Case Report: Growth hormone deficiency and response to treatment in MIRAGE syndrome: expanding the endocrine phenotype

Background: MIRAGE syndrome, a rare autosomal dominant disorder, is caused by heterozygous gain-of-function mutations in the SAMD9 gene. A key characteristic of MIRAGE syndrome is growth restriction. Although initially thought to stem mainly from prenatal and systemic factors, this growth restriction can also be a consequence of panhypopituitarism, leading to growth hormone deficiency (GHD). The use of recombinant human growth hormone (rhGH) to treat the characteristic severe growth failure is controversial due to an inherent risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia.Case presentation: We report an 11-year-old male diagnosed with MIRAGE syndrome confirmed by a heterozygous de novo SAMD9 variant (c.4615T>A; p.Leu1539Ile) who had previously undergone allogeneic hematopoietic stem cell transplantation for MDS with monosomy 7. Severe pre- and postnatal growth restriction, characterized by short stature and slow growth velocity, marked the clinical course. Comprehensive hormonal testing was performed and ultimately revealed a growth hormone deficiency (GHD). At age 6, growth hormone therapy began after a brain MRI to assess the pituitary gland anatomy. This decision followed a comprehensive risk-benefit analysis and a hematological evaluation that showed no signs of clonal evolution. Over a six-year follow-up period, the patient demonstrated a significant improvement in growth velocity and height standard deviation score, with stable hematological parameters and no adverse events.Conclusion: This case expands the known endocrine phenotype of MIRAGE syndrome, providing the first report, to our knowledge, of a favorable and safe medium-term response to rhGH therapy in this condition. Our observations support systematic GH stimulation testing in MIRAGE patients with marked growth failure who survive beyond early childhood and suggest that, in carefully selected cases with proven GHD, rhGH replacement may be considered in close collaboration with hematology/oncology teams and under strict hematological monitoring.