PEDBASE.org - The Pediatric Database - Detailed information of HYPOCHONDROPLASIA

HYPOCHONDROPLASIA

DEFINITION:

A non-lethal type of congenital dwarfism characterized by typical skeletal dysplasias (rhizometric micromelia).

EPIDEMIOLOGY:

incidence: rare
age of onset:
- early through late childhood
risk factors:
- familial - autosomal dominant (but with a high spontaneous mutation rate)
  - chrom.#: 4p
  - gene: fibroblast growth factor receptor-3 gene
- increased paternal age
- M = F

PATHOGENESIS:

1. Background

the fibroblast growth factor receptor-3 gene (FGFR3 gene) is a transmembrane receptor comprised of three domains:
- an extracellular ligand-binding domain consisting of three immunoglobulin-like (sub)domains
- a transmembrane domain
- an intracellular cytoplasmic domain consisting of two tyrosine kinase (sub)domains
a mutation in the FGFR3 gene as the cause of Hypochondroplasia was first reported by two groups - Bellus, G.A. et al., Nature Genetics 10:357-359 (1995); Prinos, P. et al., Hum. Mol. Genet. 4:2097-2101 (1995).
there are several disorders which arise from mutations within the FGFR3 gene:
1. Chondrodysplastic Disorders
- Achondroplasia
- Hypochondroplasia
- Thanatophoric Dwarfism - Types I and II
2. Nonchondrodysplastic Disorders
- Crouzon Syndrome (with acanthosis nigricans)
- Pfeiffer-like Craniosynostosis Syndrome

2. Genetic Defect

adenosine or guanosine replacement of cytosine at nucleotide 1620 of the FGFR3 gene -> Asn540Lys substitution -> mutation of one of the tyrosine kinase (sub)domains of the FGFR3 receptor -> inhibition of linear bone growth

CLINICAL FEATURES:

1. Musculoskeletal Manifestations

1. Limbs

rhizometric micromelia
- shortened limbs
- proximal > distal shortening
elbows - lack of full extension and supination
legs - mild genu varum (bowleg)
hands - broad and short

2. Head

normal or increased size with frontal bossing
normal facial features

3. Spine

short stature (dwarf)
lumbar - lordotic
coxa varum

INVESTIGATIONS:

1. Imaging Studies

1. Skeletal X-Rays

limbs - as above
pelvis - square, short and broad femoral necks

MANAGEMENT:

1. Supportive

management of complications
orthopedic problems (leg bowing, lumbar spinal cord claudication)

2. Prognosis

normal life expectancy
may be associated with mild mental deficiency

ADDITIONAL REFERENCES:

1. Horton, W.A., Current Opinion in Pediatrics, 9:437-442 (1997).

Pediatric Database - HYPOCHONDROPLASIA

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