Osorio Maria Geralda F, Marui Suemi, Jorge Alexander A L, Latronico Ana C, Lo Leonard S S, Leite Claudia C, Estefan Vivian, Mendonca Berenice B, Arnhold Ivo J P
Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Av. Eneas de Carvalho Aguiar 155, PAMB 2 Andar Bloco 6, 01065-970 São Paulo, Brazil.
J Clin Endocrinol Metab. 2002 Nov;87(11):5076-84. doi: 10.1210/jc.2001-011936.
Pituitary stalk interruption and ectopic posterior lobe on magnetic resonance imaging (MRI) are frequently observed in patients with GH deficiency (GHD), but their pathogenesis remains controversial. We performed pituitary stimulation tests, MRI, and studied GH-1, GHRH receptor (GHRH-R), and Prophet of Pit-1 (PROP-1) genes in 76 patients with GHD. Of 33 patients with isolated GHD, 4 had GH-1 deletions and 4 had GHRH-R mutations; of 43 patients with combined pituitary hormone deficiency, 1 had PIT-1 and 5 had PROP-1 mutations. Compared with the 62 patients without mutations, 14 patients with mutations had higher frequency of consanguinity (57 vs. 2%, P < 0.001), familial cases (21 vs. 3%, P < 0.05), and lower frequency of breech delivery or hypoxemia at birth (0 vs. 39%, P < 0.005). On MRI, all patients with mutations had an intact stalk, whereas it was interrupted or thin in 74% without mutations (P < 0.001). The posterior pituitary lobe was in normal position in 92% of patients with mutations against 13% without mutations (P < 0.001). Among patients with combined pituitary hormone deficiency, hormonal deficiencies were of pituitary origin in all with PROP-1 and PIT-1 mutations and suggestive of hypothalamic origin in 81% without mutations. Perinatal insults were associated with thin/interrupted pituitary stalk, ectopic posterior lobe, and hypothalamic origin of hormonal deficiencies. In contrast, GH-1, GHRH-R, and PROP-1 mutations were associated with consanguineous parents, intact pituitary stalk, normal posterior lobe, and pituitary origin of hormonal deficiencies. We conclude that pituitary MRI and hormonal response to stimulation tests are useful in selection of patients and candidate genes to elucidate the etiological diagnosis of GHD.
生长激素缺乏症（GHD）患者的磁共振成像（MRI）常显示垂体柄中断和异位后叶，但它们的发病机制仍存在争议。我们对76例GHD患者进行了垂体刺激试验、MRI检查，并研究了生长激素-1（GH-1）、生长激素释放激素受体（GHRH-R）和垂体特异性转录因子1（PROP-1）基因。在33例孤立性GHD患者中，4例有GH-1缺失，4例有GHRH-R突变；在43例联合垂体激素缺乏症患者中，1例有PIT-1突变，5例有PROP-1突变。与62例无突变患者相比，14例有突变患者的近亲结婚频率更高（57%对2%，P<0.001），家族病例更多（21%对3%，P<0.05），出生时臀位分娩或低氧血症的频率更低（0对39%，P<0.005）。MRI显示，所有有突变的患者垂体柄完整，而无突变患者中74%的垂体柄中断或变细（P<0.001）。92%有突变患者的垂体后叶位置正常，无突变患者中这一比例为13%（P<0.001）。在联合垂体激素缺乏症患者中，所有有PROP-1和PIT-1突变患者的激素缺乏源于垂体，而无突变患者中81%提示激素缺乏源于下丘脑。围产期损伤与垂体柄变细/中断、异位后叶以及激素缺乏的下丘脑起源有关。相反，GH-1、GHRH-R和PROP-1突变与近亲结婚的父母、完整的垂体柄、正常的后叶以及激素缺乏的垂体起源有关。我们得出结论，垂体MRI和激素对刺激试验的反应有助于选择患者和候选基因，以阐明GHD的病因诊断。
