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症(Aho)是一种罕见的遗传性疾病，由刺激基因蛋白(Gs)编码基因的杂合性失活突变引起。在其他异常中，它与身材矮小和肥胖有关。由于组织特异性印迹，具有母系遗传等位基因GNAS突变的患者对多种G蛋白偶联激素具有抵抗力，这种变异被称为假性甲状旁腺功能减退症1a型(PHP1a)。从父亲的等位基因中遗传突变的患者有类似的表型，但没有激素抵抗，称为假性假性甲状旁腺功能减退(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患者生长激素(GH)缺乏。生长激素治疗导致生长速度加快，成人身高增加，体重指数和肥胖度降低，血脂、骨密度、幸福感和自尊得到改善，使用生长激素没有任何明显的副作用。然而，生长激素缺乏并不是PHP1a身材矮小的唯一原因。 骨龄较高的骨痂过早融合也是一个原因，在生长激素充足的PHP1a患者和PPHP患者中也会发生。体外和小鼠的研究表明，PHP1a和PPHP中软骨细胞G蛋白单倍性不足导致软骨细胞提前分化，这可能是其病因。基于生长激素试验在生长激素缺乏的PHP1a患者身上的可喜结果，假设生长激素对生长激素充足的PHP1a儿童以及PPHP儿童也有价值，因为GH在早期骨融合继发生长停止之前最大限度地加速了生长速度。 本研究将研究生长激素对患有PHP1a和PPHP的青春期前生长激素充足的儿童生长速度的影响。将收集生长激素的安全性和剂量以及对生活质量的影响的初步数据。如果结果是有希望的，这些孩子将在完成这项拟议的初步调查后被跟踪到最终身高。这最终可能导致FDA批准在所有AHO儿童中使用GH的新适应症，从而消除对这些儿童进行GH测试的需要。总体目标是提高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.