Rodd Celia, Millette Maude, Iacovazzo Donato, Stiles Craig E, Barry Sayka, Evanson Jane, Albrecht Steffen, Caswell Richard, Bunce Benjamin, Jose Sian, Trouillas Jacqueline, Roncaroli Federico, Sampson Julian, Ellard Sian, Korbonits Márta
Pediatrics and Child Health (C.R.), University of Manitoba, Winnipeg MB R3E 0Z2, Canada; Department of Pediatrics (M.M.), Centre mère-enfant Soleil, Centre Hospitalier de l'Université de Quebec, QC G1V 4G2, Canada; Endocrinology (D.I., C.E.S., S.B., J.E., M.K.), Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Pathology (S.A.), McGill University, Montreal QC H4A 2J1, Canada; Molecular Genetics (R.C., B.B., S.E.), University of Exeter, Exeter EX4 4SB, United Kingdom; Institute of Medical Genetics (S.J., J.S.), School of Medicine, Cardiff University, Cardiff CF10 3XQ, United Kingdom; Centre de Pathologie Est (J.T.), Hospices Civils de Lyon, University of Lyon, 69622 Lyon, France; and Neuropathology (F.R.), University of Manchester, Manchester M13 9PL, United Kingdom.
J Clin Endocrinol Metab. 2016 May;101(5):1927-30. doi: 10.1210/jc.2015-4366. Epub 2016 Mar 16.
Recent reports have proposed that sporadic or familial germline Xq26.3 microduplications involving the GPR101 gene are associated with early-onset X-linked acrogigantism (XLAG) with a female preponderance.
A 4-year-old boy presented with rapid growth over the previous 2 years. He complained of sporadic headaches and had coarse facial features. His height Z-score was +4.89, and weight Z-score was +5.57. Laboratory testing revealed elevated serum prolactin (185 μg/L; normal, <18 μg/L), IGF-1 (745 μg/L; normal, 64-369 μg/L), and fasting GH > 35.0 μg/L. Magnetic resonance imaging demonstrated a homogenous bulky pituitary gland (18 × 15 × 13 mm) without obvious adenoma. A pituitary biopsy showed hyperplastic pituitary tissue with enlarged cords of GH and prolactin cells. Germline PRKAR1A, MEN1, AIP, DICER1, CDKN1B, and somatic GNAS mutations were negative. Medical management was challenging until institution of continuous sc infusion of short-acting octreotide combined with sc pegvisomant and oral cabergoline. The patient remains well controlled with minimal side effects 7 years after presentation. His phenotype suggested XLAG, but his peripheral leukocyte-, saliva-, and buccal cell-derived DNA tested negative for microduplication in Xq26.3 or GPR101. However, DNA isolated from the pituitary tissue and forearm skin showed duplicated dosage of GPR101, suggesting that he is mosaic for this genetic abnormality.
Our patient is the first to be described with somatic microduplication leading to typical XLAG phenotype. This patient demonstrates that a negative test for Xq26.3 microduplication or GPR101 duplication on peripheral blood DNA does not exclude the diagnosis of XLAG because it can result from a mosaic mutation affecting the pituitary.
最近的报告提出，涉及GPR101基因的散发性或家族性种系Xq26.3微重复与女性占优势的早发性X连锁肢端肥大症（XLAG）有关。
一名4岁男孩在过去2年中出现快速生长。他主诉偶发头痛，面部特征粗糙。他的身高Z评分是+4.89，体重Z评分是+5.57。实验室检查显示血清催乳素升高（185μg/L；正常，<18μg/L）、胰岛素样生长因子-1（IGF-1，745μg/L；正常，64 - 369μg/L），空腹生长激素>35.0μg/L。磁共振成像显示垂体均匀增大（18×15×13mm），无明显腺瘤。垂体活检显示垂体组织增生，生长激素和催乳素细胞索增粗。种系PRKAR1A、MEN1、AIP、DICER1、CDKN1B以及体细胞GNAS突变均为阴性。在开始持续皮下注射短效奥曲肽联合皮下注射培维索孟和口服卡麦角林之前，药物治疗颇具挑战性。该患者在就诊后7年仍得到良好控制，副作用最小。他的表型提示XLAG，但他外周血白细胞、唾液和颊细胞来源的DNA检测Xq26.3或GPR101微重复为阴性。然而，从垂体组织和前臂皮肤分离的DNA显示GPR1重复剂量增加，提示他存在这种基因异常的嵌合体。
我们的患者是首例被描述为体细胞微重复导致典型XLAG表型的病例。该患者表明，外周血DNA检测Xq26.3微重复或GPR101重复阴性并不能排除XLAG的诊断，因为它可能由影响垂体的嵌合突变引起。
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