Daly Adrian F, Lysy Philippe A, Desfilles Céline, Rostomyan Liliya, Mohamed Amira, Caberg Jean-Hubert, Raverot Veronique, Castermans Emilie, Marbaix Etienne, Maiter Dominique, Brunelle Chloe, Trivellin Giampaolo, Stratakis Constantine A, Bours Vincent, Raftopoulos Christian, Beauloye Veronique, Barlier Anne, Beckers Albert
Department of EndocrinologyCentre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Human GeneticsCentre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumPediatric Endocrinology UnitUniversité Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, BelgiumCliniques Universitaires Saint Luc and Department of PathologyUniversité Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, BelgiumLaboratory of Molecular BiologyAPHM, Hôpital la Conception, 13385, Marseille, FranceAix Marseille UniversitéCRNS, CRN2M-UMR 7286, 13344, Marseille, FranceSection on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland 20892, USALaboratoire d'Hormonologie - CBPEGroupement Hospitalier Est, Hospices Civils de Lyon, 59 bd Pinel - 69677 Bron Cedex, FranceUniversité Catholique de LouvainPole d'endocrinologie, diabete et nutrition (EDIN), Brussels, BelgiumDepartment of NeurosurgeryUniversité Catholique de Louvain, Brussels, Belgium
Department of EndocrinologyCentre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Human GeneticsCentre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumPediatric Endocrinology UnitUniversité Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, BelgiumCliniques Universitaires Saint Luc and Department of PathologyUniversité Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, BelgiumLaboratory of Molecular BiologyAPHM, Hôpital la Conception, 13385, Marseille, FranceAix Marseille UniversitéCRNS, CRN2M-UMR 7286, 13344, Marseille, FranceSection on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland 20892, USALaboratoire d'Hormonologie - CBPEGroupement Hospitalier Est, Hospices Civils de Lyon, 59 bd Pinel - 69677 Bron Cedex, FranceUniversité Catholique de LouvainPole d'endocrinologie, diabete et nutrition (EDIN), Brussels, BelgiumDepartment of NeurosurgeryUniversité Catholique de Louvain, Brussels, Belgium.
Endocr Relat Cancer. 2016 Mar;23(3):161-70. doi: 10.1530/ERC-15-0478. Epub 2015 Dec 15.
X-linked acrogigantism (X-LAG) syndrome is a newly described form of inheritable pituitary gigantism that begins in early childhood and is usually associated with markedly elevated GH and prolactin secretion by mixed pituitary adenomas/hyperplasia. Microduplications on chromosome Xq26.3 including the GPR101 gene cause X-LAG syndrome. In individual cases random GHRH levels have been elevated. We performed a series of hormonal profiles in a young female sporadic X-LAG syndrome patient and subsequently undertook in vitro studies of primary pituitary tumor culture following neurosurgical resection. The patient demonstrated consistently elevated circulating GHRH levels throughout preoperative testing, which was accompanied by marked GH and prolactin hypersecretion; GH demonstrated a paradoxical increase following TRH administration. In vitro, the pituitary cells showed baseline GH and prolactin release that was further stimulated by GHRH administration. Co-incubation with GHRH and the GHRH receptor antagonist, acetyl-(d-Arg(2))-GHRH (1-29) amide, blocked the GHRH-induced GH stimulation; the GHRH receptor antagonist alone significantly reduced GH release. Pasireotide, but not octreotide, inhibited GH secretion. A ghrelin receptor agonist and an inverse agonist led to modest, statistically significant increases and decreases in GH secretion, respectively. GHRH hypersecretion can accompany the pituitary abnormalities seen in X-LAG syndrome. These data suggest that the pathology of X-LAG syndrome may include hypothalamic dysregulation of GHRH secretion, which is in keeping with localization of GPR101 in the hypothalamus. Therapeutic blockade of GHRH secretion could represent a way to target the marked hormonal hypersecretion and overgrowth that characterizes X-LAG syndrome.
X连锁肢端巨大症（X-LAG）综合征是一种新描述的遗传性垂体巨大症，始于儿童早期，通常与混合性垂体腺瘤/增生导致的生长激素（GH）和催乳素分泌显著升高有关。Xq26.3染色体上包括GPR101基因的微重复导致X-LAG综合征。个别病例中，随机生长激素释放激素（GHRH）水平升高。我们对一名散发型X-LAG综合征年轻女性患者进行了一系列激素分析，随后在神经外科切除术后对原发性垂体肿瘤培养物进行了体外研究。该患者在术前检查期间循环GHRH水平持续升高，同时伴有显著的GH和催乳素分泌过多；促甲状腺激素释放激素（TRH）给药后GH出现反常增加。在体外，垂体细胞显示基础GH和催乳素释放，GHRH给药可进一步刺激其释放。与GHRH和GHRH受体拮抗剂乙酰-（d-精氨酸（2））-GHRH（1-29）酰胺共同孵育可阻断GHRH诱导的GH刺激；单独使用GHRH受体拮抗剂可显著降低GH释放。帕西瑞肽可抑制GH分泌，而奥曲肽则不能。胃饥饿素受体激动剂和反向激动剂分别导致GH分泌出现适度的、具有统计学意义的增加和减少。GHRH分泌过多可伴随X-LAG综合征中出现的垂体异常。这些数据表明，X-LAG综合征的病理可能包括下丘脑对GHRH分泌的调节异常，这与GPR101在下丘脑的定位一致。治疗性阻断GHRH分泌可能是针对X-LAG综合征特征性的显著激素分泌过多和过度生长的一种方法。
