MOLECULAR STUDY OF HUMAN GROWTH-HORMONE GENE-CLUSTER IN 3 FAMILIES WITH ISOLATED GROWTH-HORMONE DEFICIENCY AND SIMILAR PHENOTYPE

The growth hormone (GH) gene (hGH-N) cluster was analysed using polyme rase chain reaction, Southern and polymorphism analysis in five patien ts (including two pairs of siblings) with extreme short stature and ab sence of GH secretion. Patients 1 and 2 (siblings) were homozygous for a large deletion removing four genes of the cluster: hGH-N, hCS-L, hC S-A and hGH-V. Both siblings produced high anti-GH antibody levels in response to exogenous GH therapy, followed by growth arrest a few mont hs after starting replacement therapy. In patient 3 we detected a hete rozygous deletion which involved three genes of the cluster (hCS-A, hG H-V, hCS-B) and left an intact hGH-N gene. Direct sequencing of hGH-N specific amplified fragments excluded the presence of any point mutati ons in exons and splicing regions. In patients 4 and 5 (sisters) our s tudy did not demonstrate any gene deletions. Analysis of polymorphic r estriction patterns in this family demonstrated that both sisters inhe rited the same alleles from the father but different alleles from the mother, suggesting that the defect was not linked to the hGH-N gene. T hese results confirm the difficulty of clinical identification of subj ects with hGH-N deletion and underline the importance of DNA analysis in patients with absence of GH secretion and extreme growth retardatio n.