Clinical manifestations

Presentation and course

The physical abnormalities of achondroplasia include disproportionate short stature, an enlarged head with frontal bossing, midface hypoplasia, rhizomelic (proximal) shortening of the limbs with redundant skin folds, limited elbow extension, thoracolumbar gibbus in infancy, exaggerated lumbar lordosis, genu varum (bow legs), trident-shaped hands (short fingers with divergent ring and middle fingers), and a protuberant abdomen (24). Abnormal bone in people with achondroplasia is subject to distortion, and the result is that bone impinges on nervous tissue, most commonly at the foramen magnum, spinal canal, and nerve root outlet foramen. Awareness of the range of these complications allows early and more effective intervention so as to ameliorate the nature and severity of the long-term effects of the neurologic complications in patients with achondroplasia (09).

There are numerous neurologic manifestations of achondroplasia (33; 93; 09). Neonatal and childhood neurologic features include hydrocephalus, small craniocervical junction, truncal hypotonia, and articulation problems. For the newborn, hydrocephalus may be due to a small craniocervical junction leading to foramen magnum or aqueduct stenosis. As growth continues, hydrocephalus is often the communicating type resulting from increased intracranial venous pressure (28; 13). In rare cases, hydrocephalus may be caused by a concomitant Chiari II malformation (04). Intelligence is typically normal, unless hydrocephalus or other central nervous system complications occur (35). Developmental delays are often the consequence of transient neuromuscular hypotonia, chronic upper airway obstruction, middle ear dysfunction, craniocervical junction stenosis, lordosis or kyphosis, and bowing of the legs (127; 49). Thoracolumbar kyphosis is common in children and typically improves without treatment as they begin to ambulate; however, when individuals enter adulthood, lumbar lordosis and bowing of the legs become a significant problem.

Achondroplasia carries with it many associated disorders, including obstructive sleep apnea, recurrent otitis media, obesity, and joint laxity (46; 20). Mid-face hypoplasia leads to narrow upper airways and shortened eustachian tubes, predisposing patients to obstructive sleep apnea and recurrent otitis media, respectively (46). Conductive hearing loss secondary to recurrent otitis is seen in up to 40% of patients, and hearing screening should be performed when language delay is present (48). An underdeveloped chest cavity can lead to restrictive lung disease, especially in early childhood. Ligamentous laxity in the lower extremities, defined as the clinician’s ability to passively oppose the lateral borders of the feet when brought together in the midline, above the level of the pelvis in a seated position, was found in about 90% of individuals with achondroplasia. This sign has been termed “Scott sign” after Dr. Charles Scott, former Chairman of the Medical Advisory Board to the Little People of America (08).

Radiographic findings in children include narrow interpediculate space of the caudal spine, a notch-like sacroiliac-groove, and chevron-shaped epiphyseal ossification centers on the metaphysis (65; 30; 117).

A 2000 to 2019 study of 108 participant children with achondroplasia showed 52 (48%) participants presenting with craniocervical stenosis, 15 (13.9%) with hydrocephalus, 66 (61.1%) with hearing impairment, 44 (40.7%) with sleep-disordered breathing, 46 (42.6%) with lower-limb malalignment, 24 (22.2%) with thoracolumbar kyphosis, 10 (9.3%) with symptomatic spinal stenosis, 12 (11.1%) with obesity, and 16 (14.8%) who had at least one admission for respiratory illness (03).

Prognosis and complications

Over their lifespan, individuals with achondroplasia often have multisystem complications, reduced quality of life and functionality, and increased pain (03; 72). Most individuals with achondroplasia are of normal intelligence and are able to lead independent and productive lives (124). Unexpected death in the absence of aggressive acute evaluation occurs in about 2% to 5% of infants with achondroplasia (95; 99). Early or unexpected death typically results from respiratory insufficiency because of a small thoracic cage and neurologic deficit from cervicomedullary stenosis (30; 24).

Children up to 7 years of age with achondroplasia show delayed milestone acquisition and a greater need for caregiver assistance for all domains (51). Examination of development in patients with achondroplasia show that height, weight, or head circumference do not appear to influence timing of gross motor skills before 5 years (53). The exception was lie to sit transitioning, which appears likely to occur earlier if the child is taller and heavier at 12 months, and later if the child has significant head-to-body disproportion. As functional delays are likely to be related to common musculoskeletal impairments associated with achondroplasia, access to physiotherapists, occupational therapists, and speech and language pathologists skilled in achondroplasia management may assist children and families to become more independent, particularly around the time of starting school. Advances in genetics may enable personalized medicine interventions that promote independent functioning and participation for individuals with achondroplasia (83).

The adult males attain an average height of approximately 131 cm, and females, a height of 124 cm. The average adult male weighs 55 kg, and average female, 40 kg (46; 42). Individuals with achondroplasia have an increased overall and age-specific mortality (34; 140). Progressive kyphosis or lordosis may lead to symptomatic spinal stenosis requiring surgical decompression. Heart disease-related mortality between the ages of 25 and 35 years is 10 times higher than in the general population. Overall mortality in individuals with achondroplasia is decreased by about 10 years (34). Today, mortality in babies with achondroplasia may be decreasing when compared to historic studies (115). Recurrent acute life-threatening events have been associated with achondroplasia (05).

At Johns Hopkins Hospital an MRI study involving 16 children with achondroplasia and 16 matched controls suggests that in children with achondroplasia, the variation in ventricular dilatation may be related to an unquantifiable interdependent relationship of emissary vein enlargement, venous channel narrowing, and foramen magnum compression. Secondly, stable ventricular size facilitated by interdependent factors likely obviates the need for ventricular shunt placement (10). Another study involving diffusion tensor imaging (DTI) showed reduction in fractional anisotropy and increase in diffusivities in the lower brainstem of participants with achondroplasia, which may reflect secondary encephalomalacic degeneration and cavitation of the affected white matter tracts as shown by histology. In children with achondroplasia, DTI may serve as a potential biomarker for brainstem white matter injury and aid in the care and management of these patients (11). An investigational study was conducted to evaluate early postnatal FGFR3 therapy to prevent obesity in achondroplasia (103).

Biological basis

Etiology and pathogenesis

Achondroplasia is an autosomal dominant disorder caused by mutations in fibroblast growth factor receptor type 3 (FGFR3) (100; 111; 93). About 80% of patients are born to unaffected parents, representing a high rate of de novo mutations. In 1994, the achondroplasia locus was mapped to 4p16.3 (68; 130). Individuals with achondroplasia have one normal copy of FGFR3 and one mutant copy. Gene penetrance is 100%, meaning all individuals who have a single copy of altered FGFR3 have achondroplasia. Homozygosity for the mutation results in fatality before or shortly after birth (94). About 98% of cases are caused by point mutations that result in the amino acid substitution Gly380Arg, and about 1% of cases are caused by glycine and cysteine point mutation (111; 07; 101). A technique called quantitative imaging FRET showed a statistically significant increase in FGFR3 dimerization in the achondroplasia mutation compared to wild type HEK293T cells, suggesting a structural change in the plasma membrane that affects both the stability and activity of FGFR3 dimers in the absence of the ligand (98). Paternal allelic germline mosaicism has been noted in sperm, suggesting increased mutability of FGFR3 during spermatogenesis or a selective advantage for this pathogenic mutation in the male cell line (86). Advanced paternal age is associated with the mutation and disease severity (96; 119; 121). Evidence of positive selection helps to explain the paternal age effect in achondroplasia (113; 29).

Achondroplasia, hypochondroplasia, and thanatophoric dysplasia are syndromes of short-limbed dwarfism caused by activating mutations of fibroblast growth factor receptor-3, which result in over-activation of the MEK/ERK MAP kinase pathway. C-type natriuretic peptide (CNP) is a crucial regulator of endochondral bone growth. In these skeletal dysplasias, elevated plasma levels of proCNP products suggest the presence of tissue resistance to CNP (89).

Hypochondroplasia is an autosomal dominant skeletal dysplasia with milder features than those seen in achondroplasia. McKusick and colleagues noted that achondroplasia and hypochondroplasia possessed phenotypic similarities and proposed that these similarities are based on the same allele (80). Although this was found to be true, polymerase chain reaction, linkage studies, and restriction analysis of the FGFR3 gene show a tendency for N540K mutations to result in hypochondroplasia, whereas mutations at G1138A were found more frequently in achondroplasia (07; 73). De novo variants in the transmembrane domain of FGFR3 have been reported to cause achondroplasia (85).

The FGFR3 cDNA was originally isolated when scientists were searching for the Huntington disease gene on chromosome 4p16.3 (122). The FGFR3 gene codes for a protein involved in the negative regulation of bone growth. Therefore, mutations result in gain-of-function and abnormal growth control exerted by the FGFR3 pathway (19; 123). Two pathways involved in FGFR3 signaling, signal transducers and activators of transcription, and extracellular signal-related kinases inhibit chondrocyte proliferation and differentiation through mitogen-activated protein kinase signaling, thus, delaying endochondral ossification (102; 84; 70). Increased FGFR3 activity raises the probability of phosphorylation of unliganded mutant dimers (32). Thus, dysfunctional FGFR3 protein results in a gain-of-function enhancement of tyrosine kinase activity, disruption of chondrocyte proliferation and differentiation, and ultimately affects growth plate architecture (76).

Epidemiology

The estimated incidence of achondroplasia is 1 in 10,000 to 1 in 30,000 live births (87; 91; 75; 127). It is the most common form of inherited disproportionate short stature (127; 24). A population-based epidemiologic study in Europe used data from the European Surveillance of Congenital Anomalies (EUROCAT) network to report after adjusting for maternal age; fathers older than 34 years of age had a significantly higher risk of having infants with de novo achondroplasia than younger fathers (16).

Prevention

There are no preventative measures available to avoid disease onset.

Differential diagnosis

Achondroplasia is a member of the osteochondrodysplasias that share common features of short stature, micromelia, short hands, and narrow thorax. There are over 100 skeletal dysplasia disorders that cause short stature. Conditions that may be confused with achondroplasia include severe hypochondroplasia (also FGFR3 mutation), cartilage-hair hypoplasia (metaphysical chondrodysplasia, McKusick type), and pseudoachondroplasia (similar features, except normal facial features and head size, caused by COMP mutations) (24). Achondroplasia is also part of a spectrum of disorders caused by different mutations of FGFR3, which include hypochondroplasia, severe achondroplasia with developmental delay, and acanthosis nigricans (SADDAN), thanatophoric dysplasia, Muenke coronal craniosynostosis, and Crouzon syndrome with acanthosis nigricans (82; 69; 128; 120). An article from Japan reports an epilepsy phenotype in FGFR3-related bilateral medial temporal lobe dysgenesis (88).

Diagnostic workup

Features of achondroplasia are so distinctive that physical examination and radiographic features are often sufficient to make a diagnosis. Genetic testing for FGFR3 mutations is not routinely performed but may be confirmatory. Many patients are diagnosed by the third trimester of pregnancy by prenatal ultrasound demonstrating foreshortened limbs (< 3rd percentile), increased biparietal diameter (> 95th percentile), and a low nasal bridge (17; 81; 12; 15). Caution should be exercised when counseling a family about a suspected in utero diagnosis of achondroplasia because disproportionately short limbs are seen in a heterogenous group of disorders.

Fetal MRI is a useful diagnostic tool for skeletal dysplasias and excluded the diagnosis in nearly half of referred pregnancies (27). In addition to providing fetal lung volumes, fetal MRI demonstrates findings of the brain in achondroplasia and thanatophoric dysplasia, of the spine in achondroplasia and achondrogenesis, of the calvarium in osteogenesis imperfecta and thanatophoric dysplasia, and of the cartilage in Kniest dysplasia (27). Using MRI findings to predict cervical myelopathy and hydrocephalus may be useful for the management of achondroplasia. The cord constriction ratio for cervical myelopathy and frontal horn width and posterior indentation grade for hydrocephalus are significant predictors and may be useful parameters for management. Posterior indentation grade may also be used to determine the treatment method for hydrocephalus (112).

There have been few studies that study the correlation between second-trimester ultrasonographic findings and underlying molecular defect in cases of FGFR3-related skeletal dysplasias (31). Widening of the femoral diaphysis-metaphysis angle at 20 to 24 weeks may be a marker for the detection of achondroplasia prior to the onset of skeletal shortening (57). The combination of ultrasound and a molecular genetic approach may be helpful for establishing an accurate diagnosis of FGFR3-related skeletal dysplasias in utero and, subsequently, for appropriate genetic counseling and perinatal management. Gene testing for bone dysplasias using targeted next-generation sequencing shows promise for improving diagnostics of common skeletal dysplasias (145).

Growth charts for height, weight, head circumference, body mass index, and developmental milestones have been established for patients with achondroplasia (46; 127; 42; 44; 40; 43). Although features are distinctive at birth, short stature becomes gradually evident in childhood and through adulthood.

Management

Management of individuals with achondroplasia requires an understanding of the natural history of the disorder and a multidisciplinary approach because of the multiple medical problems that can arise. Hoover-Fong and colleagues offer a critical review and discussion of the natural history of achondroplasia based on evidence in the current literature and the perspectives of clinicians with extensive knowledge and practical experience in managing individuals with this diagnosis (41).

There are numerous publications of guidelines for management of individuals with achondroplasia. For example, Australia has published guidelines on management of children with achondroplasia (126). Europe has published best practices on diagnosis and referral (18). Recommendations for the management and anticipatory guidance of individuals with achondroplasia were published by the American Academy of Pediatrics (127). A group of 55 international experts from 16 countries and five continents developed consensus statements and recommendations that aim to capture the key challenges and optimal management of achondroplasia across each major life stage and subspecialty area using a modified Delphi process (105). The primary purpose of this first International Consensus Statement is to facilitate the improvement and standardization of care for children and adults with achondroplasia worldwide to optimize their clinical outcomes and quality of life.

Recommendations for anticipatory guidance and management of individuals with achondroplasia

	(1) Monitor height, weight, and head circumference using growth curves standardized for achondroplasia.
	(2) Neurologic examinations (including consideration of tests such as CT, MRI, somatosensory evoked potentials, and polysomnography)
	(3) Surgical enlargement of the foramen magnum in cases of severe stenosis
	(4) Management of frequent middle ear infections and dental crowding. Repeated audiometry should be routinely performed during the first 3 years of life
	(5) Measures to control obesity starting in early childhood
	(6) Growth hormone therapy (experimental)
	(7) Limb-lengthening of the long bones
	(8) Tibial osteotomy of epiphysiodesis of the fibular growth plate to correct bowing of the legs
	(9) Lumbar laminectomy for symptomatic spinal stenosis
	(10) Genetic counseling for individuals and families to understand the cause of achondroplasia, the chance of having another child with achondroplasia, and to understand reproductive options
	(11) Pregnant women with achondroplasia can deliver by cesarean section.
	(12) Prenatal detection of fetuses with achondroplasia through ultrasound (eg, short femora < 24 weeks gestation)

This comprehensive policy statement may be helpful for clinicians directing ongoing care. Because adults with achondroplasia are at increased risk for spinal stenosis, a clinical history and neurologic examination is warranted every 3 to 5 years once the person with achondroplasia reaches mid-life (24). Quality-of-life indicators are helpful for assessing the need for support in both children and adults with achondroplasia (97; 144). The physician should consider in practice to monitor height, weight, and head circumference; discuss measures to avoid obesity; consider MRI or CT for evaluation of severe hypotonia or signs of spinal cord compression; adenotonsillectomy, continuous positive airway pressure by nasal mask, and tracheostomy to correct obstructive sleep apnea; suboccipital decompression as indicated for lower-limb hyperreflexia or clonus and central hypopnea; surgery to correct spinal stenosis; and educational support in socialization and school adjustment (24). A study of patients in Australia examined the use of services related to health management of achondroplasia (50). Growth charts and growth parameters for Australian children with achondroplasia have been published (125; 105). Recommendations for optimal management of complications were published as a result of these data (52). Access to geneticists and pediatricians within the first year is high as recommended by the 2005 American Academy of Pediatrics guidelines. Utilization of craniocervical magnetic resonance imaging/computed tomography, polysomnography studies, and formal speech review appears low, reflecting more emphasis on clinical monitoring for cervical cord compression and disordered sleep breathing as well as possible difficulties in accessing services for polysomnography and speech pathology. Over half of the children accessed physiotherapy or occupational therapy services, warranting consideration of these professionals in future guideline recommendations. Best practices in the evaluation and treatment of foramen magnum stenosis during infancy have been published (135).

Orthopedic surgery in the form of humeral and femoral lengthening in achondroplasia is an established technique. There are a variety of techniques and high complication rates (107). Controversy surrounding the risk of complications with cosmetic gains and quality of life persists (58; 59). With regard to thoracolumbar kyphosis, a study from Johns Hopkins Orthopaedics reported that kyphosis resolved at walking age in 15% of patients and after a year of walking in 58% of patients (74). The group suggests that earlier bracing may slow thoracolumbar kyphosis progression in patients with achondroplasia and developmental motor delay. Patients with kyphotic curves between 20 and 40 degrees should be examined intermittently for progressive deformity or worsening symptoms of spinal cord compression.

Data suggest a high population prevalence of hypertension among short-stature adults (39). Blood pressure should be monitored as part of routine medical care, and measuring at the forearm appears to be the only viable clinical option in rhizomelic short-stature adults with elbow contractures (39).

Trials investigating the efficacy of growth hormone therapy for increasing height in achondroplasia have long been reported, but most have been short-term studies (142; 56; 114; 133; 118; 110). Results showed an average increased growth velocity of 65% to 75% during the first year of treatment (14). One long-term study examined growth hormone treatment in children over 5 years (2 years of treatment followed by 1 year of observation, followed by 2 more years of treatment), and showed a 1.5 standard deviation increase in height without adverse effect on trunk-leg disproportion (37).

Current therapeutic strategies have targeted reduction in FGFR3 signaling through tyrosine kinase inhibitors and neutralizing antibodies. These therapies are in the preclinical phases as of 2022 and have not yet translated into management options (64). Novel tyrosine kinase inhibitors such as A31 have been shown to inhibit FGFR3 phosphorylation and to restore the size of embryonic dwarf mice femurs in an ex vivo culture system (55). The increase in length of the treated mutant femurs was 2.6 times more than for the wild-type. A novel FGFR3 binding peptide, P3, inhibited tyrosine kinase activity of FGFR3 and its typical downstream molecules, extracellular signal-regulated kinase/mitogen-activated protein kinase, promoted proliferation and chondrogenic differentiation of cultured ATDC5 chondrogenic cells, alleviated the bone growth retardation in bone rudiments from mice mimicking human thanatophoric dysplasia type II (TDII), and reversed the neonatal lethality of TDII mice (54). These studies support the development of tyrosine kinase inhibitors for the treatment of FGFR3-related chondrodysplasias. Mutations in C-type natriuretic peptide present a novel cause for autosomal dominant short stature (38). Discoveries such as C-type natriuretic peptide administration counteracting signal transduction pathways downstream of FGFR3 in mice to ameliorate the clinical phenotype hold promise for therapeutic intervention (66; 143). A study observed an increase in the axial and appendicular skeleton lengths, and improvements in dwarfism-related clinical features included flattening of the skull, reduced crossbite, straightening of the tibias and femurs, and correction of the growth-plate defect in mice given BMN 111, a NEP-resistant C-type natriuretic peptide analog (71). A clinical trial in children with achondroplasia demonstrated that once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild (104). Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months.

Soluble FGFR-3 is being investigated as therapy for achondroplasia (02; 25). Clustered regularly interspaced short palindromic repeat (CRISPR) has arisen as a frontrunner for efficient genome engineering. Using this technology, Wojtal and colleagues demonstrated preferential elimination of the dominant-negative FGFR3 c.1138G>A allele in fibroblasts of an individual affected by achondroplasia (138).

Yamashita and colleagues showed that treatment of achondroplastic model mice with statin led to a significant recovery of bone growth (141). Statin treatment rescued patient-specific induced pluripotent stem cell (iPSC) models and a mouse model of FGFR3 skeletal dysplasia. These results suggest that statins could represent a medical treatment for infants and children with achondroplasia (90; 141).

A preclinical proof of concept study for applying meclizine, an anti-motion sickness medication, showed improvement in short stature phenotype in mice as evidenced by stimulation of longitudinal bone growth, bone volume, and metaphyseal trabecular bone quality (77). A randomized, double-blind, controlled, phase 3, multicenter trial of once-daily subcutaneous vosoritide demonstrated that it is an effective treatment for increasing growth in children with achondroplasia (106). It is not known whether final adult height will be increased or what the detriments of long-term therapy might be.

Neurosurgical management of achondroplasia includes shunting for hydrocephalus and decompression surgery for spinal stenosis (60; 06). Cervicomedullary compression can cause pain, ataxia, incontinence, apnea, progressive quadriparesis, and respiratory arrest (28). The prevalence of cervicomedullary decompression among individuals with achondroplasia is about 20%, with more recently treated patients undergoing first cervicomedullary decompression at younger ages than earlier patients (67). The use of neuroimaging and polysomnogram screening modalities increased over time, suggesting that increased and better surveillance contributed to earlier identification and intervention in patients with cervicomedullary stenosis. Surgical relief of venous pressure is often used, but up to 10% of patients with hydrocephalus will require ventricular shunting (34; 28; 45). Clinical findings such as brisk tendon reflexes, small foramen magnum, and central hypopnea may be an indication for surgery, but the decision to operate can be difficult because cord compression may resolve spontaneously (28). Concerns arise when persistent kyphosis or lordosis progresses to spinal stenosis. Symptomatic stenosis is common in the third and fourth decades of life, and nearly one in three patients require lumbar laminectomy (117; 108; 109; 60). Surgical decompression with instrumentation significantly reduces the symptoms of lumbar stenosis and the likelihood of revision surgery in children with achondroplasia (06).

Similarly, orthopedic surgery has been proposed for bone deformities in achondroplasia. Growth modulation is able to correct varus deformities of the legs in achondroplasia (79). Although most individuals with achondroplasia have normal intelligence, the cognitive profile for individuals with achondroplasia may be unique. Neuropsychological evaluation and monitoring of children with achondroplasia suggest verbal IQ, arithmetic, attention, and executive functioning are particularly common areas of impairment (136).

Stigmas associated with short stature may affect individuals with achondroplasia and result in poor socialization. School adjustment may be a challenge for children. In addition to medical care, support in the form of groups (eg, Little People of America), peer support, programs to assist with employment and disability rights, camps, newsletters, and seminars may be instrumental in helping individuals reach their full potential and integrate into society.

Special considerations

Pregnancy

Women with achondroplasia are fertile and require both genetic counseling and an experienced gynecologist. Caesarian section delivery is necessary due to small pelvis (01).

Anesthesia

Numerous case reports have been published discussing the challenges faced during both general and local anesthesia in the patient with achondroplasia. Limited neck extension, foramen magnum stenosis, a large tongue, and large mandible can lead to increased difficulty of airway management (131; 78; 132; 47; 129; 137). Cardiorespiratory function may be reduced due to narrow rib cage and kyphoscoliosis (131). In gravid achondroplastics, severe lumbar lordosis and prominent lower back musculature often present challenges during administration and spread of epidural anesthesia (132; 47). Anesthesia with intubation can be given safely with special consideration for limited neck extension and appropriate endotracheal tube size, which may be a smaller tube than expected for age (116).