3) gene . Two specific mutations in the FGFR3 gene account for almost all cases of achondroplasia. These mutations occur at the same nucleotide in the FGFR3 gene, 1138G>A (98 percent) and 1138G>C (1 percent), in both cases resulting in a glycine-to-arginine substitution in amino acid 380 (p.Gly380Arg) in the transmembrane domain of the FGFR3 gene. This mutation permanently activates the FGFR3 receptor, inhibiting chondrocyte proliferation, which ultimately leads to impaired endochondral bone formation, growth restriction, bone shortening, and other skeletal anomalies .
INHERITANCE — Achondroplasia is inherited in an autosomal dominant manner. Approximately 80 percent of cases are the result of new (de novo) mutations, while the remaining are inherited. When both parents have achondroplasia, the risk to their children of having homozygous achondroplasia (a lethal condition) is 25 percent and of having achondroplasia is 50 percent.
CLINICAL MANIFESTATIONS — Achondroplasia is characterized by distinctive craniofacial features, disproportionate short stature with rhizomelic shortening of the arms and the legs (picture 1), brachydactyly (shortening of the fingers and toes) (picture 2), kyphoscoliosis (figure 1), and accentuated lumbar lordosis. The craniofacial features and bone shortening are clearly present at birth. The craniofacial features include macrocephaly, frontal bossing, and midface retrusion. The nose is flattened out, often referred to as saddle nose deformity. The kyphoscoliosis can be seen from birth through infancy and typically decreases once the child starts to bear weight and ambulate. The lumbar lordosis is typically seen after ambulation starts at approximately 1.5 years of age.
The chest is often narrow. The back displays kyphosis of the thoracolumbar junction, which is prominent during the first year of life and mostly resolves as the spine straightens, the muscle tone improves, and the child starts walking. Exaggerated lumbar lordosis is a common finding that becomes prominent after walking begins (picture 1). The lumbar spine may become stenotic at a later age, typically not until after the second and third decades (most often as an adult).
The extremities have shortening that is more pronounced in the proximal/rhizomelic segments (picture 1). Because of this, children with achondroplasia often have redundant skin folds that are most noticeable in their upper extremities. The elbows may have limitations, primarily affecting extension and oftentimes limiting complete supination. The hands show short fingers with a trident appearance of the hands secondary to short metacarpal bones (picture 2). Joint laxity is common. The knees often have varus deformities, initially due to joint laxity and later on secondary to tibial bowing and fibular overgrowth.
Achondroplasia is associated with slow motor development (figure 2). These children hold their head at approximately 4 to 7 months of age, sit alone at 9 to 11 months, crawl at 9 to 10 months, and walk alone by 16 to 22 months. The delay in these motor milestones is the result of a combination of joint laxity and a large head to support [3,4]. These delays resolve by age two to three years provided no other medical problems exist, such as cervical medullary compression. (See 'Complications' below.)
●Large calvaria and narrowing of the foramen magnum region (this requires computed tomography [CT] of the base of the skull with special attention to the foramen magnum)
●Progressive caudal narrowing, rather than widening, of the vertebral body interpediculate distance in the lumbosacral region (image 1)
●Proximal scooping of the femoral metaphyses (image 2)
●Short and narrow chest (image 1)
Narrowing of the subarachnoid space at the foramen magnum level, narrowing of sagittal and transverse diameters of the foramen magnum, and dilation of the lateral and third ventricles can be visualized by magnetic resonance imaging (MRI) or CT scanning [6,7].
DIAGNOSIS — The diagnosis of achondroplasia is based upon clinical and radiographic findings.
Prenatally, achondroplasia is suspected when shorter long bones and macrocephaly are present. The evaluation and diagnosis of a short fetal femur is discussed in greater detail separately. (See "Approach to prenatal diagnosis of the lethal skeletal dysplasias".)
Radiographs are suggested if achondroplasia is suspected after birth based upon clinical manifestations including distinct craniofacial features and bone shortening. The most useful radiographs are the anteroposterior (AP) view of the thorax and pelvis to look for the lack of widening of the interpedicular distances of the vertebral bodies, iliac abnormalities, and shortening of the long bones with metaphyseal abnormalities and hand films to look for shortening, brachydactyly, and trident deformity.
The diagnosis is confirmed by molecular testing. Most laboratories offer targeted testing for classical 1138 mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. Broader sequencing of the FGFR3 gene, including multiple exons or the full gene, is suggested if the clinical diagnosis is in doubt and other conditions such as hypochondroplasia are suspected. Parents should consult with a geneticist during the initial evaluation to discuss diagnosis, recurrence risk, and prenatal testing, when applicable. (See 'Clinical manifestations' above and 'Radiographic findings' above and 'Genetics' above and 'Differential diagnosis' below.)
DIFFERENTIAL DIAGNOSIS — There are several other skeletal disorders that are also caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene (allelic diseases). These conditions share many of the clinical and/or radiologic features seen in patients with achondroplasia, although each has its own distinctive features.
Hypochondroplasia — This condition is caused by FGFR3 mutations at nucleotide c.1620C>A or C>G that result in an N540K change (asparagine to lysine) in the intracellular domain. Hypochondroplasia is characterized by short stature, rhizomelic limb shortening, and brachydactyly but no macrocephaly . The clinical presentation is milder, with more proportionate features, although the radiographic skeletal findings are still similar.
Thanatophoric dysplasia — This disorder is caused by mutations in the intracellular and extracellular domains of the FGFR3 gene. These patients have similar but more severe findings than achondroplasia . There are two types of thanatophoric dysplasia. Type I is distinguished by bowed femurs and flatten vertebral bodies (platyspondyly) that are under-ossified. Type II is characterized by straight femurs and a severe craniosynostosis (termed a cloverleaf skull due to the shape of the deformity) that is caused by premature intrauterine closure of the coronal, sagittal, and lambdoid sutures. Both types of patients exhibit extremely short limbs, a very short and narrow chest with underdeveloped lungs, macrocephaly with frontal bossing and hypertelorism, and severe cervical medullary compression leading to early death.
Homozygous achondroplasia — Homozygous achondroplasia results from transmission of the FGFR3 mutation from both parents who have achondroplasia. Clinically, this presents as a severe form of achondroplasia resembling the bone changes seen in thanatophoric dysplasia. Most with this disorder are stillborn or die in early infancy. Patients who survive the neonatal period die in the first few years of life due to pulmonary hypoplasia and respiratory failure .
COMPLICATIONS — Complications associated with achondroplasia include recurrent otitis media, obstructive sleep apnea, obesity, leg bowing, narrowing of the lumbar spine, and cervical medullary compression.
●Recurrent otitis media – Patients with achondroplasia have a narrow auditory canal that contributes to recurrent ear infections.
●Obstructive sleep apnea – Midface retrusion in conjunction with adenoid and tonsil enlargement can reduce the airway space, leading to obstructive sleep apnea (OSA). OSA is clinically manifested by loud snoring, breath holding during sleep (apnea), poor sleep, poor school performance, and behavioral problems in some cases.
●Obesity – This is a common occurrence in achondroplasia that ultimately can negatively impact knee joints and lower spine in older individuals, worsen sleep apnea, and potentially lead to hypertension and diabetes .
●Leg bowing – Most children with achondroplasia have leg bowing (genu varum) during the first years of life secondary to joint laxity. The early bowing is typically followed conservatively. The leg bowing in later childhood, typically after five to six years of age, can be the result of tibial bowing and fibular overgrowth. The bowing can interfere with ambulation, causing stress in the joints and subsequent pain in the knees and ankles and, in some cases, tripping and frequent falling.
●Spinal stenosis – Narrowing of the lumbar spine can occur in patients after their second or third decades. Typical presenting symptoms include claudication and bladder dysfunction. Magnetic resonance imaging (MRI) studies and a thorough neurologic exam are important to making the diagnosis.
●Cervical medullary compression – One area of controversy in achondroplasia is the prevalence and management of cervical medullary compression due to narrowing of the foramen magnum [12,13]. It is estimated that 5 to 10 percent of patients with achondroplasia develop true cervical medullary stenosis even though some degree of narrowing occurs in many more. Cervical medullary compression is associated with significant morbidity and mortality, including an increased risk of sudden infant death . The maximum anatomical narrowing occurs at approximately 12 months of age. Thus, all infants should have computed tomography (CT) or MRI of the cervical medullary junction for surveillance around that time.
Signs of narrowing of the cervical medullary junction should be closely followed, but rushing to surgical intervention should be avoided in the absence of other clinical findings. Warning signs for compression include motor delay that is more severe, persists in time, or is associated with an abnormal neurologic exam. Other concerning findings include clonus, hyperreflexia of the lower limbs, central apnea/hypopnea, and a rapidly growing head circumference. A thorough evaluation should be performed to rule out cervical medullary compression, and urgent referral to a neurosurgeon should be initiated if any of these findings are present. It is best if these evaluations and surgical decisions involve a multidisciplinary team including geneticists, orthopedists, neurologists, and neurosurgeons.
This evaluation includes a complete neurologic assessment, CT scan of the head with foramen magnum measurements, cerebrospinal fluid (CSF) flow studies of the cervical spine done with MRI with flexion-extension images, somatic-sensory evoked potentials (SSEPs), and sleep studies to assess sleep apnea. Most groups do not recommend routine CT or MRI studies.
MRI studies with T2-weighed images in conjunction with flow studies can be valuable in assessing cord compression. Lack of flow anteriorly and posteriorly suggests compression . In the experience of some groups, however, a decreased space around the cord in the cervical medullary junction and extra-axial fluid accumulation in the brain around the parietal and temporal areas, as well as occipital bone impingement of the posterior cord, can be seen in patients with achondroplasia with no neurologic sequela .
MANAGEMENT — The management of achondroplasia focuses on maximizing functional capacity and monitoring, preventing, and treating complications.
●Developmental delay – Physical therapy is appropriate for those children who present with delayed motor milestones in the first two years of life.
●Activities of daily living – The limb shortening can interfere with daily self-care tasks such as reaching out, feeding, bathing, dressing, and independent toileting and self-care. Thus, adaptive arrangements are very important. An example is adapting furniture used in the home and school environment, such as using lower chairs and desks or using stools to reach the toilet seat or sink. In addition, hand extenders can be used for reaching objects or self-cleaning. Occupational therapy is also important for individuals with achondroplasia to achieve their best functional potential.
●Growth – The linear growth (height) and head circumference should be plotted on the proper disease-specific growth curves (figure 3 and figure 4) [16,17]. Failure to do so may result in unnecessary imaging studies. As an example, plotting the head of a child with achondroplasia on the regular growth curve may lead to extra brain imaging studies and potentially referrals to neurosurgery, with subsequent surgical procedures for suspected cervical medullary compression due to an apparent rapidly increasing head circumference.
●Limb-lengthening surgery – Limb-lengthening surgeries have been used in the past and are resurging thanks to emerging surgical techniques. However, these therapies have a high financial and social cost. In the past, these surgeries were performed by surgical distractions of the long bones (humeri, femurs) followed by the use of external fixators (Ilizarov procedure) . The best results with this technique were seen if it was performed after the completion of growth. This technique is being replaced by the use of rodding technologies that use limb distraction followed by implantation of intramedullary magnetic nails. The rods can then be stretched by the aid of powerful external magnets. The rods are used in place of external fixators that often led to infection, scarring, and other complications . These surgeries can be performed in younger patients. Limb-lengthening surgery is still controversial among the little people community and opposed by most patient support groups.
●Weight management – Avoiding obesity should be discussed early on. Proper nutrition and physical activity are important measures in preventing obesity.
●Otitis media – An aggressive approach to preventing and treating otitis media in infancy and childhood is required to avert problems related to speech development. In some instances, otolaryngology evaluation and placement of tympanostomy (pressure equalization [PE]) tubes are necessary in those children with recurrent otitis media.
●Snoring and sleep apnea – Sleep studies are indicated in patients with snoring and/or suspected sleep apnea. Referral to otolaryngology for further evaluation and possible tonsillectomy and adenoidectomy is suggested if obstructive sleep apnea (OSA) is confirmed.
●Leg bowing – The initial leg bowing due to joint laxity is addressed by physical therapy and rarely braces. Leg bowing after five to six years of age due to tibial bowing and fibular overgrowth requires frequent monitoring and, if needed, surgical intervention that may include osteotomies of the proximal fibula and epiphysiodesis (image 5) . Standing lower leg radiographs can be performed by the primary care clinician. Orthopedic referral for evaluation and monitoring is recommended.
●Spinal stenosis – Referral to neurosurgery or orthopedics is warranted if the diagnosis is confirmed.
●Cervical medullary compression – Neurosurgical referral is indicated in children with suspected compression of the cervical medullary junction. Patients with cervical medullary compression should avoid contact sports, trampoline use, diving, and gymnastic exercises or other athletic activities that could aggravate the compression. Some providers recommend avoidance of the previously mentioned sports and physical activities in all children with achondroplasia. Those requiring decompression surgery typically undergo a suboccipital craniectomy, as well as posterior C1 and C2 laminectomies.
●Pregnancy – Pregnant women with achondroplasia will require cesarean section for delivery due to their small pelvic size. In addition, a woman with achondroplasia has a 50 percent chance of having an affected child who will have macrocephaly, another clear indication for a cesarean section.
RESOURCES FOR PATIENTS AND FAMILIES — Networking through groups such as the Little People of America is very important for families of children with achondroplasia and the patients themselves as they get older. Oftentimes, practical information and value tips for families and patients can be obtained from these groups, such as how to retrofit the home to accommodate little people, installing low-profile bedding, furniture options, light switches’ placement, and use of extenders.
EXPERIMENTAL DRUG THERAPIES — Therapies based upon the action of cartilage natriuretic peptide (CNP) are under development for skeletal dysplasias. CNP promotes bone growth and endochondral ossification  and has rescued achondroplasia mouse models through inhibition of a mitogen activated protein kinase (MAP-K)-dependent pathway . A phase-II clinical research trial is in place, with phase-III trials to follow, for the treatment of children ages 5 to 10 years with achondroplasia using vosoritide, a recombinant CNP that has a longer half-life than natural CNP.
PROGNOSIS — The overall prognosis for patients with achondroplasia is good unless they are affected with spinal compression of the cervical medullary junction, which is the most significant cause of morbidity and mortality in achondroplasia. A vigilant follow-up of lumbar stenosis in older individuals is also required to avoid complications.
●Achondroplasia is an autosomal dominant disorder caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. It is the most common bone dysplasia in humans. (See 'Introduction' above and 'Genetics' above.)
●Clinical manifestations include distinctive craniofacial features, disproportionate short stature with rhizomelic shortening of the arms and the legs, brachydactyly, kyphoscoliosis, and accentuated lumbar lordosis (picture 1 and picture 2). (See 'Clinical manifestations' above.)
●Diagnosis is based on typical clinical findings. Radiologic findings (image 1 and image 2 and image 3 and image 4), as well as molecular testing, can confirm diagnosis. (See 'Radiographic findings' above and 'Differential diagnosis' above.)
●The differential diagnosis includes hypochondroplasia, thanatophoric dysplasia, and homozygous achondroplasia. (See 'Differential diagnosis' above.)
●Careful monitoring is needed to assess for potential complications including cervical medullary cord compression in infancy, recurrent otitis media, obstructive sleep apnea (OSA), leg bowing, and lumbosacral spinal stenosis in older individuals. (See 'Complications' above.)
●The management of achondroplasia focuses on maximizing functional capacity and monitoring, preventing, and treating complications. An alternative approach to correct the molecular defect and the developmental bone abnormalities caused by the FGFR3 defects is under investigation. (See 'Management' above and 'Experimental drug therapies' above.)
●Narrowing of the cervical medullary junction in infants should be closely followed, but rushing to surgical intervention should be avoided in the absence of other clinical findings. (See 'Complications' above.)
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