Pituitary gigantism is a rare manifestation of chronic growth hormone (GH) excess that begins before closure of the growth plates. Nearly half of pituitary gigantism patients have an identifiable genetic cause. X-linked acrogigantism (X-LAG; 10% of pituitary gigantism) typically begins during infancy and can lead to the tallest individuals described. In the 10 years since its discovery, about 40 patients have been identified. Patients with X-LAG usually develop mixed GH and prolactin macroadenomas with occasional hyperplasia that secrete copious amounts of GH, and frequently prolactin. Circulating GH releasing hormone (GHRH) is also elevated in a proportion of patients. X-LAG is caused by constitutive or sporadic mosaic duplications at chromosome Xq26.3 that disrupt the normal chromatin architecture of a topologically associating domain (TAD) around the orphan G protein coupled receptor (GPCR), GPR101. This leads to the formation of a neoTAD in which GPR101 over-expression is driven by ectopic enhancers ("TADopathy"). X-LAG has been seen in three families due to transmission of the duplication from affected mothers to sons. GPR101 is a constitutively active receptor with an unknown natural ligand that signals via multiple G proteins and protein kinases A and C to promote GH/prolactin hypersecretion. Treatment of X-LAG is challenging due to the young patient population and resistance to somatostatin analogs; the GH receptor antagonist pegvisomant is often an effective option. GH, insulin-like growth factor 1 (IGF-1) and prolactin hypersecretion and physical overgrowth can be controlled before definitive adult gigantism occurs, often at the cost of permanent hypopituitarism.

中文翻译：

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TAD 病（X 连锁巨巨症）的遗传病理生理学和临床治疗。


垂体巨人症是慢性生长激素 (GH) 过量的罕见表现，在生长板关闭之前开始。近一半的垂体巨人症患者有可识别的遗传原因。 X连锁巨人症（X-LAG；占垂体巨人症的10%）通常始于婴儿期，并可能导致个体最高。自发现以来的 10 年间，已有约 40 名患者被确诊。 X-LAG 患者通常会出现混合性 GH 和催乳素大腺瘤，偶尔会出现增生，分泌大量 GH，并且经常分泌催乳素。部分患者的循环 GH 释放激素 (GHRH) 也升高。 X-LAG 是由染色体 Xq26.3 上的组成型或散发性嵌合复制引起的，该复制破坏了孤儿 G 蛋白偶联受体 (GPCR) GPR101 周围拓扑关联结构域 (TAD) 的正常染色质结构。这导致 NeoTAD 的形成，其中 GPR101 过度表达由异位增强子驱动（“TAD 病”）。由于复制基因从受影响的母亲传给儿子，X-LAG 已在三个家庭中出现。 GPR101 是一种组成型活性受体，具有未知的天然配体，通过多种 G 蛋白以及蛋白激酶 A 和 C 发出信号，促进 GH/催乳素过度分泌。由于年轻的患者群体和对生长抑素类似物的耐药性，X-LAG 的治疗具有挑战性； GH 受体拮抗剂培维索孟通常是一种有效的选择。 GH、胰岛素样生长因子 1 (IGF-1) 和催乳素分泌过多以及身体过度生长可以在确定的成人巨人症发生之前得到控制，但通常会导致永久性垂体功能减退。