背景:身材矮小和生长激素(GH)抵抗的罕见患者在GH受体中具有显性阴性变体。我们描述了由于GH结合蛋白水平升高而导致GH抵抗的患者,并证明了精密医学干预的潜力。
目的:确定高剂量GH是否可以克服该特定患者的GH抵抗,从而导致正常的IGF-1水平和提高的生长速度。
方法:单患者试验的GH剂量递增,然后是剂量稳定期;总共12个月的治疗。
方法:患者在GH受体中具有杂合变体,导致GH结合蛋白水平升高,表现为GH抵抗和严重身材矮小。
方法:每日皮下GH从50微克/千克/天开始,并逐步升级到250微克/千克/天,直到达到IGF-1目标。受试者持续250微克/千克/天,总治疗持续时间为12个月。
方法:主要结果指标是达到IGF-1水平高于正常范围中点所需的GH剂量。次要终点包括治疗第一年期间的身高速度和身高SDS的变化。
结果:剂量为250微克/千克/天的GH达到目标IGF-1水平。患者的年化身高速度为8.7厘米/年,从基线增加3.4厘米/年,导致高度增加0.81SD。
结论:极高剂量GH的精准医学方法能够克服GH受体显性阴性变异导致GH结合蛋白水平升高的患者的GH抵抗。
BACKGROUND: Rare patients with short stature and growth hormone (GH) resistance have dominant-negative variants in the GH receptor. We describe a patient with GH resistance due to elevated levels of GH binding protein and demonstrate the potential for a precision medicine intervention.
OBJECTIVE: To determine whether high dose GH can overcome GH resistance in this specific patient resulting in normal IGF-1 levels and improved growth rates.
METHODS: Single patient
trial of ascending doses of GH followed by dose stable phase; total 12 months of treatment.
METHODS: Patient has a heterozygous variant in GH receptor resulting in elevated levels of GH binding protein manifesting as GH resistance and severe short stature.
METHODS: Daily subcutaneous GH starting at 50 micrograms/kg/day and escalating to 250 micrograms/kg/day until goal IGF-1 achieved. Subject continued 250 micrograms/kg/day for a total treatment duration of 12 months.
METHODS: The primary outcome measure was the dose of GH required to achieve an IGF-1 level above the mid-point of the normal range. Secondary endpoints included height velocity and the change in height SDS during the 1st year of treatment.
RESULTS: A dose of GH of 250 micrograms/kg/day achieved the target IGF-1 level. The patient\'s annualized height velocity was 8.7 cm/year, an increase of 3.4 cm/year from baseline, resulting in a 0.81 SD gain in height.
CONCLUSIONS: A precision medicine approach of extremely high dose GH was able to overcome GH resistance in a patient with a dominant-negative variant in the GH receptor resulting in elevated GH binding protein levels.