X 染色体基因剂量作为特纳综合征患者生长发育迟缓及成年身高矮小的决定因素。

X-chromosome gene dosage as a determinant of impaired pre and postnatal growth and adult height in Turner syndrome.

机构信息

Assistance Publique-Hôpitaux de ParisHôpital Robert Debré, Service d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, INSERM U 1141, 48 Bd Sérurier, F-75019 Paris, FranceUniversité Paris DiderotSorbonne Paris Cité, F-75019 Paris, FranceInstitut National de la Santé et de la Recherche Médicale (Inserm)Unité 1141, DHU Protect, F-75019 Paris, FranceAP-HPHôpital Robert Debré, Unit of Clinical Epidemiology, F-75019, Paris, FranceInsermCIC-EC 1426, F-75019 Paris, France Assistance Publique-Hôpitaux de ParisHôpital Robert Debré, Service d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, INSERM U 1141, 48 Bd Sérurier, F-75019 Paris, FranceUniversité Paris DiderotSorbonne Paris Cité, F-75019 Paris, FranceInstitut National de la Santé et de la Recherche Médicale (Inserm)Unité 1141, DHU Protect, F-75019 Paris, FranceAP-HPHôpital Robert Debré, Unit of Clinical Epidemiology, F-75019, Paris, FranceInsermCIC-EC 1426, F-75019 Paris, France.

出版信息

Eur J Endocrinol. 2016 Mar;174(3):281-8. doi: 10.1530/EJE-15-1000. Epub 2015 Dec 14.

DOI:10.1530/EJE-15-1000

PMID:26744895

Abstract

OBJECTIVE

Short stature is a key aspect of the phenotype of patients with Turner syndrome (TS). SHOX haploinsufficiency is responsible for about two-thirds of the height deficit. The aim was to investigate the effect of X-chromosome gene dosage on anthropometric parameters at birth, spontaneous height, and adult height (AH) after growth hormone (GH) treatment.

DESIGN

We conducted a national observational multicenter study.

METHODS

Birth parameter SDS for gestational age, height, and AH before and after GH treatment respectively, and height deficit with respect to target height (SDS) were classified by karyotype subgroup in a cohort of 1501 patients with TS: 45,X (36%), isoXq (19%), 45,X/46,XX (15%), XrX (7%), presence of Y (6%), or other karyotypes (17%).

RESULTS

Birth weight, length (P<0.0001), and head circumference (P<0.001), height and height deficit with respect to target height (SDS) before GH treatment, at a median age of 8.8 (5.3-11.8) years and after adjustment for age and correction for multiple testing (P<0.0001), and AH deficit with respect to target height at a median age of 19.3 (18.0-21.8) years and with additional adjustment for dose and duration of GH treatment (P=0.006), were significantly associated with karyotype subgroup. Growth retardation tended to be more severe in patients with XrX, isoXq, and, to a lesser extent, 45,X karyotypes than in patients with 45,X/46,XX karyotypes or a Y chromosome.

CONCLUSION

These data suggest that haploinsufficiency for an unknown Xp gene increases the risk of fetal and postnatal growth deficit and short AH with respect to target height after GH therapy.

摘要

目的

特纳综合征（Turner syndrome，TS）患者的表型关键特征之一为身材矮小。SHOX 基因单倍体不足导致身高缺陷的比例约占三分之二。本研究旨在探讨 X 染色体基因剂量对特纳综合征患者出生时的人体测量参数、自发性身高和生长激素（growth hormone，GH）治疗后的成人身高（adult height，AH）的影响。

设计

我们进行了一项全国性的观察性多中心研究。

方法

根据核型亚组，将 1501 例特纳综合征患者的出生时胎龄的参数 SDS、身高和 GH 治疗前后的 AH 以及相对于靶身高的身高缺陷（SDS）进行分类：45，X（36%）、isoXq（19%）、45，X/46，XX（15%）、XrX（7%）、存在 Y 染色体（6%）或其他核型（17%）。

结果

出生体重、长度（P<0.0001）和头围（P<0.001）、GH 治疗前的身高和相对于靶身高的身高缺陷（SDS）、中位年龄 8.8（5.3-11.8）岁且经年龄和多次检测校正（P<0.0001）、以及 GH 治疗中位年龄 19.3（18.0-21.8）岁且经剂量和治疗时间调整后的相对于靶身高的 AH 缺陷（P=0.006），与核型亚组显著相关。XrX、isoXq 核型患者的生长迟缓程度较 45，X/46，XX 核型患者严重，而与存在 Y 染色体的患者相比则程度较轻。