New proposed clinico‐radiologic and molecular criteria in hypochondroplasia: FGFR 3 gene mutations are not the only cause of hypochondroplasia

Abstract

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.

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

“…The best known examples are thanatophoric dysplasia, achondroplasia, and hypochondroplasia, each associated with different locations of the mutation. The clinical presentation of hypochondroplasia is milder and more variable than achondroplasia and includes rhizomelic limb shortening, limitation of elbow extension, brachydactyly, relative macrocephaly, generalized laxity, and specific radiologic features (5,108). We recently reported a novel activating FGFR3 mutation in a family with proportionate short stature (109).…”

Children with short‐limbed short stature in pediatric endocrinological services in Japan

“…As noted earlier, some patients with SHOX gene mutation were reported to have an overlapping phenotype with hypochondroplasia patients with FGFR3 gene mutation, although some patients did not have either SHOX or FGFR3 gene mutation among those in whom hypochondroplasia was clinically suspected.…”

“…This difference in accurate diagnosis is presumably due to the difference in clinical and radiological features between achondroplasia and hypochondroplasia, as described previously. As noted earlier, some patients with SHOX gene mutation were reported to have an overlapping phenotype with hypochondroplasia patients with FGFR3 gene mutation, 10 although some patients did not have either SHOX orFGFR3 gene mutation among those in whom hypochondroplasia was clinically suspected.…”

“…SHOX gene haploinsufficiency results in a broad spectrum of clinical features and would explain the continuous range of change between proportional short stature and short‐limbed short stature. Recently, SHOX gene abnormality has also been shown to produce idiopathic short stature, Leri–Weill dyschondrosteosis, and hypochondroplasia: from proportional short stature to short‐limbed short stature. Consequently, clear differentiation of each disease resulting from SHOX gene haploinsufficiency is difficult.…”

Unique association of hypochondroplasia with craniosynostosis and cleft palate in a Mexican family

“…Hypochondroplasia (HCH; MIM #146000) is a skeletal dysplasia characterized by macrocephaly, short stature, stocky build, disproportionately short arms and legs, broad and short hands and feet, and mild joint laxity (Bellus et al, ; Rousseau et al, ). Radiological features include shortening of long bones with mild metaphyseal flare; mild to moderate brachydactyly; narrowing of inferior lumbar interpedicular distance; short, broad femoral neck; and squared, shortened ilia (Heselson, Cremin, & Beighton, ; Song et al, ). Less common but significant clinical features include scoliosis, mild genu varum , lumbar lordosis with protruding abdomen, acanthosis nigricans (Castro‐Feijóo et al, ), mild to moderate intellectual disability (9–20%), and temporal lobe dysplasia/epilepsy (Linnankivi, Mäkitie, Valanne, & Toiviainen‐Salo, ).…”