Akcay Arzu, Ulucan Korkut, Taskin Necati, Boyraz Mehmet, Akcay Teoman, Zurita Olga, Gomez Ana, Heath Karen E, Campos-Barros Angel
Department of Pediatric Hematology, Kanuni Sultan Suleyman Education and Research Hospital, Istanbul, Turkey.
Eur J Med Genet. 2013 Aug;56(8):445-51. doi: 10.1016/j.ejmg.2013.06.006. Epub 2013 Jul 3.
Mutations in PROP1 are the most frequent defect detected in patients with combined pituitary hormone deficiency (MIM #262600), characterized by a clinical phenotype of proportionate growth deficit due to impaired production of growth hormone in combination with deficiency of one or more of the additional anterior pituitary hormones. Approximately one third of patients with PROP1 inactivating mutations present with abnormal development of the anterior lobe of the pituitary gland as revealed by MRI. We report on the clinical and molecular characterization of the fourth complete PROP1 deletion in a girl with proportional short stature, combined pituitary hormone deficiency and a suprasellar mass mimicking a hypothalamic glioma. The proband, born to consanguineous parents, presented with proportional growth failure (height 108.8 cm, -3.48 SDS), combined pituitary hormone deficiency (GH, TSH, PRL and gonadotropins) and a suprasellar mass with optic chiasm invasion, compatible with a diagnosis of chiasmatic hypothalamic glioma, as revealed by MRI. PROP1 mutation screening by PCR and MLPA detected a homozygous deletion of the entire PROP1. The deletion was delimited to at least 7.7 kb upstream of PROP1 and more finely to ∼541-74 bp downstream from PROP1 by aCGH and PCR mapping. We describe the fourth case with a complete PROP1 deletion in homozygosis. The apparent location of the respective 5' (within a highly repetitive region, rich in Alu sequences) and 3' (within an Alu sequence) breakpoints, suggests that the deletion may have arisen through homologous recombination. The differentiation between PROP1 mutation associated pituitary enlargements from craniopharyngioma, pituitary adenoma, dys-germinoma, or Rathke's pouch cyst, is critical for the correct patient management. It is important to recognize that PROP1 mutations can present associated with evolving pituitary masses and/or other MRI alterations of the pituitary during early childhood and that surgery is not indicated in these patients. Therefore, in the presence of combined pituitary hormone deficiency and a pituitary or hypothalamic mass, PROP1 analysis should be considered before referring the patient to a neurosurgeon.
PROP1基因突变是联合垂体激素缺乏症（MIM #262600）患者中检测到的最常见缺陷，其临床表型为生长激素分泌受损导致的匀称生长发育迟缓，并伴有一种或多种其他垂体前叶激素缺乏。MRI显示，约三分之一携带PROP1失活突变的患者存在垂体前叶发育异常。我们报告了第四例完全性PROP1缺失的病例，患者为一名身材匀称矮小、患有联合垂体激素缺乏症且鞍上有一肿块酷似下丘脑胶质瘤的女孩。先证者父母为近亲结婚，表现为匀称性生长发育迟缓（身高108.8 cm，-3.48 SDS）、联合垂体激素缺乏（生长激素、促甲状腺激素、催乳素和促性腺激素）以及鞍上肿块侵犯视交叉，MRI显示符合交叉性下丘脑胶质瘤的诊断。通过PCR和MLPA进行PROP1突变筛查，检测到整个PROP1基因纯合缺失。通过aCGH和PCR定位，该缺失被限定在PROP1上游至少7.7 kb处，更精确地定位在PROP1下游约541 - 74 bp处。我们描述了第四例纯合子完全性PROP1缺失的病例。各自5'（位于富含Alu序列的高度重复区域内）和3'（位于一个Alu序列内）断点的明显位置表明，该缺失可能是通过同源重组产生的。区分PROP1突变相关的垂体增大与颅咽管瘤、垂体腺瘤、生殖细胞瘤或拉克氏囊肿，对于正确的患者管理至关重要。重要的是要认识到，PROP1突变在儿童早期可能与不断发展的垂体肿块和/或垂体的其他MRI改变相关，并且这些患者不适合手术治疗。因此，在存在联合垂体激素缺乏症和垂体或下丘脑肿块的情况下，在将患者转诊给神经外科医生之前应考虑进行PROP1分析。
