Question

    Achondroplasia (SADDAN)

    Achondroplasia is a common type of dwarfism.

    Achondroplasia develops due to the following process: congenital.

    Presentation

    Achondroplasia is present at birth and is seen as disproportionately short-limbs, and specific facial features due to abnormal bone growth. Infants with achondroplasia suffer a high rate of apnea and sudden death in the neonatal period [12]. The principle features of achondroplastic dwarfism include [2] [7] [11] [13]:

    • Rhizomelic (proximal) shortening of the extremities with normal trunk size
    • Decreased growth of the long bones of the proximal extremities (humerus and femur)
    • Macrocephaly 
    • Abnormal development of the base of the skull with narrowing of the foraman magnum
    • Under-development of the mid-face
    • Stenosis of the spinal canal and intervertebral foramen
    • Genu varum

    Macrocephaly is often present due to triventricular enlargement and hydrocephalus may result [8] [11]. However, intracranial pressure is not elevated significantly [8] [9]. The distinctive facial features include [3] [11]:

    • Frontal bossing 
    • Flattened nasal bridge
    • Hypoplasia of the mid-face
    • Prominent mandible

    Achondroplasia is a short-limb dwarfism. These individuals have a sitting height that is normal, while standing height is below the third percentile. The mean adult standing height for men is 132 cm (52 in), and that for women is 125 cm (49 in) [3] [11]. The upper arms and thighs are more severely involved than the forearms, legs, hands, and feet [3]. There is normal development of clavicle and musculature resulting in broad, strong shoulders. The anterior-posterior chest diameter is flattened, lower ribs flared, and the abdomen protrudes [3] [11].

    Complications associated with achondroplasia include [3] [9] [11] [14]:

    Respiratory complications

    The most serious complications of achondroplasia are restrictive respiratory disease, apnea, pneumonia, and sudden infant death resulting from compression of the medulla oblongata [3] [12]. The prevalence of respiratory complications in this population is reported to be 12% versus 0.92% in the general population [12]. Pneumonia remains a primary cause of death [12].

    Neurologic complications

    Half of the patients with achondroplasia show neurological complications [2] [9]. Abnormal development of the base of the skull results in compression of the cervicomedullary region. Affected individuals also have smaller foramen magnum dimensions and abnormal shape [9] [11] [13]. These two conditions may cause respiratory insufficiency, apnea, cyanotic episodes, feeding problems, quadriparesis, and sudden death [9].

    Spinal deformities are the most common and potentially disabling problems seen in achondroplasia [9] [11]. Stenosis of the spinal canal and intervertebral foramen can result in sensory deficits, lower and upper motor neuron involvement which result in low back pain, leg pain, dysesthesia, paresthesia, paraparesis, and incontinence [9]. 

    Narrowing of the foramen magnum may result in a variety of neurologic problems in the first several years of life particularly [4] [9] [11]. It is the primary factor responsible for respiratory problems and sudden infant death of infants with achondroplasia in the neonatal period [4].

    Abnormal curvature of the spine (kyphosis, lordosis, scoliosis) is present in 33-50% of adults with achondroplasia [9] [11]. It may cause back pain, respiratory dysfunction, neurologic deficits, or symptoms of spinal stenosis [9]. These abnormalities generally do not require treatment [10].

    Developmental issues

    In achondroplasia children milestones are delayed across all ages and domains compared with the general population [3] [14]. Children up to 7 years of age have a greater need for caregiver assistance in all areas [14]. Functional delays are related to musculoskeletal impairments [3] [14]. Head control, sitting, standing, and ambulation may lag by 3-6 months [8][14]. Children with achondroplasia show improvement in functioning with physical therapy between the ages of 3 and 5 years, but not after this [14].

    Speech and language problems are common with achondroplasia. They are caused by tongue thrust that usually resolve spontaneously [8] [14]. Cognitive development and the intelligence levels in these children are generally normal [8] [14].

    Recurrent otitis media is common due to poor drainage of the Eustachian tubes from underdevelopment of the mid-face. This may result in moderate to severe hearing loss [3] [10].

    Obesity is a lifelong issue for affected individuals. As a result these individuals are at higher risk of chronic diseases such as diabetes and cardiovascular disease [3] [10]. These conditions have a direct causal relationship with early mortality rates due to stroke and myocardial infarction [10].

    Entire body system
    Developmental Delay
    • Associations SADDAN syndrome : severe achondroplasia with developmental delay and acanthosis nigricans Almost all the bones of the skeleton are affected, and hence all parts of the body have bony changes with secondary soft tissue changes.[radiopaedia.org]
    • Cord compression at the level of the foramen magnum can be encountered in infancy and early childhood causing central apnea, developmental delay, and long-track signs.[orpha.net]
    • Developmental delays, intellectual disabilities, and mild to moderate retardation are characteristic of this genetic condition.[sharecare.com]
    Recurrent Otitis Media
    • Clinical Findings Delayed motor development Recurrent otitis media Normal intelligence Short stature Lower extremity radiculopathy Imaging Findings Can be detected before birth by the use of prenatal ultrasound After birth, conventional radiography is[learningradiology.com]
    • Recurrent otitis media is common due to poor drainage of the Eustachian tubes from underdevelopment of the mid-face.[symptoma.com]
    • Achondroplasia: Complications Review possible medical complications related to Achondroplasia: Spinal symptoms Paraplegia #in 2nd or 3rd decade Dental malocclusion Strabismus Kyphosis Recurrent otitis media Neurologic problems #occurs in early adulthood[rightdiagnosis.com]
    • Ear, nose and throat abnormalities such as recurrent otitis media, upper respiratory tract obstruction, deafness, speech delay, and jaw malocclusion can also lead to disabilities in communication and learning. [ 9 ] Respiratory complications may include[patient.info]
    • Results Of the 22 patients, 15 (68%) received an otologic diagnosis, including 6 with recurrent otitis media and 5 with otitis media with effusion, and 11 patients (50%) underwent an otologic procedure, with 10 undergoing tympanostomy tube insertion.[archfaci.jamanetwork.com]
    Short Finger
    • At birth, a child with this condition will likely have: a short stature that’s significantly below average for age and sex short arms and legs, especially the upper arms and thighs, in comparison to body height short fingers in which the ring and middle[healthline.com]
    • People who have achondroplasia have abnormal bone growth that causes the following clinical symptoms: short stature with disproportionately short arms and legs, short fingers, a large head (macrocephaly) and specific facial features with a prominent forehead[genome.gov]
    • Disproportionate dwarfism Shortening of the proximal limbs (called rhizomelic shortening) Short fingers and toes with trident hands Large head with prominent forehead frontal bossing Small midface with a flattened nasal bridge Spinal kyphosis (convex[en.wikipedia.org]
    • fingers Trident hand, a condition in which you have an extra space between the middle and ring fingers Weak muscle tone.[marchofdimes.org]
    • fingers held in a trident configuration Bowed legs Thoracolumbar gibbus (hump or protuberance) in infancy Exaggerated lumbar lordosis (swayback) develops when walking begins Large head with frontal bossing (prominence) Midface hypoplasia Modestly constricted[en.wikibooks.org]
    Short Stature in Children
    • The most common reasons for short stature in children are familial short stature, a difference in the timing of growth (called constitutional growth delay) and, in girls, Turner syndrome.[gemssforschools.org]
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  • Face, Head & Neck
    Frontal Bossing
    • This disorder is characterized by frontal bossing, midface hypoplasia, otolaryngeal system dysfunction, and rhizomelic short stature.[orthobullets.com]
    • Affected individuals exhibit short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and mid-face hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, GENU VARUM, and trident hand.[fpnotebook.com]
    • Features Bowing of extremities, waddling gait, limited ROM of major joints, frontal bossing, short stubby fingers, moderate hydrocephalus, depressed nasal bridge, lumbar lordosis.[medical-dictionary.thefreedictionary.com]
    • […] development Recurrent otitis media Normal intelligence Short stature Lower extremity radiculopathy Imaging Findings Can be detected before birth by the use of prenatal ultrasound After birth, conventional radiography is the study of first choice Skull Frontal[learningradiology.com]
    Mid-Face Hypoplasia
    • Affected individuals exhibit short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and mid-face hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, GENU VARUM, and trident hand.[fpnotebook.com]
    • According to the BioMarin press release, Beyond disproportionate short stature, people with achondroplasia can experience serious health complications, including foramen magnum compression, sleep apnea, bowed legs, mid-face hypoplasia, permanent sway[starcasm.net]
    • Achondroplasia is the most frequent form of short-limb dwarfism. [ 1 ] As well as short stature due to shortening of limbs, affected individuals have characteristic facies with frontal bossing and mid-face hypoplasia, exaggerated lumbar lordosis, limitation[patient.info]
    • Beyond disproportionate short stature, people with achondroplasia can experience serious health complications, including foramen magnum compression, sleep apnea, bowed legs, mid-face hypoplasia, permanent sway of the lower back, spinal stenosis, recurrent[globenewswire.com]
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  • neurologic
    Dysesthesia
    • Bracing may be needed if the radiograph shows and irreversible curve of 30 Surgical intervention may be necessary Lumbosacral Spinal Stenosis- Stenosis of the entire spinal canal is uniformly present; more problematic in adults Symptoms include: numbness, dysesthesias[en.wikibooks.org]
    • Stenosis of the spinal canal and intervertebral foramen can result in sensory deficits, lower and upper motor neuron involvement which result in low back pain, leg pain, dysesthesia, paresthesia, paraparesis, and incontinence. [symptoma.com]
    Paresthesia
    • Stenosis of the spinal canal and intervertebral foramen can result in sensory deficits, lower and upper motor neuron involvement which result in low back pain, leg pain, dysesthesia, paresthesia, paraparesis, and incontinence. [symptoma.com]
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  • respiratoric
    Pneumonia
    • Pneumonia remains a primary cause of death.[symptoma.com]
    • Sisk et al 10 also described complications in 6 patients with achondroplasia after undergoing TA, including postoperative pneumonia, postobstructive pulmonary edema, and bleeding.[archfaci.jamanetwork.com]
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  • gastrointestinal
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  • musculoskeletal
    Back Pain
    • It may cause back pain, respiratory dysfunction, neurologic deficits, or symptoms of spinal stenosis.[symptoma.com]
    • Some affected people also develop abnormal front-to-back curvature of the spine ( kyphosis ) and back pain.[ghr.nlm.nih.gov]
    • According to the press release, “The majority of [adverse effects] reported were mild (Grade 1) and included injection site reactions, headache, hypotension, back pain and cough.”[starcasm.net]
    • The problems with the lower back can cause back pain leading to difficulty with walking.[genome.gov]
    • If your child has achondroplasia, call the healthcare provider if your child has back pain or trouble breathing.[urmc.rochester.edu]
    Lordosis
    • Affected individuals exhibit short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and mid-face hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, GENU VARUM, and trident hand.[fpnotebook.com]
    • The lumbar lordosis is persistent into adulthood.[medicinenet.com]
    • Features Bowing of extremities, waddling gait, limited ROM of major joints, frontal bossing, short stubby fingers, moderate hydrocephalus, depressed nasal bridge, lumbar lordosis.[medical-dictionary.thefreedictionary.com]
    • But walking often leads to the lower back curving inward (lordosis).[urmc.rochester.edu]
    Low Back Pain
    • This can cause low back pain, problems with urination and weakness, tingling and pain in the legs.[marchofdimes.org]
    • Stenosis of the spinal canal and intervertebral foramen can result in sensory deficits, lower and upper motor neuron involvement which result in low back pain, leg pain, dysesthesia, paresthesia, paraparesis, and incontinence. [symptoma.com]
    Macrocephaly
    • These clinical findings include: shortened limbs especially of upper arms and legs, macrocephaly, abnormally shaped skull, flat face and abnormal maxilla.[symptoma.com]
    • Patients with ACH exhibit macrocephaly ( 3 ).[jci.org]
    • Achondroplasia is a genetic disorder that causes short stature, called dwarfism, and a large head, also known as macrocephaly.[uvahealth.com]
    • Clinical description Characteristic clinical features (short limbs with rhizomelia, long and narrow trunk and macrocephaly with frontal bossing and midfacial hypoplasia with depressed nasal bridge) are visible at birth.[orpha.net]
    • Characteristic features of achondroplasia include an average-size trunk, short arms and legs with particularly short upper arms and thighs, limited range of motion at the elbows, and an enlarged head ( macrocephaly ) with a prominent forehead .[ghr.nlm.nih.gov]
    Short Arm
    • This causes a series of signs, such as short arms and legs and a large head.[urmc.rochester.edu]
    • Sufferers have an average height of just 1.2 metres and have disproportionately short arms and legs.[dictionary.reverso.net]
    • The appearance is of short stature with disproportionately short arms and legs and a large head.[rightdiagnosis.com]
    • At birth or within the first year of life, with disparity between large skull, normal length trunk and short arms and legs.[patient.info]
    Short Extremities
    • Achondroplasia is a disorder of bone formation, primarily affecting the long bones of the extremities and the base of the skull, resulting in characteristic features of short extremities, a large head, and trident-shaped hands ( Emerson 1909 ).[medlink.com]
    • The baby with achondroplasia has a relatively long, narrow torso (trunk) with short extremities (arms and legs) and a disproportionate shortening of the proximal (near the torso) segments of the limbs (the upper arms and thighs).[medicinenet.com]
    Short Hands
    • hands with fingers that assume a "trident" or three-pronged position during extension.[webmd.com]
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  • cardiovascular
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  • urogenital
    Incontinence
    • Neurosurgical symptoms that may indicate the need for corrective surgery include back pain, muscle weakness, incontinence, hypotonia, psychomotor delay, apnea, and respiratory arrest.[symptoma.com]
    • Hydrocephalus, a narrow foramen magnum, spinal deformity, and spinal canal stenosis can cause neurological problems (eg, progressive quadriparesis, pain, ataxia, incontinence) leading to disabilities in locomotion, communication, and learning.[patient.info]
    • Lumbar spinal stenosis can also lead to neurologic deficits later in life, such as leg claudication and incontinence.[archfaci.jamanetwork.com]
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  • Ears
    Hearing Problem
    • Chronic otitis media can lead to hearing problems.[orpha.net]
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  • Workup

    Diagnosis of achondroplasia is made based on physical examination and genetic testing [3] [10]. Early identification of the disorder is generally made either prenatally or in early infancy by the presence of the distinctive features of the disease [3]. These clinical findings include: shortened limbs especially of upper arms and legs, macrocephaly, abnormally shaped skull, flat face and abnormal maxilla [2]. The particular pattern of long-bone growth is specific to achondroplasia [2] [11].

    Diagnosis of achondroplasia may also be made using prenatal ultrasonography to detect the skeletal abnormalities. However changes in limb lengths do not occur until 20-24 weeks’ gestation, after this time the growth rate decreases [2] [3].

    Laboratory studies

    Recent advances in molecular biology has made cell free fetal deoxyribonuleic acid (DNA) analysis allows genetic diagnosis of this condition using a maternal blood sample [2]. Analysis of plasma for the fibroblast growth factor receptor 3 (FGFR3) mutation in the mother can be done when a short-limb skeletal dysplasia is diagnosed prenatally on ultrasound [3] [7].

    Imaging studies [10] [11]

    • Radiography: X-rays of individuals with achondroplasia show the characteristic features of the disease.
    • Ultrasonography of brain in the neonate can detect ventricle size and other abnormalities [9].
    • Computed tomography of brain, skull, trunk,and rib cage.
    • Magnetic resonance imaging evaluation is needed in any patient with neurological symptoms [9] [10]. A baseline scan is strongly recommended in infancy to evaluate potential problems [10]. 

    Other tests when indicated [9] [10]:

    • Pulmonary function tests are indicated when respiratory symptoms are present. These show the vital capacity decreased by 68% for males and 72% for females.
    • Sleep apnea studies are useful in those with sleep hypoxia
    • Intracranial pressure monitoring with moderate ventriculomegaly. Treatment is recommended when the ICP is greater than 15 mm. 
    • Somatosensory evoked potential (SSEP) as abnormalities have been reported in 44% of patients with Achondroplasia.

    Further evaluation of individuals with achondroplasia should include consultation by [8] [10]:

    • Geneticist
    • Neurologist, neurosurgeon
    • Pulmonary specialist
    • Orthopedist
    • Rehabilitation physiatrist
    • Speech therapist

    Test Results

    Pulmonary Function Test
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  • Imaging

    X-ray
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  • Treatment

    There is no specific treatment for achondroplasia at this time. Prenatal gene therapy is still in the future. Current therapy is essentially supportive to prevent the common complications associated with the disease [3] [10]. Therapeutic strategies are aimed at reducing fibroblast growth factor receptor 3 signals, such as kinase inhibitors and neutralizing antibodies [3] [6]. Administration of C-type natriuretic peptide is currently in the early stages of development. Further research into long-term effectives and safety of this drug is needed [3] [6].

    Growth hormone is used to increase the height of patients with achondroplasia. There is no long-term data about the routine use of growth hormone and it remains controversial [3] [6]. There may be metabolic effects on the patient's lipid profile, bone mineral density, and muscle mass, and cardiovascular risk [6]. Somatotropin, a recombinant human growth hormone, for the treatment of short stature has shown acceleration in growth, particularly in the first year of treatment. It is recommended that therapy be started between age 1 to 6 years for maximum benefits [6].

    Early identification and immediate cervicomedulary decompression procedure are needed to prevent serious neurological complications occurring in achondroplasia. These complications include respiratory failure, apnea and sudden death [9] [10].

    Neurosurgical symptoms that may indicate the need for corrective surgery include back pain, muscle weakness, incontinence, hypotonia, psychomotor delay, apnea, and respiratory arrest [9][10].

    Surgical procedures [3] [9] [10]:

    • Foramen magnum decompression and C1 laminectomy.
    • Ventriculoperitoneal shunts are indicated for patients with progressive hydrocephalus, increased intracranial pressures, and Chiari malformation.
    • Limb lengthening of the upper and lower extremities is controversial.
    • Surgical correction of genu varum.

    Children with achondroplasia require more assistance for self-care and mobility skills. Interventions in this area should include physical therapy, occupational therapy, and speech therapy [8][14].

    Obesity is a common complication in individuals with achondroplasia [15]. Obesity increases the risk for health problems such as cardiovascular disease and diabetes [5].

    Prognosis

    Overall survival and the average life expectancy for those with achondroplasia are decreased by approximately 10 years from the general population, despite advances in the knowledge of and health care needs [4] [10]. Early mortality generally results from the effects of skeletal and neurologic deformities, and is due to respiratory or cardiovascular complications [9].

    The risk of producing a second affected child is negligible with a 1 in 443 risk of recurrence in the siblings of an affected child with unaffected parents [3] [7]. Normal sized siblings have no increased risk of producing a child with achondroplasia [7].

    When both parents have achondroplasia [3] [7]:

    • 50% of their offspring are heterozygous and affected
    • 25% are homozygous which is usually fatal in the first few months of life
    • 25% are unaffected

    If DNA testing shows the gene mutation present in both parents their infants have a 50% risk of inheriting affected genes from both parents (double homozygous). They are either stillborn or die shortly after birth [7].

    Complications

    Apnea
    • Sleep apnea studies are useful in those with sleep hypoxia. [symptoma.com]
    • Pulmonology and apnea Respiratory disorders are seen frequently, including apnea and abnormalities of pulmonary gas exchange.[emedicine.medscape.com]
    • Midface hypoplasia in combination with adenoid and tonsil hypertrophy can lead to obstructive sleep apnea.[orpha.net]
    • Apnea and sudden expected death in infants with achondroplasia.[archfaci.jamanetwork.com]
    • Babies often have episodes of apnea.[urmc.rochester.edu]
    Craniosynostosis
    • The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans.[ghr.nlm.nih.gov]
    • Vajo Z, Francomano CA, Wilkin DJ: The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: The achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans.[link.springer.com]
    Deafness
    • Ear, nose and throat abnormalities such as recurrent otitis media, upper respiratory tract obstruction, deafness, speech delay, and jaw malocclusion can also lead to disabilities in communication and learning. [ 9 ] Respiratory complications may include[patient.info]
    Genu Varum
    • Note squaring of the iliac wings (tombstone pelvis), flattening of the acetabular angles (yellow arrows), genu varum deformities (white arrows) with widened but shorter femurs and flaring of the metaphyses (green arrow).[learningradiology.com]
    • Affected individuals exhibit short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and mid-face hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, GENU VARUM, and trident hand.[fpnotebook.com]
    • Surgical correction of genu varum.[symptoma.com]
    • Lower extremity alignment often is characterized by genu varum, which may require correction osteotomy.[journals.lww.com]
    • Bowed legs (genu varum) Spine curvatures called kyphosis and lordosis Delay in reaching developmental milestones Delay in walking independently until 2-3 years of age Difficulty with speech because of a tongue thrust, but this usually resolves by school[nationwidechildrens.org]
    Hydrocephalus
    Kyphosis
    • Kyphosis (a small hump in the upper back).[marchofdimes.org]
    • At Columbia University Medical Center/NewYork-Presbyterian Hospital, we specialize in surgically treating brain- and spine-related conditions that may arise with achondroplasia, such as hydrocephalus , kyphosis , spinal stenosis or an abnormal craniocervical[columbianeurosurgery.org]
    • They report thoracolumbar kyphosis is seen in most infants, but typically it resolves when the child begins to walk.[orthobullets.com]
    • Musculoskeletal- Kyphosis- Present in 90-95% of infants Usually spontaneously resolves Clinical evaluation of the spine every 6 months through 3 years of age If kyphosis is moderate or marked, radiographic assessment should be obtained Parents should[en.wikibooks.org]
    • Clinical features include megalocephaly, short limbs, prominent forehead, thoracolumbar kyphosis and mid-facial hypoplasia.[en.wikipedia.org]
    Obesity
    • Obesity is a common complication in individuals with achondroplasia.[symptoma.com]
    • Preventing obesity, to reduce joint and back problems, is also important.[nationwidechildrens.org]
    • Measures to avoid obesity at an early age are recommended.[genome.gov]
    • Control of obesity is essential, and obesity can be a significant problem in people with achondroplasia.[medicinenet.com]
    • Obesity is a common issue.[orpha.net]
    Otitis Media
    • Chronic otitis media can lead to hearing problems.[orpha.net]
    • Clinical Findings Delayed motor development Recurrent otitis media Normal intelligence Short stature Lower extremity radiculopathy Imaging Findings Can be detected before birth by the use of prenatal ultrasound After birth, conventional radiography is[learningradiology.com]
    • Recurrent otitis media is common due to poor drainage of the Eustachian tubes from underdevelopment of the mid-face.[symptoma.com]
    • Children with achondroplasia who develop middle ear infections (acute otitis media ) will require quick treatment with antibiotics and careful monitoring in order to avoid hearing loss.[encyclopedia.com]
    • Complications like dental malocclusion, hydrocephalus and repeated otitis media can be observed.[en.wikipedia.org]
    Paraparesis
    • Stenosis of the spinal canal and intervertebral foramen can result in sensory deficits, lower and upper motor neuron involvement which result in low back pain, leg pain, dysesthesia, paresthesia, paraparesis, and incontinence. [symptoma.com]
    Quadriparesis
    • These two conditions may cause respiratory insufficiency, apnea, cyanotic episodes, feeding problems, quadriparesis, and sudden death.[symptoma.com]
    • Hydrocephalus, a narrow foramen magnum, spinal deformity, and spinal canal stenosis can cause neurological problems (eg, progressive quadriparesis, pain, ataxia, incontinence) leading to disabilities in locomotion, communication, and learning.[patient.info]
    Respiratory Failure
    • When homozygous, the condition is fatal due to respiratory failure 7 .[radiopaedia.org]
    • These individuals are usually stillborn or die shortly after birth from respiratory failure.[ghr.nlm.nih.gov]
    • These complications include respiratory failure, apnea and sudden death.[symptoma.com]
    Scoliosis
    • Abnormal curvature of the spine (kyphosis, lordosis, scoliosis) is present in 33-50% of adults with achondroplasia.[symptoma.com]
    • Patients with Marfan syndrome might also have a curved spine (known as scoliosis), low muscle tone or strength, and possibly a learning disability.[sharecare.com]
    Skeletal Dysplasia
    • Achondroplasia is a congenital genetic disorder resulting in rhizomelic dwarfism and is the most common skeletal dysplasia .[radiopaedia.org]
    • Additionally, a Korean study reported dwarfism-related skeletal dysplasias from the Joseon Dynasty ( Woo et al 2015 ).[medlink.com]
    • Achondroplasia, the most common skeletal dysplasia, is caused by a mutation of fibroblast growth factor receptor-3.[orthobullets.com]
    • Plasma can be analysed for the FGFR3 mutation in the mother when a short-limb skeletal dysplasia is diagnosed prenatally on ultrasound. [ 8 ] A full skeletal survey should be undertaken if there is clinical suspicion of skeletal dysplasia, such as disproportionate[patient.info]
    Spinal Stenosis
    • For instance, antibiotics are given for ear infections and surgery may be performed in severe cases of spinal stenosis .[healthline.com]
    • Notice the short pedicles, which often leads to spinal stenosis in these patients.[orthobullets.com]
    • Some patients may require a laminectomy for spinal stenosis as young adults.[nationwidechildrens.org]
    • Related abnormalities, including spinal stenosis and spinal cord compression, should be treated when they cause problems.[mountsinai.org]
    Sudden Death
    Upper Airway Obstruction
    • Sleep and upper airway obstruction in children with achondroplasia.[archfaci.jamanetwork.com]
    • Severe upper airway obstruction occurs in less than 5% in children with achondroplasia.[emedicine.medscape.com]
    • Compression of the spinal cord and/or upper airway obstruction increases the risk of death in infancy.[genome.gov]
    • The risk of death in infancy is increased due to the likelihood of compression of the spinal cord with or without upper airway obstruction.[en.wikipedia.org]
    • airway obstruction, apnea, feeding problems Hydrocephalus Recurrent otitis media with subsequent hearing loss Spinal deformities: kyphosis, lordosis, scoliosis Developmental delays Obesity Genu varum (bowing of lower legs) Cardiovascular complications[symptoma.com]
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  • Etiology

    The term achondroplasia, though inaccurate, means absence of cartilage. It was first used by Parrot in 1878 [3]. Achondroplasia is the most common osteochondrodysplasia, a genetic disorder which is associated with abnormal bone growth at the growth plates [3] [7] [8]. The mode of inheritance is autosomal dominance, however, most cases represent as a new mutation [6] [8].

    The genetic defect responsible for achondroplasia has been known for over a decade [3]. More than 95% of patients have a mutation in the gene for fibroblast growth factor receptor 3 (FGFR3) [3] [7]. This gene is responsible for the transmission of the signal to stimulate bone growth. Without this activation, individuals with achondroplasia fail to grow, particularly, the long bones of the proximal extremities [7].

    Achondroplasia is associated with a number of life-threatening complications [8] [9]. No effective treatments to stimulate bone growth have been found [3] [6]. Life-expectancy for those with achondroplasia continues to be 10 or more years shorter than the general population [4]. The causes of death for these individuals are related to the complications associated with the skeletal deformities and their impact on the neurologic and cardiovascular systems [3] [4] [9].

    In children younger than 4 years, brain stem compression is the most common cause of death [4]. In those 5-24 years of age, the common causes of mortality are central nervous system and respiratory problems [4]. In persons aged 25-54 years, cardiovascular problems are the most frequent causes of death [4].

    The complexity of the condition led to the development of Heath Supervision Guidelines published by the American Academy of Pediatrics in 1995 and revised in 2005 [8] [10].

    Epidemiology

    The prevalence of achondroplasia is estimated to be approximately 10,000 individuals in the United States and 150,000 to 250,000 worldwide [3]. The incidence of achondroplasia is 5–15 per 100 000 live births [2] [4].

    Achondroplasia affects all races [2]. It occurs with equal frequency in males and females [2].
    More than 95% of patients have a mutation in the gene for fibroblast growth factor receptor 3 [3]. 

    Higher death rates when adjusted for age are seen in the affected population [4]. Heart disease-related mortality, between ages 25 and 35, is more than 10 times higher than the general population [4].

    Sex distribution
    Age distribution

    Pathophysiology

    The skeleton is divided into 2 parts, the axial skeleton, or central core unit, and the appendicular skeleton, the bones of the extremities [11]. The primary defect of achondroplasia is abnormal endochondral ossification of the appendicular skeleton [8] [11].

    The molecular basis for achondroplasia is related to the fibroblast growth factors which are stimulate cell growth and migration, wound healing, and angiogenesis [7]. The cause of the disorder is a mutation of the fibroblast growth factor receptor 3 (FGFR3) [7] [3] located on the fourth chromosome [2]. The primary function of fibroblast growth factor receptor 3 is to limit osteogenesis [2] [7]. Fibroblast growth factor receptors transmit a mitogenic signal that is unique to growth plate chondrocytes [3] [7]. The mutation negatively regulates chondrocyte production and differentiation by suppressing mitogenic activity [9]. Recent research suggests that the disorder is due to increased signal transduction from the mutant receptor resulting in the failure of cell production and growth at the growth plate [2] [3].

    The genetic abnormality responsible for achondroplasia is a single gene mutation on the short arm of the fourth chromosome [2]. It can be transmitted as an autosomal dominant trait or as a new random mutation [2] [3]. Eighty percent of cases are the result of a new mutation which is linked to a paternal age over 36 years [2] [7]. Most parents are of normal size with no family history of a dwarfism [2].

    Prevention

    Most serious complications of achondroplasia can be prevented or reduced by anticipation and early treatment [3] [10]. Early neurological evaluation and intervention when indicated are required to prevent the high morbidity and mortality in infancy and childhood [9].

    Little People of America is an excellent resource for individuals with achondroplasia. This national organization deals with the social, physical, and medical needs of this population.

    Summary

    Achondroplasia is the most common type of short-limb skeletal dysplasia [1] [2]. It is a form of dwarfism characterized by intrinsic abnormalities in the growth of cartilage and bone [3] [4]. It causes short stature (dwarfism) with a standing height below the third percentile for age [4]. Achondroplasia accounts for 80% of all individuals recognized as "little people" [3]. It has an estimated worldwide prevalence of 250,000 [4] [5].

    Achondroplasia is a genetically inherited disease caused by a gene mutation of the fibroblast growth factor receptor 3 (FGFR3) [6]. This gene mutation affects the cartilaginous growth plate of the growing skeleton [3] [7]. It can result in a variety of deformities and complications [3].

    The disorder can be transmitted as an autosomal dominant disease from either or both parents [3] [7]. However, in 80% of affected infants it occurs as a new sporadic mutation, the highest incidence of which occur with fathers over 40 years of age [3].

    The life expectancy of individuals with achondroplasia is significantly lower than those not affected [3] [4]. Achondroplasia is associated with a number of life-threatening complications related to its skeletal abnormalities [4] [8]. Early mortality is the result of complications due to skeletal deformities causing restrictive respiratory disease, neurologic deficits, and cardiovascular problems [4] [9].

    Patient Information

    What is achondroplasia?

    Achondroplasia is a form of dwarfism characterized by shortened extremities with near normal trunk length. It is accompanied by a larger than normal head and specific, distinctive facial features. It is present at birth and accounts for a high rate of deaths in the neonatal period and early infancy. In those individuals with Achondroplasia, who survive early childhood, life expectancy is generally shorter due to cardiovascular and respiratory complications.

    What causes achondroplasia?

    Achondroplasia is a genetically inherited disorder due to a mutation on the gene that controls bone growth at the growth plates of the long bones. It affects primarily the long bones of the upper arms and legs, the rib cage, and the bones of the base of the skull and face.

    What are the symptoms?

    Decreased growth of the long bones of the extremities ( humerus and femur),

    • Abnormal development of the base of the skull
    • Narrowing of the spinal canal
    • Under-development of the mid-face with characteristic features
    • Macrocephaly (enlarged head)

    Who gets Achondroplasia?

    Achondroplasia is an inherited genetic disorder. Individuals with this disease inherit it from either one or both of their parents. The majority inherit it due to a new, mutation in the gene from one parent (paternal age over 40 years has been associated with a high incidence of achondroplasia).
    Parents generally are of normal height.

    How is it diagnosed?

    Achondroplasia is usually diagnosed by its characteristic skeletal features seen at birth or on prenatal ultrasound. Definitive diagnosis is made by the presence of the gene mutation on DNA analysis.

    What are the complications?

    The complications of achondroplasia are related to the skeletal deformities associated with the disease and include:

    How is achondroplasia treated?

    There is no specific treatment at this time. Research is being done on genetic interventions to overrule the effects of the gene mutation. The individual with achondroplasia is currently treated to prevent the life threatening complications of the disease. Early intervention and treatment to prevent neurologic and respiratory defects and prevention of obesity will hopefully extend the life expectancy of these individuals.

    How can achondroplasia be prevented?

    Achondroplasia cannot be prevented currently, however, research is being done involving gene therapy. Genetic counseling and prenatal testing can predict the disorder. Most serious complications can be prevented or reduced by anticipation and early treatment. Early neurological evaluation and intervention, when indicated, can prevent the high morbidity and mortality in infancy and childhood.

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    References

    1. Achondroplasia. (2015). In Encyclopædia Britannica. 
    2. Chitty LS, Griffin DR, Meaney C, Barrett A, Khalil A, Pajkrt E, J. Cole T. New aids for the non-invasive prenatal diagnosis of achondroplasia: dysmorphic features, charts of fetal size and molecular confirmation using cell-free fetal DNA in maternal plasma. Ultrasound Obstet Gynecol . 2011; 37: 283–289.
    3. Horton WA, Hall JG, Hecht JT. Achondroplasia. Lancet. 2007;370(9582):162-72. 
    4. Wynn J, King TM, Gambello MJ, Waller DK, Hecht JT. Mortality in achondroplasia study: A 42-year follow-up. Am J Med Genet A. 2007;143(21):2502-11. 
    5. Hoover-Fong JE, Schulze KJ, McGready J, Barnes H, Scott CI. Age-appropriate body mass index in children with achondroplasia: interpretation in relation to indexes of height. Am J Clin Nutr. 2008;88(2):364-71. 
    6. Mehta A, Hindmarsh PC. The use of somatropin (recombinant growth hormone) in children of short stature. Paediatr Drugs. 2002;4(1):37-47. 
    7. Wang Q, Green RP, Zhao G, Ornitz DM. Differential regulation of endochondral bone growth and joint development by FGFR1 and FGFR3 tyrosine kinase domains. Development. 2001;128(19):3867-76. 
    8. Ireland PJ, Johnson S, Donaghey S, Johnston L, Ware RS, Zankl A, et al. Medical management of children with achondroplasia: Evaluation of an Australasian cohort aged 0-5 years. J Paediatr Child Health. 2012:48(5);443-9. 
    9. Gil Z, Tauman R, Sivan J, et al. Neurosurgical aspects in achondroplasia: evaluation and treatment. Harefuah. 2001;140(11):1026-31, 1118.
    10. American Academy of Pediatrics Committee on Genetics. Health supervision for children with achondroplasia. Pediatrics. 1995;95(3):443-51. 
    11. Smoker WR, Khanna G. Imaging the craniocervical junction. Childs Nerv Syst. 2008;24(10):1123-45.

    • Anaesthesia for the achondroplastic dwarf - JF Mayhew, J Katz, M Miner, B Leiman - Canadian Journal of , 1986 - Springer
    • A glycine 375-to-cysteine substitution in the transmembrane domain of the fibroblast growth factor receptor-3 in a newborn with achondroplasia - A Superti-Furga, B Steinmann, R Gitzelmann - European journal of , 1995 - Springer
    • And genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome - Z Vajo, CA Francomano, DJ Wilkin - Endocrine reviews, 2000 - Endocrine Soc
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    • Achondroplasia and hydrocephalus A computerized tomographic, roentgenographic, and psychometric study - SM Mueller, W Bell, S Cornell, K deS HAMSHER - Neurology, 1977 - AAN Enterprises
    • A gene for achondroplasia–hypochondroplasia maps to chromosome 4p - M Le Merrer, F Rousseau, L Legeai-Mallet - Nature , 1994 - nature.com
    • A Case of Recurrent Craniopharyngioma - G Gayen, NC Mahapatra - 30th WB State PEDICON 2011, 2011 - iapwb.in
    • Achondroplasia - LO LANGER, PA BAUMANN - American Journal of , 1967 - Am Roentgen Ray Soc

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