We report a 12-year-old girl with developmental delay, dysmorphic features, and short stature initially diagnosed with growth hormone deficiency at age 7. Despite appropriate growth hormone treatment for four years with documented insulin-like growth factor-1 (IGF-1) normalization (64→241.7 ng/ml), growth velocity remained suboptimal (5–6 cm/year vs. expected 7–8 cm/year). Clinical examination revealed triangular facies, hypertelorism, gingival hyperplasia, moderate intellectual disability, and delayed language development (first words at 3 years). Whole exome sequencing identified a novel de novo heterozygous KMT2C mutation (c.7444_7445insCC, p.Phe2482Serfs*34), confirming Kleefstra-2 syndrome diagnosis. Treatment resistance despite a biochemical response suggests possible post-receptor IGF-1 resistance, potentially related to epigenetic dysregulation. This represents the first documented case of growth hormone deficiency with detailed endocrine characterization in Kleefstra-2 syndrome, expanding the phenotypic spectrum and highlighting the importance of considering genetic syndromes in treatment-refractory short stature.