GENETICS/BASIC DEFECTS CLINICAL FEATURES Achondroplasia

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

and 5.57 ×10

per gamete per generation. Most infants with achondroplasia are born unexpectedly to parents of average stature.

GENETICS/BASIC DEFECTS

1. Inheritance

a. Autosomal dominant disorder with complete pene- trance

b. Sporadic in about 80% of the cases, the result of a de

c. Presence of paternal age effect (advanced paternal age in sporadic cases)

d. Gonadal mosaicism (two or more children with clas- sic 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 argi- nine residue for a glycine at position 380 (G380A) of the mature protein in the transmembrane domain of

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 verte- bral bodies, while membranous ossification (skull, facial bones) is not affected

b. Physeal growth zones show normal columnization, hypertrophy, degeneration, calcification, and ossifica- tion. 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 dispropor- tionately shortened limbs

CLINICAL FEATURES

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 ambu- lation)

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:

15

i. Hypotonia ii. Sleep apnea

iii. Sudden infant death syndrome

e. Symptomatic hydrocephalus in infancy and early child- hood 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 sec- ondary 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” con- figuration of the hand)

o. Short fingers (brachydactyly)

p. Bowing of the legs (genu varum) due to lax knee lig- aments

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 achon- droplasia

iii. Apnea

iv. Communicating hydrocephalus v. Spinal stenosis

vi. Paraparesis vii. Quadriparesis viii. Infantile hypotonia e. Obesity

i. Aggravating the morbidity associated with lum- bar stenosis

ii. Contributing to the nonspecific joint problems and to the possible early cardiovascular mortal- ity 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 hydro- cephalus 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 compli- cations

ii. Mean life expectancy approximately 10 years less than the general population

e. Homozygous achondroplasia

i. A lethal condition with severe respiratory dis- tress 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 man- agement

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 achon- droplasia 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

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 ver- tebral 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 cervi- comedullary 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 achon- droplasia, 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 par- ents: 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 achondropla- sia) if the spouse is normal

ii. 25% affected with homozygous achondroplasia and 50% affected with heterozygous achondropla-

sia if the spouse is also affected with achondropla- sia. 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 dur- ing 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 achon-

droplasia 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 homozy- gous, heterozygous, and unaffected fetuses, in case of both affected parents

b. Prenatal molecular testing

i. Molecular technology applied to prenatal diag- nosis 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 clin- ically significant persistent obstruction

iii. Extremely rare for requiring temporary tra- cheostomy

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 sig-

nificant 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 unrespon-

sive cases

g. Surgical decompression for unequivocal evidence for cervical cord compression

h. Decompression laminectomy for severe and progres- sive 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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Fig. 1. A newborn with achondroplasia showing large head, depressed nasal bridge, short neck, normal length of the trunk, narrow chest, rhi- zomelic micromelia, and trident hands. The radiographs showed nar- row chest, characteristic pelvis, micromelia, and oval radiolucent proximal portion of the femurs. Molecular analysis showed 1138G→C mutation.

Fig. 2. A 4-month-old boy with achondroplasia showing typical cranio- facial features and rhizomelic shortening of limbs (confirmed by radi- ograms). Molecular study revealed 1138 G-to-A transition mutation.

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. 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.

Fig. 5. Two older children with achondroplasia showing rhizomelic micromelia, typical craniofacial features, exaggerated lumbar lordosis, and trident hands.

Fig. 6. A boy with achondroplasia and i(21q) Down syndrome pre- sented 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 clini- cal 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.

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. 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).

Fig. 9. Homozygous achondroplasia. Both parents are achondroplas- tic. 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.