Gagliardi Lucia, Hotu Cheri, Casey Graeme, Braund Wilton J, Ling King-Hwa, Dodd Thomas, Manavis James, Devitt Peter G, Cutfield Richard, Rudzki Zbigniew, Scott Hamish S, Torpy David J
Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia.
Clin Endocrinol (Oxf). 2009 Jun;70(6):883-91. doi: 10.1111/j.1365-2265.2008.03471.x. Epub 2008 Nov 5.
Cushing's syndrome due to familial ACTH-independent macronodular adrenal hyperplasia (AIMAH) has been reported in small kindreds. In vasopressin-sensitive AIMAH (VPs-AIMAH), VP stimulates an aberrant, ACTH-independent increase in cortisol. The aims of this study were to (i) delineate the preclinical phenotype of VPs-AIMAH in a three-generation kindred (AIMAH-01) and two smaller kindreds (AIMAH-02 and AIMAH-03) and (ii) investigate the aetiology of VP sensitivity in AIMAH-01.
Clinical studies of three kindreds for adrenal tumours or early Cushing's and molecular studies of adrenal tumours (AIMAH-01).
Thirty-three individuals, from three kindreds, were screened for perturbations of the hypothalamic-pituitary-adrenal axis or adrenal tumours.
Patients underwent clinical, biochemical and adrenal imaging investigations. Evaluation included low-dose (1 IU/70 kg) VP stimulation. Adrenal VP receptor (AVPR1A, AVPR1B, AVPR2) expression (AIMAH-01) was assessed using RT-PCR and immunohistochemistry (IHC). IHC for VP was also performed.
AIMAH-01 had three siblings with Cushing's, and four individuals with suppressed ACTH/aberrant VP responses and/or adrenal nodules. In AIMAH-02, a father and son were affected. AIMAH-03 had three siblings with Cushing's. RT-PCR showed adrenal overexpression of AVPR1A and AVPR1B. IHC detected AVPR1A. The adrenal tumour from one patient also stained weakly for VP and AVPR2.
Adrenal nodules, suppressed ACTH and increased VP sensitivity may represent preclinical disease, allowing early detection, and treatment, of affected individuals. In AIMAH-01, increased VP sensitivity may be due to adrenal VP receptor overexpression. In these kindreds, VPs-AIMAH is familial, and autosomal dominant inheritance is most likely.
家族性促肾上腺皮质激素非依赖性大结节性肾上腺增生（AIMAH）所致的库欣综合征已在少数家族中被报道。在血管加压素敏感型AIMAH（VPs - AIMAH）中，血管加压素（VP）可刺激皮质醇出现异常的、不依赖促肾上腺皮质激素（ACTH）的升高。本研究的目的是：（i）在一个三代家族（AIMAH - 01）以及另外两个较小家族（AIMAH - 02和AIMAH - 03）中描绘VPs - AIMAH的临床前表型；（ii）研究AIMAH - 01中VP敏感性的病因。
对三个家族进行肾上腺肿瘤或早期库欣综合征的临床研究，并对肾上腺肿瘤（AIMAH - 01）进行分子研究。
对来自三个家族的33名个体进行下丘脑 - 垂体 - 肾上腺轴紊乱或肾上腺肿瘤筛查。
患者接受临床、生化及肾上腺影像学检查。评估包括低剂量（1 IU/70 kg）VP刺激试验。采用逆转录 - 聚合酶链反应（RT - PCR）和免疫组织化学（IHC）评估肾上腺血管加压素受体（AVPR1A、AVPR1B、AVPR2）表达（AIMAH - 01）。还进行了VP的免疫组织化学检测。
AIMAH - 01有3名患库欣综合征的兄弟姐妹，以及4名促肾上腺皮质激素受抑制/VP反应异常和/或有肾上腺结节的个体。在AIMAH - 02中，父亲和儿子患病。AIMAH - 03有3名患库欣综合征的兄弟姐妹。RT - PCR显示肾上腺中AVPR1A和AVPR1B过表达。免疫组织化学检测到AVPR1A。一名患者的肾上腺肿瘤对VP和AVPR2染色也较浅。
肾上腺结节、促肾上腺皮质激素受抑制及VP敏感性增加可能代表临床前疾病，从而能够对受影响个体进行早期检测和治疗。在AIMAH - 01中，VP敏感性增加可能是由于肾上腺血管加压素受体过表达。在这些家族中，VPs - AIMAH具有家族性，最可能为常染色体显性遗传。
