University:
Western Sydney University
Course:
MEDI 2003 | Clinical Sciences 2
Academic year:

2024
Views:

309

Pages:

2
Author:

Mariam A.

Skeletal dysplasia   Skeletal dysplasia (dwarfism) is used to describe disproportionately short stature. If the short stature is proportional, condition may be endocrine/metabolic disorder or chromosomal, but not skeletal dysplasia. o Examples: Achondroplasia (short limbed) and Morquio syndrome (short trunk) Diagnostic steps and clinical evaluation: o Accurate history and family history – including birth length, fetal size vs. gestational size, parental height o Physical examination – of height, weight, head circumference, upper segment : lower segment, arm : height o Imaging – skeletal radiograph, which parts of skeleton are involved o Molecular Diagnosis Achondroplasia    This is one of the most common, non-lethal forms of chondroplasia. Its genetic inheritance pattern is autosomal dominant, with complete penetrance and 75-80% mutations are de novo. It should be noted that homozygous achondroplasia is usually fatal within the first year of life. It is caused by mutations in the gene fibroblast growth factor receptor-3 (FGFR3). The gene has been mapped to chromosome 4p16.3. The FGFR3 protein is involved in a variety of activities including: o Regulation of cell growth and division o Determination of cell type o Angiogenesis (new blood vessels) o Wound healing o Embryo development FDFRs are protein tyrosine kinase receptors, consisting of a single transmembrane domain. Receptors exist in the monomer form until activated by FGF. The extracellular domain contains three Ig-like domains, a signal peptide (SP) and an acidic box (A). Upon binding of FGF, FGFR monomers dimerise. The TK domains then autophosphorylate one another, which initiates an intracellular signalling pathway. This ultimately leads to a modification of transcription, promoting differentiation of cartilage into bone. Thus, the patient’s bone do not grow to the extent that they would have, since differentiation of cartilage to bone is happening too early on in life   The mutation in the FGFR3 gene is usually a gain of function mutation (99% of cases at G380R). The receptor becomes constitutively active (protein produced undergoes its function too much – turned on all the time), leading to premature conversion of the growth plate into bone. Furthermore, there is decreased cellular hypertrophy and decreased cartilage matrix production. The prognosis is generally normal intelligence and a normal life expectancy. One of the main risk factors for achondroplasia is increased paternal age