ESPE Abstracts

Introduction: Diagnosis of growth hormone (GH) deficiency is known to have unreliable results, especially due to low specificity of GH stimulation tests. Children diagnosed with GH deficiency (GHD) therefore form a heterogeneous group with a cause frequently unrelated to GH secretion or function. On the other hand, children with extremely low maximal stimulated GH concentrations (<3 ug/L) are believed to have “real” GH deficiency (GHD). However, this assumption has not been evaluated in a clinical study yet.

Patients and Methods: All the children treated with GH in our center with severe primary isolated GHD (maximal stimulated GH concentration <3 ug/L in both clonidine and insulin hypoglycemia tests; normal function of other pituitary hormones; no secondary causes of GHD) whose legal representatives signed an informed consent with genetic examination were enrolled to the study. Children were examined by targeted next-generation sequencing (NGS) panel containing 398 genes known to influence growth. All the variants with a potential clinical significance were evaluated by the American College of Medical Genetics and Genomics (ACMG) standards.

Results: Currently, a total of 42 children with severe primary isolated GHD are treated with GH in our center. Their median age is 12.6 years (IQR 8.4 to 15.3 years), height prior to GH treatment initiation -2.8 SD (-2.3 to -3.2 SD), pre-treatment IGF-1 -1.7 SD (-1.5 to -2.2 SD) and maximal stimulated GH 2.2 ug/L (1.7 to 2.6 ug/L). Of them, 16 children had MRI midline defect (6 small pituitary, 4 pituitary stalk interruption syndrome, 3 microphthalmos and/or optic nerve hypoplasia, 2 dysgenesis of corpus callosum and one complex brain defect). Causative genetic etiology was confirmed in 7/42 (17%) children. Out of these, 3 children carried causative genetic variant in genes known to play an important role in GH secretion (OTX2 [2], GHSR genes), 3 had impaired fundamental intracellular processes (LMNA, KMTD2, NF1 genes) and one had primary growth plate disorder (COL9A2 gene). In 6 additional children we found a variant of uncertain significance (FLNB, GLI2, IHH, NPR2, PTCH1 and TRPS1 genes).

Conclusion: The genetic etiology of short stature remains unresolved in most children with clinically diagnosed severe GHD. Impaired fundamental intracellular processes might be responsible for some of the cases. In individual children with clinically diagnosed severe GHD, genetic cause apparently unrelated to GH secretion (e.g., primary growth plate disorders) can be discovered. The study was funded by AZV grant NU22J-07-00014