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Reduced human growth hormone (hGH) bioactivity without a defect of the GH‐1 gene in three patients with rhGH responsive growth failure
Author(s) -
Gerhard Binder,
Benz Mr,
Martin W. Elmlinger,
Pflaum Cd,
C. J. Strasburger,
Ranke Mb
Publication year - 1999
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1046/j.1365-2265.1999.00744.x
Subject(s) - medicine , endocrinology , radioimmunoassay , polyclonal antibodies , antibody , short stature , growth hormone deficiency , growth hormone , biology , hormone , immunology
BACKGROUND A GH deficiency‐like phenotype with normal or high hGH secretion, pathologically low IGF‐I serum levels, and catch‐up growth under treatment with recombinant hGH is suggestive of the presence of biologically inactive hGH syndrome, whose presumably heterogenous molecular basis is substantially unknown. DESIGN Serum samples from patients who fulfilled the above criteria and from controls with idiopathic short stature were measured by polyclonal hGH‐RIA, Nb2 rat lymphoma proliferation assay, and hGH immunofunctional assay (IFA). If assays were suggestive of the presence of bioinactive GH, mutational analysis of the hGH‐1 gene was performed. PATIENTS Three patients were selected because of clinical and biochemical evidence. At the time of diagnosis mean age was 3.4 (2.2, 3.5, 4.5) years, mean height −3.5 (−2.8, −3.6, −4.2) SD score (SDS) and mean growth rate −1.5 (−1.4, −1.5, −1.6) SDS. Mean IGF‐I serum levels were −1.9 (−0.7, −2.4, −2.5) SDS and mean IGFBP‐3 serum levels −1.2 (−1.1, −1.2, −1.2) SDS. Stimulated and spontaneous GH peaks measured by a polyclonal radioimmunoassay were all above 14 μg/l. GHBP serum levels were normal, and antihGH antibodies were not detected. Therapy with rhGH was effective in causing catch‐up growth of the three children with an initial mean growth rate of + 2.9 (+ 1.7, + 2.1, + 5.0) SDS, and normalization of IGF‐I (mean: −0.66 SDS: −1.8, − 1.2, + 1.1 SDS) and IGFBP‐3 serum levels (mean: + 0.81 SDS: −0.2, + 0.8, + 1.8 SDS). RESULTS In comparison to controls, the patients' serum hGH levels were much lower when measured by Nb2 rat lymphoma cell proliferation bioassay (mean: −2.3 SDS, range: −1.7– −4.1) and by the immunofunctional assay (IFA) (−1.5 SDS, range: −0.2– −3.1) than by RIA. Retesting of two of the three patients including an one year break of therapy confirmed the rhGH dependence of growth in spite of normal endogenous GH secretion. Radioactive direct sequencing of both strands of PCR‐amplified genomic DNA and cDNA excluded a GH‐1 gene mutation in all three children. CONCLUSION Mutations of the GH‐1 gene are probably not the main genetic defect in children with biologically inactive hGH syndrome. Posttranslational processing of hGH might reduce the biological activity of the normal translation product.