Growth characteristics and response to growth hormone therapy in patients with hypochondroplasia: genetic linkage of the insulin‐like growth factor I gene at chromosome 12q23 to the disease in a subgroup of these patients

Hypochondroplasia, a heterogeneous and usually mild form of chondrodystrophy, is a common cause of short stature. It often goes unrecognized in childhood and is diagnosed in adult life when disproportionate short stature becomes obvious. We performed restriction enzyme analysis of the insulin-like growth factor I (IGF-I) gene on the families of 20 white British Caucasian children with short stature attributed to hypochondroplasia by radiological and clinical criteria, who were undergoing human growth hormone (r-hGH) treatment, in 60 children with isolated growth hormone deficiency and in 50 normal individuals. The frequency of the heterozygous pattern (Hind III: 8.2, 5.2, 4.8, 3.2 kb fragments, Pvu: 8.4, 5.1, 4.7, 2.5 kb fragments) in children with hypochondroplasia was significantly higher (chi2: P less than 0.05) than in the control groups. The hypochondroplastic children whose response to r-hGH treatment was characterized by a proportionate increase in both spinal and subischial leg length were all heterozygous for two co-inherited IGF-I gene restriction fragment length polymorphism (RFLP) alleles (Hind III: 5.2, 4.8 kb; Pvu II: 5.1, 4.7 kb). Children whose response was characterized by accentuation of the body disproportion by r-hGH treatment were all homozygous for these alleles (Hind III: 4.8, 4.8 kb; Pvu II: 4.7, 4.7 kb). Their response to r-hGH treatment is significantly different (P less than 0.01). Studies of the families of the heterozygous affected children demonstrated strong linkage (lod score 3.311 at zero recombination) of the IGF-I gene locus at chromosome 12q23 to this subgroup of hypochondroplasia. The 5.2 kb Hind III and 5.1 kb Pvu II alleles are in strong linkage disequilibrium with this trait. These data indicate that IGF-I gene may be a candidate gene for involvement in the aetiology of short stature presenting with hypochondroplastic features and a proportionate response to r-hGH treatment; they also provide support for the concept of genetic heterogeneity in chondrodystrophy.