Ramaswami, Uma; (2001) Hypochondroplasia: Clinical and molecular spectrum and response to growth hormone therapy. Doctoral thesis (M.D.), University College London.

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Abstract

Hypochondroplasia (HCH) is a genetic disorder of short stature with a wide spectrum of clinical severity, from short-limbed dwarfism to proportionately short children with diminution of the pubertal growth spurt. The invariable radiological feature is a lack of increase in interpedicular distance between lumbar vertebrae LI to L5 and with short pedicles. 73 children with clinical and radiologically proven HCH were screened for the C1620A and C1620G mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Both these mutations resulted in an asparagine to lysine substitution in codon 540 (Asn540Lys) of the proximal tyrosine kinase domain of FGFR3. In mutation negative patients (n=45), single strand conformation polymorphism analysis was performed to screen for sequence variants in the tyrosine kinase and transmembrane domains of FGFR3 gene. 28/73 (38%) patients were heterozygous for the C1620A mutation and these patients had severe HCH with disproportionate short stature. No patient in this study had the C1620G mutations or mutations in the transmembrane domain described in Achondroplasia (ACH). The mutation negative patients although short, were not obviously disproportionate and presented later with short stature relative to their family height. A sequence variant, a nucleotide insertion in intron 12 was found in a small proportion of mutation negative patients and in normal individuals, presumably reflecting a sequence polymorphism with no functional significance. The patients were divided into C1620A mutation positive (group 1) and C1620A mutation negative groups (Group 2) and the responses to recombinant human growth hormone (r-hGH) therapy was analysed in both groups. The majority were prepubertal at the start of treatment (88%). 16 patients in Group 1 and 22 patients in Group 2 received r-hGH at a median dose of 30U/m2/week (16-44 U/m2/week). Responses to r-hGH therapy between 1-5 years were significant in both groups, with children under 10 years of age having a significantly better response. This response was predominantly due to an increase in the length of the back in the mutation positive group, thus accentuating the existing disproportion. In the mutation negative group, there was a more proportionate growth response. The response to growth hormone therapy in ACH was also analysed and compared with responses to r-hGH therapy in HCH. The C1620A positive HCH group had a similar response to r-hGH therapy when compared to ACH. The phenotype within these two groups was also similar. However, the severity of short stature and disproportion in children with C1620A positive HCH was less severe than those with ACH. Genotyping of patients with HCH permits the definition of patients into C1620A positive and negative groups. This allows critical examination of the efficacy of growth hormone treatment of what is otherwise a rather heterogeneous group of patients, defined by radiological parameters alone. Further analysis of the 2.5kb mRNA performed in other centres has not identified any further mutations in FGFR3 in the C1620A mutation negative group. Future collaborative work with other centres will be needed to clarify the situation in these patients and whether they have mutations in FGFR3 or in other genes.

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