Mullis P E, Patel M S, Brickell P M, Hindmarsh P C, Brook C G
Endocrine Unit, Middlesex Hospital, London, UK.
Clin Endocrinol (Oxf). 1991 Apr;34(4):265-74. doi: 10.1111/j.1365-2265.1991.tb03765.x.
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.
软骨发育不全性侏儒症是一种具有异质性且通常较为轻度的软骨发育不良形式，是身材矮小的常见原因。它在儿童期常未被识别，在成年期当不成比例的身材矮小变得明显时才被诊断出来。我们对20名因放射学和临床标准被归因于软骨发育不全性侏儒症且正在接受人生长激素（r-hGH）治疗的英国白人高加索儿童、60名孤立性生长激素缺乏症儿童以及50名正常个体的家庭进行了胰岛素样生长因子I（IGF-I）基因的限制性内切酶分析。软骨发育不全性侏儒症儿童中杂合模式（Hind III：8.2、5.2、4.8、3.2 kb片段，Pvu：8.4、5.1、4.7、2.5 kb片段）的频率显著高于对照组（卡方检验：P<0.05）。对r-hGH治疗反应表现为脊柱和坐骨下腿长度均成比例增加的软骨发育不全性侏儒症儿童，对于两个共同遗传的IGF-I基因限制性片段长度多态性（RFLP）等位基因（Hind III：5.2、4.8 kb；Pvu II：5.1、4.7 kb）均为杂合子。对r-hGH治疗反应表现为身体不成比例加重的儿童对于这些等位基因均为纯合子（Hind III：4.8、4.8 kb；Pvu II：4.7、4.7 kb）。他们对r-hGH治疗的反应有显著差异（P<0.01）。对杂合子受累儿童家庭的研究表明，位于12q23染色体上的IGF-I基因座与该亚组软骨发育不全性侏儒症有很强的连锁关系（在零重组时优势对数记分3.311）。5.2 kb Hind III和5.1 kb Pvu II等位基因与该性状有很强的连锁不平衡。这些数据表明，IGF-I基因可能是参与具有软骨发育不全性特征且对r-hGH治疗有比例性反应的身材矮小病因的候选基因；它们也为软骨发育不良中遗传异质性的概念提供了支持。
