New proposed clinico-radiologic and molecular criteria in hypochondroplasia: FGFR 3 gene mutations are not the only cause of hypochondroplasia.
We applied a comprehensive set of clinical and radiological criteria for the diagnosis of hypochondroplasia (HCH) in 160 patients with short stature 58 of whom were diagnosed to have HCH. Taking into account the genotypic and phenotypic variations in HCH, we conducted a study with these 58 patients and tested them for mutations in the fibroblast growth factor receptor 3 (FGFR3) and the short stature homeobox (SHOX) gene. We characterized the phenotypes by clinical and radiologic findings. In the patients with HCH, 19 were included in Group I (FGFR3 mutations-mutations of definite significance), and 39 were in Group II (6 SHOX mutations and 33 negative for disease-causing FGFR3 mutations). The clinical findings were similar in two groups regardless of the presence or absence of mutations. More than 95% of the patients had mesomelic proportions. In Group I, the radiological findings of mesomelia of upper and lower limbs and, L1/L4 ratio in anterior-posterior and lateral view were more typical than in Group II. This study proposes comprehensive clinico-radiological criteria for the diagnosis of HCH, which would help in detecting the true incidence of this underdiagnosed condition. The presence of SHOX mutations suggest genotypic-phenotypic overlap between HCH and Leri-Weill dyschondrosteosis, though further investigation is needed to effectively elucidate the importance of these mutations. Also, the 56.9% of HCH patients with negative mutations for FGFR3 suggests that there are other undiscovered gene mutations associated with this phenotypic entity.
Department of Orthopaedic Surgery, Institute for Rare Diseases, Korea University Medical Center Guro Hospital, Guro-Gu, Seoul, Korea.
Sang-Heon
SH
Song
Gracia Cielo Estrera
GC
Balce
Mandar Vikas
MV
Agashe
Hanna
H
Lee
Suk-Joo
SJ
Hong
Young-Eun
YE
Park
Sang-Gyun
SG
Kim
Hae-Ryong
HR
Song
D000130:Achondroplasia / Q000235:genetics; D001842:Bone and Bones / Q000002:abnormalities / Q000000981:diagnostic imaging / Q000473:pathology; D004392:Dwarfism / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D017880:Limb Deformities, Congenital / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D008141:Lordosis / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D011859:Radiography; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D000074122:Short Stature Homeobox Protein
D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein; D051498:Receptor, Fibroblast Growth Factor, Type 3