Phase 2 of Growth Hormone for Treatment of Albright Hereditary Osteodystrophy

描述（由申请人提供）： 奥尔布赖特遗传性骨营养不良（Albright hereditary osteodystrophy，AHO）是一种罕见的遗传性疾病，由编码刺激基因蛋白（Gs）的α链基因的杂合失活突变引起。 在其他异常中，它与身材矮小和肥胖有关。 由于组织特异性印记，在母系遗传等位基因上具有GNAS突变的患者对多种G蛋白偶联激素具有抗性，这种变体称为假性甲状旁腺功能减退症1a型（PHP1a）。 从父系等位基因遗传突变的患者具有相似的表型，但没有激素抵抗，称为假甲状旁腺功能低下症（PPHP）。 研究人员假设PHP1a患者对生长激素释放激素有抵抗力，并发现大约三分之二的人缺乏生长激素（GH）。 生长激素治疗导致生长速度增加，成人身高更高，BMI和肥胖降低，血脂，骨密度，幸福感和自尊改善，而没有任何显着的副作用。 然而，GH缺乏不是PHP1a矮小的唯一原因。 骨龄提前反映的骨骺过早融合也是一个原因，发生在GH充足的PHP1a患者和PPHP患者中。 体外和小鼠研究表明，PHP1a和PPHP中软骨细胞中G蛋白的单倍不足导致软骨细胞过早分化，这可能是病因。 基于GH缺乏PHP1a患者中GH试验的良好结果，假设GH在GH充足的PHP1a儿童以及PPHP儿童中也可能有价值，因为在继发于早期骨融合的生长停止之前，GH可最大限度地加速生长速度。 本研究将探讨生长激素对青春期前生长激素不足的PHP1a和PPHP儿童生长速度的影响。 将收集GH安全性和剂量以及生活质量影响的初步数据。 如果结果令人满意，则在完成拟定的初步研究后，将对这些儿童进行随访，直至最终身高。 这最终可能导致FDA批准的所有AHO儿童使用GH的新适应症，从而消除这些儿童对GH检测的需要。 总体目标是改善这些患者的生活质量。

DESCRIPTION (provided by applicant): Albright hereditary osteodystrophy (AHO) is a rare genetic disorder caused by heterozygous inactivating mutations in the gene encoding the a chain of stimulatory gene proteins (Gs). Among other abnormalities, it is associated with short stature and obesity. Because of tissue-specific imprinting, patients with GNAS mutations on maternally inherited alleles are resistant to multiple G protein-coupled hormones, a variant termed pseudohypoparathyroidism type 1a (PHP1a). Patients who inherit mutations from the paternal allele have a similar phenotype but without hormonal resistance, termed pseudopseudohypo- parathyroidism (PPHP). The investigators hypothesized that PHP1a patients are resistant to growth hormone releasing hormone and found that approximately two-thirds are growth hormone (GH) deficient. GH therapy has led to increased growth velocities, taller adult heights, decreased BMI and adiposity, and improvements in lipids, bone density, sense of well-being, and self-esteem without any significant side effects from GH use. However, GH deficiency is not the only cause of the short stature in PHP1a. Premature fusion of the epiphyses reflected in advanced bone ages is also a cause and occurs in patients with PHP1a who are GH-sufficient as well as in patients with PPHP. In vitro and mouse studies have implicated that haploinsufficiency of G protein in chondrocytes in PHP1a and PPHP causes premature chondrocyte differentiation which could be the etiology. Based on the promising results with the GH trial in GH- deficient PHP1a patients, the hypothesis is that GH may also be of value in children with PHP1a who are GH-sufficient as well as in children with PPHP by accelerating growth velocity maximally prior to the cessation of growth secondary to early bone fusion. This study will examine the effects of GH on growth velocity in prepubertal GH-sufficient children with PHP1a and PPHP. Preliminary data for safety and dosing of GH, as well as quality of life effects will be gathered. If the results are promising, these children will be followed to final height after completion of this proposed initial investigation. This ultimately could lead to a new FDA-approved indication for GH use in all children with AHO, thus eliminating the need for GH testing for these children. The overall goal is to improve the quality of life in these patients.