ISOLATED GROWTH-HORMONE DEFICIENCY TYPE IA ASSOCIATED WITH A 45-KILOBASE GENE DELETION WITHIN THE HUMAN GROWTH-HORMONE GENE-CLUSTER IN AN ITALIAN FAMILY

An Italian family with three children presenting with isolated growth hormone (GH) deficiency type IA is described. Restriction endonuclease analysis revealed that the cause of hGH deficiency was a 45-kb gent d eletion within the hGH-chorionic somatomammotropin (CS) gene cluster, encompassing the GH-1, CS-L, CS-A, and GH-2 genes. DNA sequence analys is and polymerase chain reaction amplification between two sequences l ocated on each side of the deletion breakpoint accurately identified t he deletion breakpoints and indicated that the regulatory sequences lo cated upstream from the TATA box of the mutant CS-B belong to the GH-2 gene. Two of the affected children developed high-titer anti-hGH anti bodies after recombinant hGH treatment with secondary growth arrest, w hereas the third one maintained normal growth in the presence of very low-titer antibodies. This is the first report of a large deletional m utation within the hGH-CS gene cluster accompanied by phenotypic heter ogeneity in terms of growth response and antibody formation in the dif ferent patients.