Halász Zita
Semmelweis Egyetem, Általános Orvostudományi Kar I. Gyermekklinika Budapest Bókay J. u. 53-54. 1083.
Orv Hetil. 2011 Feb 6;152(6):221-32. doi: 10.1556/OH.2011.29032.
In this work I analysed the outcome of growth hormone replacement treatment in patients with inherited form of multiple pituitary hormone deficiency and examined diseased-causing mutations of pituitary transcription factor genes which may underlie this disorder. The results showed that after treatment for a longer than 7-year period with a growth hormone preparation available under well-controlled distribution, the mean height of children with growth hormone deficiency reached the normal national reference range adjusted for age and sex. After establishment of clinical criteria for screening PROP1 gene mutations, I performed mutational analysis of all coding exons of this gene in 35 patients with inherited form of multiple pituitary hormone deficiency. With these studies, diseases-causing PROP1 gene mutations were detected in 15 of the 35 patients (43%). It was also found that more than 80% of mutant alleles were accounted for by those containing the 150delA and 301-302delGA mutations of the PROP1 gene. Importantly, these findings indicated a high relevance of mutational "hot spots" of the PROP1 gene in Hungarian patients with inherited form of multiple pituitary hormone deficiency and they also offered an opportunity for the development of rational and cost-effective screening strategy. When clinical and hormonal findings of patients with and without PROP1 gene mutations were compared, results showed that growth hormone deficiency was diagnosed at earlier age of life in patients with PROP1 gene mutations, but the severity of growth retardation at the time of diagnosis of growth hormone deficiency or the age of patients at the time of manifestation of other pituitary hormone deficiencies (TSH, LH, FSH and ACTH) were similar in the two groups of patients. In 15 patients inherited form of multiple pituitary hormone deficiency who had no PROP1 gene mutations, exon 6 of the POU1F1 gene containing a mutational "hot spot" was also examined but no mutations were found. Thus, these results do not support a significant role of the mutational "hot spot" of the POU1F1 gene in Hungarian patients with inherited form of multiple pituitary hormone deficiency. Finally, I introduced a method for the detection of mutations of the PITX2 gene, a pituitary transcription factor that plays a role not only in pituitary development and differentiation but also in the lateralization of organs. With the use of this method, I performed mutational analysis of all coding exons of this gene in an exceptionally unique patient who had both situs inversus totalis and inherited form of multiple pituitary hormone deficiency, but no mutation was found. Thus, the findings in this patient failed to indicate that mutation of the PITX2 gene is involved in the pathomechanism of situs inversus totalis associated with inherited form of multiple pituitary hormone deficiency.
在这项研究中，我分析了遗传性多种垂体激素缺乏症患者生长激素替代治疗的结果，并检测了可能导致该疾病的垂体转录因子基因突变。结果显示，使用在严格管控下供应的生长激素制剂治疗超过7年后，生长激素缺乏症患儿的平均身高达到了根据年龄和性别调整后的正常国家参考范围。在确立了筛查PROP1基因突变的临床标准后，我对35例遗传性多种垂体激素缺乏症患者的该基因所有编码外显子进行了突变分析。通过这些研究，在35例患者中的15例（43%）检测到了导致疾病的PROP1基因突变。还发现超过80%的突变等位基因是由包含PROP1基因150delA和301 - 302delGA突变的等位基因构成。重要的是，这些发现表明PROP1基因突变的“热点”在匈牙利遗传性多种垂体激素缺乏症患者中具有高度相关性，同时也为制定合理且具有成本效益的筛查策略提供了契机。比较有和没有PROP1基因突变患者的临床和激素检查结果，结果显示，有PROP1基因突变的患者生长激素缺乏症在更早的年龄被诊断出来，但在生长激素缺乏症诊断时生长发育迟缓的严重程度，或在其他垂体激素缺乏症（促甲状腺激素、促黄体生成素、促卵泡生成素和促肾上腺皮质激素）出现时患者的年龄，在两组患者中相似。在15例遗传性多种垂体激素缺乏症且没有PROP1基因突变的患者中，也检测了包含突变“热点”的POU1F1基因第6外显子，但未发现突变。因此，这些结果不支持POU1F1基因突变的“热点”在匈牙利遗传性多种垂体激素缺乏症患者中起重要作用。最后，我介绍了一种检测PITX2基因突变的方法，PITX2是一种垂体转录因子，不仅在垂体发育和分化中起作用，还在器官的左右不对称中起作用。使用该方法，我对一名患有完全性内脏反位和遗传性多种垂体激素缺乏症的特殊患者的该基因所有编码外显子进行了突变分析，但未发现突变。因此，该患者的研究结果未能表明PITX2基因突变参与了与遗传性多种垂体激素缺乏症相关的完全性内脏反位的发病机制。
