517 Hypochondroplasia is a disproportionate short stature disor- der resembling achondroplasia but with less severe phenotype.
GENETICS/BASIC DEFECTS
1. Inheritance
a. Autosomal dominant with full penetrance b. Sporadic in 90% of cases
c. Observation of an increased paternal age effect at the time of conception, suggesting involvement of de novo mutations of paternal origin
d. Presence of locus heterogeneity
2. Evidence supporting the view that hypochondroplasia and achondroplasia are allelic disorders
a. A remarkable inter- and intra-familial variation in expression of hypochondroplasia with some cases resembling minor forms of achondroplasia
b. Offspring of an achondroplastic parent and hypochon- droplastic parent with severe neonatal achondroplasia resembling homozygous achondroplasia
c. Similar histopathological aspects of the growth carti- lage for the two disorders
3. Molecular defect
a. About 70% of affected individuals who are heterozy- gous for a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, which is mapped on chro- mosome 4p16.3
b. FGFR3 mutations reported
i. 1620C-A (Asn540Lys): 2/3rd of cases ii. 1620C-G (Asn540Lys): 1/3rd of cases
iii. 1658A-C (Asn540Thr) and other FGFR3 muta- tions: rare
4. Hypochondroplasia–achondroplasia compound heterozy- gote
a. Born to a hypochondroplastic parent and an achon- droplastic parent
b. The severity of the child: clinical and radiographic findings more severe than achondroplasia or hypochondroplasia alone
c. Demonstration of both the hypochondroplasia (Asn540Lys) and achondroplasia (Gly380Arg) muta- tions at the FGFR3 locus in a patient with the genetic compound
CLINICAL FEATURES
1. Short stature
a. Evident by school age b. Adult height: 128–165 cm 2. Stocky build
3. Facial appearance a. Usually normal
b. Mild macrocephaly may be present 4. Skeletal features
a. General features: usually similar but miler to achon- droplasia
b. Limbs
i. Disproportionately short compared with the length of the trunk
ii. Shortening of the proximal (rhizomelia) or mid- dle (mesomelia) segments of the extremities iii. Mild limitation of elbow extension
iv. Broad and short hands and feet (brachydactyly) v. Absence of trident hand deformity
vi. Bow legs (genu varum): usually mild vii. Adult onset osteoarthritis: less common c. Spine
i. Scoliosis
ii. Slight lumbar lordosis with a sacral tilt 5. Medical complication
a. Following complications: less frequent compared to achondroplasia
i. Spinal stenosis with neurologic complications ii. Tibial bowing
iii. Obstructive apnea
b. Deficits in mental capacity and/or function: may be more prevalent than achondroplasia
DIAGNOSTIC INVESTIGATIONS
1. Radiography
a. The most common features
i. Short proximal (rhizomelic) and/or middle (mesomelic) segments of the long bones with mild metaphyseal flare, especially femora and tibiae ii. Caudal narrowing or unchanged lumbar inter-
pedicular distance
iii. Mild to moderate brachydactyly iv. Short and broad femoral neck
v. Squared and shortened ilia
b. The less common but significant features i. Elongation of the distal fibula
ii. Anterior–posterior shortening of the lumbar ver- tebrae
iii. Dorsal concavity of the lumbar vertebral bodies iv. Shortening of the distal ulna
v. Long ulnar styloid in adults
vi. Prominence of muscle insertions on the long bones vii. Shallow “chevron” deformity of distal femur
metaphysis
viii. Low articulation of sacrum on pelvis with a hor- izontal orientation
ix. Flattened acetabular roof 2. Molecular genetic testing
a. Mutation analysis
i. 1620C-A (Asn540Lys) ii. 1620C-G (Asn540Lys) iii. Other FGFR3 mutations
Hypochondroplasia
518 HYPOCHONDROPLASIA
b. Sequence analysis of mutations in FGFR3 exons 10, 13, and 15
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib: an extremely low risk (<0.01%) of hav- ing an affected sib if parents are not affected (germline mosaicism has not been reported for hypochondroplasia)
b. Patient’s offspring
i. 50% risk of having an affected offspring if the spouse is normal
ii. If the spouse is an achondroplastic
a) 25% chance of having an affected offspring with hypochondroplasia
b) 25% chance of having an affected offspring with achondroplasia
c) 25% chance of having an affected offspring with achondroplasia–hypochondroplasia gene- tic compound
d) 25% chance of having a normal offspring iii. If the spouse also has hypochondroplasia or other
dominant form of skeletal dysplasia: genetic counseling becoming more complicated due to the high incidence of genetic heterogeneity and the lack of medical literature addressing these circumstances
2. Prenatal diagnosis
a. Prenatal diagnosis by amniocentesis or CVS for fam- ily with high-risk pregnancy with a parent who has hypochondroplasia
i. When the spouse is normal: testing for disease- causing FGFR3 mutation in the fetus
ii. When the spouse is affected with another domi- nantly inherited skeletal dysplasia caused by a known gene mutation: testing for the known mutation for that skeletal dysplasia and the mutation for the hypochondroplasia in the fetus b. Prenatal diagnosis by ultrasonography, amniocentesis
or CVS in low-risk pregnancy without family history of affected individual
i. Ultrasonography: short limbs detected by routine ultrasound examination late in pregnancy ii. DNA-based diagnosis of FGFR3 mutations to
confirm the diagnosis of hypochondroplasia 3. Management
a. Follow closely developmental milestones and signs of learning disability or mental retardation
b. Treatment of short stature
i. Trials of growth hormone therapy with mixed results
ii. Surgical limb lengthening for severe case of hypochondroplasia
a) An invasive procedure
b) Entails considerable disability and discom- fort over a long period of time
c) Prefer postponement of the procedure until adolescence when the patient can make an informed decision
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HYPOCHONDROPLASIA 519
Fig. 1. A young child affected with hypochondroplasia showing mild short stature and mild rhizomelic shortening of the extremities.
520 HYPOCHONDROPLASIA
Fig. 2. Three families with familial hypochondroplasia showing stocky build, mild short stature, normal facial appearance, rhizomelic shortening of the extremities, and absence of trident hands.
Fig. 3. Radiographs of two patients with hypochondroplasia showing unchanged interpedicular distance and mild shortening of long bones.
