Endocrine Abstracts

JOINT1015

We present the case of a rare genetic disorder in a male patient that developed over a span of 10 years. The patient was a child of a pathological pregnancy due to intrauterine growth restriction, born small for gestational age at the 35th gestation week (1970 g, 41 cm). He underwent cardiac surgery for aortic coarctation at 5 months of age, and orchiopexy at 20 months. He was transiently treated for subclinical hypothyroidism. Subsequently, a euthyroid state was achieved without the need for further medication. He is still under regular follow-up with a neurologist, urologist, ophthalmologist, and cardiologist. Due to joint contractures in the lower limbs, botulinum toxin injections were administered. Genetic counseling was first performed in early infancy (1.5 years old), confirming a normal male karyotype and exclusion of SHOX gene defects, as well as genomic imbalances. The diagnostic process was paused for several years, during which he was referred to a pediatric endocrinologist at our center, at the age of 8.5 years. Physical examination revealed significant growth retardation (height SDS -2.7), facial dysmorphism, shortened limbs and digits, skin stiffness with gross motor limitations, normal cognitive and speech development, no pubarche and adrenarche, and bilateral testicular volume of 5 mL. The criteria for growth hormone therapy as a small for gestational age (SGA) child without catch-up growth were met, and recombinant growth hormone (rGH) treatment was initiated (dose of rGH 0.035 mg/kg/day). Given the pronounced phenotype, re-evaluation of genetic counseling was conducted. Subsequent analysis identified a de novo heterozygous mutation in the SMAD4 gene (c.1499T>C; p.Ile500Thr), which is pathogenic and causal for Myhre syndrome. SMAD4 is recognized as a tumor suppressor gene, and its mutations which are presumed to result in a gain of function are associated with Myhre syndrome. To date, no systematic studies have assessed the use of supraphysiological doses of growth hormone (SGA indication) in this specific group, moreover there is a lack of evidence that there is a consistent increase in height velocity by using rGH. Based on current knowledge, we considered rGH therapy inappropriate due to its potential anabolic effects, which may interact with SMAD4’s function, and thus, treatment was immediately discontinued. Myhre syndrome is a rare, multisystemic connective tissue disorder with no specific treatment. We emphasize the importance of ongoing genetic counseling in cases of clustering pathological signs and the need for re-evaluating therapeutic approaches based on the latest evidence and interdisciplinary collaboration.