ESPE Abstracts

Growth Hormone insensitivity (GHI) is characterized by short stature, GH resistance and IGF-1 deficiency. Classical GHI includes defects in the GH receptor and other genetic abnormalities downstream the GH cascade. Various short stature syndromes have phenotypes that overlap with GHI. This report discusses two cases of nonclassical GHI. Patient 1 is a boy with STAT3 gain-of-function syndrome (STAT3 GOF), characterized by immune dysregulation and growth failure. He developed early-onset eczema, enteropathy, interstitial lung disease with oxygen-dependency and type 1 diabetes. He experienced post-natal growth failure with low IGF-1 and IGFBP-3. His somatotropic response to two stimulation tests was deficient, likely due to his severe multisystemic condition. He started recombinant GH (rGH) treatment at 4 y/o, shortly suspended for suboptimal response. At 6 y/o he underwent hematopoietic stem cell transplantation (HSCT), which is curative for STAT3 GOF. He is now 13 y/o, in good clinical conditions, oxygen-free and has normal bowel function. However, his growth hasn’t improved (height -6.7 SD) with low IGF-1. At reevaluation, GH production was normal after stimulation. He recently started recombinant human IGF-1 (rhIGF-1) treatment. Growth failure in STAT3 GOF is multifactorial; however, it persists after HSCT despite improvement of immune-mediated complications. STAT3 hyperactivity likely directly impacts the GH cascade by altering STAT5b phosphorylation. Patient 2 is a boy with Meier-Gorlin Syndrome (MGS), characterized by short stature, microtia and bilateral patellae agenesis. He displays multiple dysmorphic features, including dental agenesis, entropion, strabismus, and auricular hypoplasia with conductive hearing loss. At 5 y/o he presented with post-natal growth failure, GH deficiency after stimulation, low IGF-1 and IGFBP-3. He started rGH which was discontinued after 12 months for poor stature improvement. He is now 11 y/o with severe short stature (-10.2 SD), persistently low IGF-1 and normal basal GH. He recently began rhIGF-1 treatment. MGS is caused by an impairment in the DNA replication process resulting in reduced cellular proliferation and growth restriction. Response to rGH treatment is variable and it’s unclear if there is a direct impact on the GH axis. The spectrum of genetic abnormalities associated to GHI is expanding and managing nonclassical forms remains challenging because the underlying mechanisms of GHI are often unknown. Treatment with rhIGF-1 is promising for these syndromes but limited data is available. Long term follow-up and further clinical and molecular studies will help to better understand overlapping syndromes, their response to rhIGF-1 and GH-IGF-1 axis physiology.