Achondroplasia
CLINICAL FEATURES
Achondroplasia is the most common form of short-limbed
dwarfism. Gene frequency is estimated to be 1/16,000 and
1/35,000. There are about 5000 achondroplasts in the USA and
65,000 on Earth. The incidence for achondroplasia is between
0.5 and 1.5 in 10,000 births. The mutation rate is high and is
estimated to be between 1.72×10–5 and 5.57×10–5 per gamete
per generation. Most infants with achondroplasia are born
unexpectedly to parents of average stature.
1. Major clinical symptoms
a. Delayed motor milestones during infancy and early
childhood
b. Sleep disturbances secondary to both neurological
and respiratory complications
c. Breathing disorders
i. A high prevalence (75%) of breathing disorders
during sleep
ii. Obstructive apnea caused by upper airway
obstruction
iii. The majority of respiratory complaints due to
restrictive lung disease secondary to diminished
chest size or upper airway obstruction and rarely
due to spinal cord compression
d. Symptomatic spinal stenosis in more than 50% of
patients as a consequence of a congenitally small
spinal canal
i. Back pain
ii. Lower extremity sensory changes
iii. Incontinence
iv. Paraplegia
v. Onset of symptoms: usually after 20 seconds or
30 seconds
e. Neurologic symptoms classified based on neurologic
severity and presentation of spinal stenosis (Lutter
and Langer, 1977)
i. Type I (back pain with sensory and motor change
of an insidious nature)
ii. Type II (intermittent claudication limiting ambulation)
iii. Type III (nerve root compression)
iv. Type IV (acute onset paraplegia)
f. Symptoms secondary to foramen magnum stenosis
i. Respiratory difficulty
ii. Feeding problems
iii. Cyanosis, quadriparesis
iv. Poor head control
g. Symptoms secondary to cervicomedullary compression
i. Pain
ii. Ataxia
iii. Incontinence
iv. Apnea
v. Progressive quadriparesis
vi. Respiratory arrest
2. Major clinical signs
a. Disproportionate short stature (dwarfism)
b. Hypotonia during infancy and early childhood
c. Relative stenosis of the foramen magnum in all
patients, documented by CT
d. Foramen magnum stenosis considered as the cause of
increased incidence of:
GENETICS/BASIC DEFECTS
1. Inheritance
a. Autosomal dominant disorder with complete penetrance
b. Sporadic in about 80% of the cases, the result of a de
novo mutation
c. Presence of paternal age effect (advanced paternal
age in sporadic cases)
d. Gonadal mosaicism (two or more children with classic achondroplasia born to normal parents)
2. Caused by mutations in the gene of the fibroblast growth
factor receptor 3 (FGFR3) on chromosome 4p16.3
a. About 98% of achondroplasia with G-to-A transition
and about 1% G-to-C transversion at nucleotide 1138.
Both mutations resulted in the substitution of an arginine residue for a glycine at position 380 (G380A) of
the mature protein in the transmembrane domain of
FGFR3
b. A rare mutation causing substitution of a nearby
glycine 375 with a cysteine (G375C)
c. Another rare mutation causing substitution of
glycine346 with glutamic acid (G346E)
d. The specific mechanisms by which FGFR3 mutations
disrupt skeletal development in achondroplasia remain
elusive
3. Basic defect: zone of chondroblast proliferation in the
physeal growth plates
a. Abnormally retarded endochondral ossification with
resultant shortening of tubular bones and flat vertebral bodies, while membranous ossification (skull,
facial bones) is not affected
b. Physeal growth zones show normal columnization,
hypertrophy, degeneration, calcification, and ossification. However, the growth is quantitatively reduced
significantly
c. Achondroplasia as the result of a quantitative loss of
endochondral ossification rather than the formation of
abnormal tissue
d. Normal diameter of the bones secondary to normal
subperiosteal membranous ossification of tubular
bones; the results being production of short, thick
tubular bones, leading to short stature with disproportionately shortened limbs
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ACHONDROPLASIA
i. Hypotonia
ii. Sleep apnea
iii. Sudden infant death syndrome
e. Symptomatic hydrocephalus in infancy and early childhood rarely due to narrowing of the foramen magnum
f. Characteristic craniofacial appearance
i. Disproportionately large head
ii. Frontal bossing
iii. Depressed nasal bridge
iv. Midfacial hypoplasia
v. Narrow nasal passages
vi. Prognathism
vii. Dental malocclusion
g. A normal trunk length
h. A thoracolumbar kyphosis or gibbus usually present
at birth or early infancy
i. Exaggerated lumbar lordosis when the child begins to
ambulate
j. Prominent buttocks and protuberant abdomen secondary to increased pelvic tilt in children and adults
k. Generalized joint hypermobility, especially the knees
l. Rhizomelic micromelia (relatively shorter proximal
segment of the limbs compared to the middle and the
distal segments)
m. Limited elbow and hip extension
n. Trident hands (inability to approximate the third and
fourth fingers in extension produces a “trident” configuration of the hand)
o. Short fingers (brachydactyly)
p. Bowing of the legs (genu varum) due to lax knee ligaments
q. Excess skin folds around thighs
3. Complications/risks
a. Recurrent otitis media during infancy and childhood
i. Conductive hearing loss
ii. Delayed language development
b. Thoraco-lumbar gibbus
c. Osteoarthropathy of the knee joints
d. Neurological complications
i. Small foramen magnum
ii. Cervicomedullary junction compression causing
sudden unexpected death in infants with achondroplasia
iii. Apnea
iv. Communicating hydrocephalus
v. Spinal stenosis
vi. Paraparesis
vii. Quadriparesis
viii. Infantile hypotonia
e. Obesity
i. Aggravating the morbidity associated with lumbar stenosis
ii. Contributing to the nonspecific joint problems
and to the possible early cardiovascular mortality in this condition
f. Obstetric complications
i. Large head of the affected infant
ii. An increased risk of intracranial bleeding during
delivery
iii. Marked obstetrical difficulties secondary to very
narrow pelvis of achondroplastic women
4. Prognosis
a. Normal intelligence and healthy, independent, and
productive lives in vast majority of patients. Rarely,
intelligence may be affected because of hydrocephalus or other CNS complications
b. Mean adult height
i. Approximately 131 ± 5.6 cm for males
ii. Approximately 124 ± 5.9 cm for females
c. Psychosocial problems related to body image because
of severe disproportionate short stature
d. Life- span for heterozygous achondroplasia
i. Usually normal unless there are serious complications
ii. Mean life expectancy approximately 10 years
less than the general population
e. Homozygous achondroplasia
i. A lethal condition with severe respiratory distress caused by rib-cage deformity and upper
cervical cord damage caused by small foramen
magnum. The patients die soon after birth
ii. Radiographic changes much more severe than
the heterozygous achondroplasia
f. Normal fertility in achondroplasia
i. Pregnancy at high risk for achondroplastic
women
ii. Respiratory compromise common during the
third trimester
iii. Advise baseline pulmonary function studies
before pregnancy to aid in evaluation and management
iv. A small pelvic outlet usually requiring cesarean
section under general anesthesia since the spinal
or epidural approach is contraindicated because
of spinal stenosis
g. Anticipatory guidance: patients and their families can
benefit greatly from anticipatory guidance published
by American Academy of Pediatrics Committee on
Genetics (1995)
h. Adaptations of patients to the environment to foster
independence
i. Lowering faucets and light switches
ii. Using a step stool to keep feet from dangling
when sitting
iii. An extended wand for toileting
iv. Adaptations of toys for short limbs
i. Support groups: Many families find it beneficial to
interact with other families and children with achondroplasia through local and national support groups
DIAGNOSTIC INVESTIGATIONS
1. Diagnosis of achondroplasia made by clinical findings,
radiographic features, and/or FGFR3 mutation analysis
2. Radiologic features
a. Skull
i. Relatively large calvarium
ii. Prominent forehead
iii. Depressed nasal bridge
iv. Small skull base
v. Small foramen magnum
vi. Dental malocclusion
ACHONDROPLASIA
b. Spine
i. Caudal narrowing of interpedicular distances in
the lower lumbar spine
ii. Short vertebral pedicles
iii. Wide disc spaces
iv. Dorsal scalloping of the vertebral bodies in the
newborn
v. Concave posterior aspect of the vertebral bodies
in childhood and adulthood
vi. Different degree of anterior wedging of the vertebral bodies causing gibbus
c. Pelvis
i. Lack of iliac flaring
ii. Narrow sacroiliac notch
iii. Horizontal acetabular portions of the iliac bones
d. Limbs
i. Rhizomelic micromelia
ii. Square or oval radiolucent areas in the proximal
humerus and femur during infancy
iii. Tubular bones with widened diaphyses and flared
metaphyses during childhood and adulthood
iv. Markedly shortened humeri
v. Short femoral neck
vi. Disproportionately long fibulae in relation to tibiae
3. Craniocervical MRI
a. Narrowing of the foramen magnum
b. Effacement of the subarachnoid spaces at the cervicomedullary junction
c. Abnormal intrinsic cord signal intensity
d. Mild-to-moderate ventriculomegaly
4. Histology
a. Normal histologic appearance of epiphyseal and
growth plate cartilages
b. Shorter than normal growth plate: the shortening is
greater in homozygous than in heterozygous achondroplasia, suggesting a gene dosage effect
5. Mutation analysis
a. G1138A substitution in FGFR3 (about 98% of
cases)
b. G1138C substitution in FGFR3 (about 1% of cases)
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib
i. Recurrence risk of achondroplasia in the sibs of
achondroplastic children with unaffected parents: presumably higher than twice the mutation
rate because of gonadal mosaicism. Currently,
the risk is estimated as 1 in 443 (0.2%)
ii. 50% affected if one of the parents is affected
iii. 25% affected with homozygous achondroplasia
(resulting in a much more severe phenotype that
is usually lethal early in infancy) and 50%
affected with heterozygous achondroplasia if
both parents are affected with achondroplasia
b. Patient’s offspring
i. 50% affected (with heterozygous achondroplasia) if the spouse is normal
ii. 25% affected with homozygous achondroplasia
and 50% affected with heterozygous achondropla-
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sia if the spouse is also affected with achondroplasia. There is still a 25% chance that the offspring
will be normal
2. Prenatal diagnosis
a. Prenatal ultrasonography
i. Suspect achondroplasia on routine ultrasound
findings of a fall-off in limb growth, usually during the third trimester of pregnancy, in case of
parents with normal heights. About one-third of
cases are suspected this way. However, one must
be cautious because disproportionately short
limbs are observed in a variety of conditions
ii. Inability to make specific diagnosis of achondroplasia with certainty by ultrasonography unless
by radiography late in gestation or after birth
iii. Request of prenatal ultrasonography by an
affected parent, having 50% risk of having a
similarly affected child, to optimize obstetric
management
iv. Follow pregnancy by a femoral growth curve in
the second trimester by serial ultrasound scans to
enable prenatal distinction between homozygous, heterozygous, and unaffected fetuses, in
case of both affected parents
b. Prenatal molecular testing
i. Molecular technology applied to prenatal diagnosis of a fetus suspected of or at risk for having
achondroplasia
ii. Simple methodology requiring only one PCR
and one restriction digest to detect a very limited
number of mutations causing achondroplasia
iii. Preimplantation genetic diagnosis
a) Available at present (Montou et al., 2003)
b) The initial practice raising questions on the
feasibility of such a test, especially with
affected female patients
3. Management
a. Adaptive environmental modifications
i. Appropriately placed stools
ii. Seating modification
iii. Other adaptive devices
b. Obesity control
c. Obstructive apnea
i. Adenoidectomy and tonsillectomy
ii. Continuous positive airway pressure (CPAP) and
bilevel positive airway pressure (BiPAP) for clinically significant persistent obstruction
iii. Extremely rare for requiring temporary tracheostomy
d. Experimental growth hormone therapy resulting in
transient increases in growth velocity
e. Hydrocephalus
i. Observation for benign ventriculomegaly
ii. May need surgical intervention for clinically significant hydrocephalus
f. Kyphosis
i. Adequate support for sitting in early infancy
ii. Bracing using a thoracolumbosacral orthosis for
severe kyphosis in young children
iii. Surgical intervention for medically unresponsive cases
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ACHONDROPLASIA
g. Surgical decompression for unequivocal evidence for
cervical cord compression
h. Decompression laminectomy for severe and progressive lumbosacral spinal stenosis
i. Limb lengthening through osteotomy and stretching
of the long bones
i. Controversial
ii. Difficult to achieve the benefits of surgery
a) Need strong commitment on the part of the
patients and their families for the time in the
hospital and the number of operations
b) Occurrence of possible severe permanent
sequelae
j. Potential anesthetic risks related to:
i. Obstructive apnea
ii. Cervical compression
k. Risks associated with pregnancy in women with
achondroplasia: relatively infrequent
i. Worsening neurologic symptoms related to
increasing hyperlordosis and maternal respiratory
failure
ii. Anticipate a scheduled cesarean delivery due to
cephalopelvic disproportion
iii. Preeclampsia
iv. Polyhydramnios
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ACHONDROPLASIA
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Fig. 2. A 4-month-old boy with achondroplasia showing typical craniofacial features and rhizomelic shortening of limbs (confirmed by radiograms). Molecular study revealed 1138 G-to-A transition mutation.
Fig. 1. A newborn with achondroplasia showing large head, depressed
nasal bridge, short neck, normal length of the trunk, narrow chest, rhizomelic micromelia, and trident hands. The radiographs showed narrow chest, characteristic pelvis, micromelia, and oval radiolucent
proximal portion of the femurs. Molecular analysis showed 1138G→C
mutation.
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ACHONDROPLASIA
Fig. 3. Another achondroplastic neonate with typical clinical features
and radiographic findings. Note the abnormal vertebral column with
wide intervertebral spaces and abnormal vertebral bodies.
Fig. 5. Two older children with achondroplasia showing rhizomelic
micromelia, typical craniofacial features, exaggerated lumbar lordosis,
and trident hands.
Fig. 4. A boy (7 month and 2 year 7 month old) with achondroplasia
showing a large head, small chest, normal size of the trunk, rhizomelic
micromelia, and exaggerated lumbar lordosis.
ACHONDROPLASIA
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Fig. 6. A boy with achondroplasia and i(21q) Down syndrome presented with diagnostic dilemma. Besides craniofacial features typical
for Down syndrome, the skeletal findings of achondroplasia dominate
the clinical picture. The diagnosis of Down syndrome was based on
the clinical features and the cytogenetic finding of i(21q) trisomy 21.
The diagnosis of achondroplasia was based on the presence of clinical and radiographic findings, and confirmed by the presence of a
common FGFR3 gene mutation (Gly380Arg) detected by restriction
enzyme analysis and sequencing of the PCR products.
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ACHONDROPLASIA
Fig. 7. Schematic of the FGFR3 gene and DNA sequence of normal
allele and mutant FGFR3 achondroplasia allele (modified from
Shiang et al., 1994).
Fig. 9. Homozygous achondroplasia. Both parents are achondroplastic. The large head, narrow chest, and severe rhizomelic shortening of
the limbs are similar to those of thanatophoric dysplasia. Radiograph
shows severe platyspondyly, small ilia, and short limb bones.
Photomicrograph of the physeal growth zone shows severe retardation
and disorganization, similar to that of thanatophoric dysplasia.
Fig. 8. Nucleotide change in the 1138C allele creates a Msp1 site and
nucleotide change in the 1138A allele creates a Sfc1. The base in the
coding sequence that differs in the three alleles is boxed (modified
from Shiang et al., 1994).