ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Achondroplasia

Achondroplasia
Literature review current through: Jan 2024.
This topic last updated: Dec 08, 2023.

INTRODUCTION — Achondroplasia is the most common bone dysplasia in humans, with a prevalence of approximately 1 in 20,000 live births. It is an autosomal dominant condition caused by pathogenic variants 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 comorbidities 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".)

TERMINOLOGY — Persons with achondroplasia (as well as other conditions causing short stature) are often referred as little people. Dwarf-derived names are not preferred.

Rhizomelic shortening – Shortened limbs proximally (humeri, femora)

Brachydactyly – Short digits

Kyphosis – Gibbous (convex or protuberant) deformity in the midthoracic to lumbar region

Lordosis – Concave deformity of the lumbosacral region

Saddle nose deformity – Flattening of the nasal bridge in association with midface hypoplasia

Chondrocytes – Cells in charge of initiating extracellular cartilage matrix development that will further lead to the ossification of the long bones, spine, and medial aspect of the clavicle

Varus knee deformities – Deformities of the knees with outward deviation due to bowing and/or joint laxity

Cervicomedullary compression – Narrowing in the upper spine secondary to tightening of foramen magna

GENETICS AND PATHOPHYSIOLOGY — Achondroplasia is inherited in an autosomal dominant manner. Approximately 80 percent of cases are the result of new (de novo) pathogenic variants, while the remaining are inherited. When both parents have achondroplasia, the risk to their children of having homozygous achondroplasia (a lethal skeletal condition) is 25 percent and 50 percent of having achondroplasia.

Patients with achondroplasia have gain-of-function variant in the FGFR3 gene [1]. Two specific pathogenic variants in the FGFR3 gene account for almost all cases of achondroplasia. These variants 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 variant permanently activates the FGFR3 receptor, inhibiting chondrocyte proliferation, which ultimately leads to impaired endochondral bone formation, growth restriction, bone shortening, and other skeletal anomalies [2]. Achondroplasia most often results from spontaneous or new pathogenic variants (de novo variants). A well-known risk factor for achondroplasia and other autosomal dominant conditions is advanced paternal age. Deoxyribonucleic acid (DNA) replication defects in spermatogenesis is increased in males older than 45 years secondary to an increase in point mutations in the sperm [3,4].

EPIDEMIOLOGY — Achondroplasia is a panethnic disorder with an average prevalence of approximately 1 in 20,000. Population studies in South America, Europe, and the United States showed a prevalence that ranges from approximately 1:7000 to 30,000 [5,6], 1:15,000 [7], and 1:10,000 to 30,000 [8], respectively.

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. The lumbar lordosis is typically seen after ambulation starts at approximately 1.5 years of age. Narrowing/stenosis of the craniocervical junction and the spine is variable in pediatric patients but has been reported in up to 50 percent of cases [9,10]. Only a small number of those may require surgical correction.

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 ambulation starts. 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, with a prevalence as high as 80 percent is some reported studies [9].

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 [11,12]. These delays resolve by age two to three years provided no other medical problems exist, such as cervical medullary compression. Persons with achondroplasia have normal intellectual development and satisfactory life adjustments [13]. (See 'Complications' below.)

RADIOGRAPHIC FINDINGS — The findings in achondroplasia are fairly characteristic and easily identifiable by an experienced pediatric radiologist (image 1 and image 2 and image 3 and image 4) [14]:

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)

Undertubulated, shortened long bones with metaphyseal abnormalities (image 1 and image 2 and image 5)

Progressive caudal narrowing, rather than widening, of the vertebral body interpediculate distance in the lumbosacral region (image 1)

Round pelvis with flat, round iliac bones; small sacrosciatic notches (image 1 and image 3)

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 [15,16].

DIAGNOSIS — The diagnosis of achondroplasia is based upon clinical manifestations, radiographic findings, and molecular results.

Prenatally, achondroplasia is suspected when shorter long bones and macrocephaly are present. Fetuses affected with achondroplasia born to average-stature females may sometimes require cesarean delivery due to cephalopelvic disproportion. Affected females with achondroplasia require a cesarean delivery when pregnant due to pelvic abnormalities [17]. The evaluation and diagnosis of a short fetal femur is discussed in greater detail separately. (See "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias".)

Postnatally, a radiographic skeletal survey is strongly advised if achondroplasia is suspected 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. Radiographs are characteristic in achondroplasia and valuable in cases where molecular diagnosis is not obtained.

The diagnosis is confirmed by molecular testing. Most laboratories offer targeted testing for the classical 1138 variant in the 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 and pathophysiology' above and 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — There are many skeletal disorders listed below that are also caused by pathogenic variants in the 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. The main condition that can be mistaken for achondroplasia is hypochondroplasia. Other forms of skeletal dysplasias are discussed in greater detail separately. (See "Skeletal dysplasias: Specific disorders" and "Skeletal dysplasias: Approach to evaluation".)

Hypochondroplasia — This condition is most commonly caused by FGFR3 variants at nucleotide c.1620C>A or C>G that result in an N540K change (asparagine to lysine) in the intracellular domain of the FGFR3 gene. However, other FGFR3 variants can cause this condition. Hypochondroplasia is characterized by short stature, rhizomelic limb shortening, and brachydactyly but no macrocephaly [18]. The clinical presentation is milder, with more proportionate features, although the radiographic skeletal findings are still similar to achondroplasia.

Thanatophoric dysplasia — This disorder is caused by pathogenic variants in the intracellular and extracellular domains of the FGFR3 gene. These patients have similar but more severe findings than achondroplasia [19]. 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 pathogenic variant 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 [20].

COMPLICATIONS — Complications associated with achondroplasia include recurrent otitis media, sleep-disordered breathing, obesity, leg bowing, narrowing of the lumbar spine, hypertension, and cervical medullary compression.

Recurrent otitis media – Patients with achondroplasia have a narrow auditory canal that contributes to recurrent ear infections. (See "Acute otitis media in children: Epidemiology, microbiology, and complications" and "Acute otitis media in children: Prevention of recurrence".)

Sleep-disordered breathing and sleep apnea – Midface retrusion in conjunction with adenoid and tonsil enlargement can reduce the airway space, leading to obstructive sleep apnea (OSA) and sleep-disordered breathing. OSA is clinically manifested by loud snoring, breath holding during sleep (apnea), poor sleep, poor school performance, and behavioral problems in some cases. Sleep apnea can also be central in patients with cervicomedullary compression. (See "Evaluation of suspected obstructive sleep apnea in children" and "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)

Obesity – This is a common occurrence in achondroplasia that ultimately can negatively impact weight-bearing joints and lower spine in older individuals, worsen sleep apnea, and potentially lead to hypertension and diabetes [21]. (See "Definition, epidemiology, and etiology of obesity in children and adolescents" and "Obesity in adults: Prevalence, screening, and evaluation".)

Hypertension – Hypertension and cardiovascular disease are common findings in adults with achondroplasia. This is confounded by obesity, as the increase in blood pressure clearly correlates with body mass index (BMI). In addition, the lack of appropriately sized blood pressure cuffs may delay diagnosis and treatment [22].

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. (See "Approach to the child with bow-legs".)

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. (See "Lumbar spinal stenosis: Pathophysiology, clinical features, and diagnosis" and "Lumbar spinal stenosis: Treatment and prognosis".)

Cervicomedullary compression – One area of controversy in achondroplasia is the prevalence and management of cervicomedullary compression due to narrowing of the foramen magnum [23,24]. 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. Cervicomedullary compression is associated with significant morbidity and mortality, including an increased risk of sudden infant death [25]. 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 cervicomedullary 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 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 CSF flow signal anteriorly and posteriorly suggests compression (spinal effacement) [26]. 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 [23].

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 an option in individuals with achondroplasia to achieve their best functional potential, unless there are concerns for spinal compression.

Growth – The linear growth (height) and head circumference should be plotted on the proper disease-specific growth curves (figure 3 and figure 4) [27,28]. 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.

Use of growth hormone is not recommended and can potentially worsen the disproportion seen in these patients. Vosoritide, a recombinant C-type natriuretic peptide analog that stimulates endochondral ossification, a process that is inhibited in patients with achondroplasia, is approved by the US Food and Drug Administration (FDA) to increase linear growth in children with achondroplasia whose epiphyses are still open [29,30]. In a phase III study, 121 children with achondroplasia aged 5 to <18 years were randomly assigned to vosoritide 15 microg/kg subcutaneously daily or placebo for 52 weeks [30]. Patients treated with vosoritide had a greater increase in mean annualized growth velocity from baseline to 52 weeks compared with the placebo group (adjusted mean difference 1.57 cm/year; 95% CI 1.22-1.93). The rate of adverse events was similar in both groups, with the exception that injection site reactions were more common in the vosoritide group. Most adverse events were mild. No severe allergic reactions were observed, and no serious adverse events reported were thought to be related to the study drug. Longer-term studies are needed to determine whether vosoritide effects pubertal growth velocity, body segment proportionality, final adult height, or complications associated with achondroplasia.

Limb-lengthening surgery – Limb-lengthening surgeries have been used in the past and are resurging due 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) [31]. 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 [32]. 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 and cardiovascular health – Avoiding obesity should be discussed early on. Proper nutrition and physical activity are important measures in preventing obesity. Using proper blood pressure cuffs (narrower and better fitting) is important to monitor and treat elevated blood pressure.

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 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 may include osteotomies of the proximal fibula and epiphysiodesis (image 5) [33]. 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.

Cervicomedullary compression – Neurosurgical referral is indicated in children with suspected compression of the cervicomedullary 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.

Perioperative complications – Patients with skeletal dysplasia such as achondroplasia are at increased risk for perioperative morbidity and mortality due to abnormalities of their upper airway, chest wall, and upper cervical spine. Complications include neural compression and difficulty with intubation and securing of the airway. A best practices report from a multidisciplinary, international expert panel outlines recommendations for perioperative management of patients with skeletal dysplasia, with the goal of reducing complications and improving clinical outcomes [34]. Recommendations include preoperative pulmonary, cardiac, and neurologic evaluations and imaging of the cervical spine, as well as performance of surgeries at tertiary care centers that have the expertise to manage these patients.

Pregnancy – Pregnant females with achondroplasia will require cesarean section for delivery due to their small pelvic size. In addition, a female 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 caregivers 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 switch placement, and use of extenders.

ANTICIPATORY GUIDANCE — Vertical swings should not be used. Children with achondroplasia have larger heads, and the swings can force the head in hyperflexion position leading to cord compression. Deaths have been reported as a result of using vertical swings.

Care should be exerted when picking up a baby to support the head in neutral position and avoid extreme flexion of the head. Back strollers are favored over umbrella strollers to avoid flexion. Car seats should be rear facing and include a roller or the use of a head strap to avoid flexion of the head [35].

EXPERIMENTAL DRUG THERAPIES — Other therapies based upon the action of cartilage natriuretic peptide (CNP) are under further investigation for achondroplasia. A long-acting CNP, which promotes bone growth and endochondral ossification [36] and has rescued achondroplasia mouse models through inhibition of a mitogen activated protein kinase (MAP-K)-dependent pathway [37], is under study in a phase II clinical trial. Other strategies in experimental phase II trials include the use of the use of soluble fibroblast growth factor receptor 3 (FGFR3) acting as decoy receptor to bind fibroblast growth factor (FGF) ligands. This approach has been successfully studied in animal models [38].

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.

SUMMARY AND RECOMMENDATIONS

Overview – Achondroplasia is an autosomal dominant disorder caused by pathogenic variants in the fibroblast growth factor receptor 3 (FGFR3) gene. It is the most common bone dysplasia in humans. (See 'Introduction' above and 'Genetics and pathophysiology' above.)

Clinical features – 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 and radiographic findings – 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 'Diagnosis' above and 'Radiographic findings' above.)

Differential diagnosis – The differential diagnosis includes hypochondroplasia, thanatophoric dysplasia, and homozygous achondroplasia. (See 'Differential diagnosis' above.)

Complications – 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 persons. 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.)

Management – 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. Use of growth hormone is not recommended and can potentially worsen the disproportion seen in patients with achondroplasia. Vosoritide, a recombinant C-type natriuretic peptide analog that stimulates endochondral ossification, a process that is inhibited in patients with achondroplasia, is an option to increase linear growth in children with achondroplasia ≥5 years of age whose epiphyses are still open. (See 'Management' above and 'Experimental drug therapies' above.)

Anticipatory guidance – Vertical swings should be avoided because use can lead to sudden death due to hyperflexion of the neck and cord compression. Care should be exerted when picking up a baby to support the head in neutral position. Back strollers are favored over umbrella strollers. Rear-facing car seats are recommended, including a roller or a head strap to avoid hyperflexion. (See 'Anticipatory guidance' above.)

  1. Shiang R, Thompson LM, Zhu YZ, et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 1994; 78:335.
  2. Sahni M, Ambrosetti DC, Mansukhani A, et al. FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. Genes Dev 1999; 13:1361.
  3. Wilkin DJ, Szabo JK, Cameron R, et al. Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. Am J Hum Genet 1998; 63:711.
  4. Goriely A, Wilkie AO. Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am J Hum Genet 2012; 90:175.
  5. Orioli IM, Castilla EE, Barbosa-Neto JG. The birth prevalence rates for the skeletal dysplasias. J Med Genet 1986; 23:328.
  6. Barbosa-Buck CO, Orioli IM, da Graça Dutra M, et al. Clinical epidemiology of skeletal dysplasias in South America. Am J Med Genet A 2012; 158A:1038.
  7. Stoll C, Dott B, Roth MP, Alembik Y. Birth prevalence rates of skeletal dysplasias. Clin Genet 1989; 35:88.
  8. Stratbucker WB. In brief: Achondroplasia. Pediatr Rev 2009; 30:114.
  9. Stender M, Pimenta JM, Cheung M, et al. Comprehensive literature review on the prevalence of comorbid conditions in patients with achondroplasia. Bone 2022; 162:116472.
  10. Okenfuss E, Moghaddam B, Avins AL. Natural history of achondroplasia: A retrospective review of longitudinal clinical data. Am J Med Genet A 2020; 182:2540.
  11. Todorov AB, Scott CI Jr, Warren AE, Leeper JD. Developmental screening tests in achondroplastic children. Am J Med Genet 1981; 9:19.
  12. Fowler ES, Glinski LP, Reiser CA, et al. Biophysical bases for delayed and aberrant motor development in young children with achondroplasia. J Dev Behav Pediatr 1997; 18:143.
  13. Brust JS, Ford CV, Rimoin DL. Psychiatric aspects of dwarfism. Am J Psychiatry 1976; 133:160.
  14. Spranger JW, Brill P, Superti-Furga A, et al. Bone displasias. In: An Atlas of Genetic Disorders of Skeletal Development, 3rd ed., Oxford University Press, 2012.
  15. Kao SC, Waziri MH, Smith WL, et al. MR imaging of the craniovertebral junction, cranium, and brain in children with achondroplasia. AJR Am J Roentgenol 1989; 153:565.
  16. Hecht JT, Horton WA, Reid CS, et al. Growth of the foramen magnum in achondroplasia. Am J Med Genet 1989; 32:528.
  17. Pauli RM, Legare JM.. GeneReviews®, Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A. (Eds), University of Washington, Seattle, Seattle (WA) 1993.
  18. Bober MB, Bellus GA, Nikkel SM, Tiller GE. Hypochondroplasia. In: GeneReviews [Internet], Eds. Pagon RA, Adam MP, Ardinger HH, et al. University of Washington, Seattle, 2004.
  19. Karczeski B, Cutting GR. Thanatophoric Dysplasia. In: GeneReviews [Internet], Eds. Pagon RA, Adam MP, Ardinger HH, et al. University of Washington, Seattle, 2004.
  20. Pauli RM, Conroy MM, Langer LO Jr, et al. Homozygous achondroplasia with survival beyond infancy. Am J Med Genet 1983; 16:459.
  21. Hoover-Fong JE, McGready J, Schulze KJ, et al. Weight for age charts for children with achondroplasia. Am J Med Genet A 2007; 143A:2227.
  22. Hoover-Fong J, Alade AY, Ain M, et al. Blood pressure in adults with short stature skeletal dysplasias. Am J Med Genet A 2020; 182:150.
  23. Rimoin DL. Cervicomedullary junction compression in infants with achondroplasia: when to perform neurosurgical decompression. Am J Hum Genet 1995; 56:824.
  24. Pauli RM, Horton VK, Glinski LP, Reiser CA. Prospective assessment of risks for cervicomedullary-junction compression in infants with achondroplasia. Am J Hum Genet 1995; 56:732.
  25. Hecht JT, Francomano CA, Horton WA, Annegers JF. Mortality in achondroplasia. Am J Hum Genet 1987; 41:454.
  26. Danielpour M, Wilcox WR, Alanay Y, et al. Dynamic cervicomedullary cord compression and alterations in cerebrospinal fluid dynamics in children with achondroplasia. Report of four cases. J Neurosurg 2007; 107:504.
  27. Horton WA, Rotter JI, Kaitila I, et al. Growth curves in achondroplasia. Birth Defects Orig Artic Ser 1977; 13:101.
  28. Horton WA, Rotter JI, Rimoin DL, et al. Standard growth curves for achondroplasia. J Pediatr 1978; 93:435.
  29. Savarirayan R, Irving M, Bacino CA, et al. C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia. N Engl J Med 2019; 381:25.
  30. Savarirayan R, Tofts L, Irving M, et al. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lancet 2020; 396:684.
  31. Yasui N, Kawabata H, Kojimoto H, et al. Lengthening of the lower limbs in patients with achondroplasia and hypochondroplasia. Clin Orthop Relat Res 1997; :298.
  32. Baumgart R, Betz A, Schweiberer L. A fully implantable motorized intramedullary nail for limb lengthening and bone transport. Clin Orthop Relat Res 1997; :135.
  33. Ain MC, Shirley ED, Pirouzmanesh A, et al. Genu varum in achondroplasia. J Pediatr Orthop 2006; 26:375.
  34. White KK, Bompadre V, Goldberg MJ, et al. Best practices in peri-operative management of patients with skeletal dysplasias. Am J Med Genet A 2017; 173:2584.
  35. Pauli RM. Achondroplasia: a comprehensive clinical review. Orphanet J Rare Dis 2019; 14:1.
  36. Yasoda A, Ogawa Y, Suda M, et al. Natriuretic peptide regulation of endochondral ossification. Evidence for possible roles of the C-type natriuretic peptide/guanylyl cyclase-B pathway. J Biol Chem 1998; 273:11695.
  37. Yasoda A, Komatsu Y, Chusho H, et al. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med 2004; 10:80.
  38. Garcia S, Dirat B, Tognacci T, et al. Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. Sci Transl Med 2013; 5:203ra124.
Topic 103825 Version 10.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟