Most individuals with ACH have the recurrent mutation (p.Gly380Arg) in the transmembrane (TM) domain of the receptor and individuals with HCH show the common mutation (p.Asn540Lys) in the tyrosine kinase 1 (TK1) region.
The present case of hypochondroplasia and FGFR3 mutation in Asn540Lys associated with characteristic abnormalities involving bilaterally medial temporal lobe structures, probable hippocampal cortex focal dysplasia, and early onset of focal epilepsy underscores the possibility of a rare syndrome.
A pilot study of discontinuous, insulin-like growth factor 1-dosing growth hormone treatment in young children with FGFR3 N540K-mutated hypochondroplasia.
The p.N540K mutation is associated with 60% of patients with hypochondroplasia and the p.Q485R mutation is a novel mutation located in a highly conserved domain of FGFRs.
Molecular genetic analysis carried out retrospectively revealed that both fetuses were heterozygous for the C1620A mutation resulting in N540K substitution in FGFR3, the most common mutation in HCH.
Although 98% of ACH cases are accounted for by a single G380R substitution in the TM, a common mutation (N540K) in the TK1 region is detected in only 60-65% of HCH cases.
Using genomic DNA sequencing and RFLP analysis, G380R, an ACH-specific mutation, and N540K, an HCH-specific mutation, were detected in 13 patients (50%) and five patients (19%), respectively.
Genetic analysis revealed two germline mutations, a seven base-pair deletion in exon 12 (G70313-703129del) in one allele of the retinoblastoma gene (RB1) and the N540K (C1620C > A) mutation in one allele of the fibroblast growth factor 3 (FGFR3) gene, a frequent mutation in hypochondroplasia.
This assay, which is performed on the LightCycler thermocycler, enables the rapid and reliable detection of the two most common FGFR3 mutations associated with ACH (1138G --> A and 1138G --> C; G380R) and HYCH (1620C --> A and 1620 C --> G; N540K) in a single test.
Other mutations within the FGFR3 tyrosine kinase domain (e.g., C1620A or C1620G [both resulting in Asn540Lys]) are known to cause hypochondroplasia, a relatively common but milder skeletal dysplasia.
Individuals with hypochondroplasia heterozygous for the Asn540Lys substitution are significantly more disproportionate than individuals without this mutation.
The mother has achondroplasia and carries the common G1138 (G380R) mutation in the FGFR3 gene; the father has hypochondroplasia due to the C1620A (N540K) mutation in the same gene.
The father has achondroplasia due to the common G1138A (G380R) mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, while the mother has hypochondroplasia due to the C1620G (N450K) mutation in the FGFR3 gene.
Our results support evidence of similar frequency of common type N540K mutation of FGFR3 in Russian hypochondroplasia and of the genetic heterogeneity of hypochondroplasia, suggesting the need for further search for responsible molecular abnormalities for phenotypically similar hypochondroplasia patients negative for TK1 domain mutation in FGFR3, reported in hypochondroplasia.
Children with the common C1620A mutation met all of the criteria for the diagnosis of Hch with a severe phenotype that resembled achondroplasia and disproportionate short stature in early childhood.
Our patient demonstrated one of the common FGFR3 mutations identified in hypochondroplasia, a C-to-A change at nucleotide 1620 (C1620A) in the tyrosine kinase domain.