Hannah-Shmouni Fady, Trivellin Giampaolo, Beckers Pablo, Karaviti Lefkothea P, Lodish Maya, Tatsi Christina, Adesina Adekunle M, Adamidou Fotini, Mintziori Gesthimani, Josefson Jami L, Quezado Martha, Stratakis Constantine A
Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892, USA.
Laboratory of Cellular and Molecular Endocrinology, Humanitas Research Hospital-IRCCS, 20089 Rozzano, Italy.
J Clin Med. 2022 Apr 13;11(8):2168. doi: 10.3390/jcm11082168.
Overgrowth due to growth hormone (GH) excess affects approximately 10% of patients with neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG). Our aim is to describe the clinical, biochemical, pathological, and genetic features of GH excess in a retrospective case series of 10 children and adults with NF1 referred to a tertiary care clinical research center. Six children (median age = 4 years, range of 3−5 years), one 14-year-old adolescent, and three adults (median age = 42 years, range of 29−52 years) were diagnosed with NF1 and GH excess. GH excess was confirmed by the failure to suppress GH (<1 ng/mL) on oral glucose tolerance test (OGTT, n = 9) and frequent overnight sampling of GH levels (n = 6). Genetic testing was ascertained through targeted or whole-exome sequencing (n = 9). Five patients (all children) had an OPG without any pituitary abnormality, three patients (one adolescent and two adults) had a pituitary lesion (two tumors, one suggestive hyperplasia) without an OPG, and two patients (one child and one adult) had a pituitary lesion (a pituitary tumor and suggestive hyperplasia, respectively) with a concomitant OPG. The serial overnight sampling of GH levels in six patients revealed abnormal overnight GH profiling. Two adult patients had a voluminous pituitary gland on pituitary imaging. One pituitary tumor from an adolescent patient who harbored a germline heterozygous p.Gln514Pro NF1 variant stained positive for GH and prolactin. One child who harbored a heterozygous truncating variant in exon 46 of NF1 had an OPG that, when compared to normal optic nerves, stained strongly for GPR101, an orphan G protein-coupled receptor causing GH excess in X-linked acrogigantism. We describe a series of patients with GH excess and NF1. Our findings show the variability in patterns of serial overnight GH secretion, somatotroph tumor or hyperplasia in some cases of NF1 and GH excess. Further studies are required to ascertain the link between NF1, GH excess and GPR101, which may aid in the characterization of the molecular underpinning of GH excess in NF1.
生长激素（GH）分泌过多导致的身材过度生长影响了约10%的1型神经纤维瘤病（NF1）和视路胶质瘤（OPG）患者。我们的目的是在一个回顾性病例系列中描述10例转诊至三级医疗临床研究中心的NF1儿童和成人患者GH分泌过多的临床、生化、病理和遗传特征。6名儿童（中位年龄 = 4岁，范围为3 - 5岁）、1名14岁青少年和3名成人（中位年龄 = 42岁，范围为29 - 52岁）被诊断为NF1和GH分泌过多。口服葡萄糖耐量试验（OGTT，n = 9）时未能抑制GH（<1 ng/mL）以及频繁的夜间GH水平采样（n = 6）证实了GH分泌过多。通过靶向测序或全外显子组测序进行基因检测（n = 9）。5例患者（均为儿童）患有OPG且无任何垂体异常，3例患者（1名青少年和2名成人）有垂体病变（2例肿瘤，1例提示增生）但无OPG，2例患者（1名儿童和1名成人）有垂体病变（分别为垂体肿瘤和提示增生）且伴有OPG。6例患者的夜间GH水平连续采样显示夜间GH谱异常。2例成年患者垂体成像显示垂体体积增大。1例携带种系杂合p.Gln514Pro NF1变异的青少年患者的垂体肿瘤GH和催乳素染色呈阳性。1例在NF1第46外显子中有杂合截断变异的儿童患有OPG，与正常视神经相比，该OPG中导致X连锁肢端巨大症中GH分泌过多的孤儿G蛋白偶联受体GPR101染色强烈。我们描述了一系列GH分泌过多和NF1患者。我们的研究结果显示了夜间GH连续分泌模式的变异性，以及在一些NF1和GH分泌过多病例中的生长激素细胞肿瘤或增生。需要进一步研究以确定NF1、GH分泌过多和GPR101之间的联系，这可能有助于阐明NF1中GH分泌过多的分子基础。
