Growth hormone deficiency in monozygotic twins with autosomal dominant pseudohypoparathyroidism type Ib.
Growth hormone deficiency in monozygotic twins with autosomal dominant pseudohypoparathyroidism type Ib.
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DOI：
10.1507/endocrj.ej15-0033
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发表时间：
2015-04
影响因子：
2
通讯作者：
S. Sano;H. Iwata;K. Matsubara;M. Fukami;M. Kagami;T. Ogata
中科院分区：
文献类型：
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作者：
S. Sano;H. Iwata;K. Matsubara;M. Fukami;M. Kagami;T. Ogata
假性甲状旁腺功能减退症（PHP）与PTH受体（PTH-R）和其他G蛋白偶联受体（包括GHRH-R）的信号转导受损有关。迄今为止，虽然GH缺乏症（GHD）已在多名患有由母体表达的GNAS编码区上的突变引起的PHP-Ia的患者和两名患有伴有母体来源的GNAS差异甲基化区域（DMR）的广泛甲基化缺陷的散发形式的PHP-Ib的患者中报道，尚未在伴有STX 16微缺失和外显子A/B-DMR处甲基化的孤立缺失（LOM）的常染色体显性形式的PHP-Ib（AD-PHP-Ib）患者中鉴定出。我们研究了5例4/12岁的同卵双胞胎，他们身材矮小（均为-3.4 SD），患有GHD（精氨酸和可乐定刺激后GH峰值<6.0 μg/L）。分子生物学研究显示，在双胞胎中，母亲来源的STX 16微缺失和外显子A/B-DMR处的孤立LOMs，证实了AD-PHP-Ib的诊断。未发现GNAS突变，GH 1、POU 1F 1、PROP 1、GHRHR、LHX 3、LHX 4和HESX 1在双胞胎中均未检测到突变或拷贝数变异。结合先前发现GNAS在垂体中显示母体表达的结果，该结果表明双胞胎的GHD主要归因于由AD-PTH-Ib引起的GHRH-R信号转导受损。因此，AD-PHP-Ib应考虑对多种激素（包括GHRH）的耐药性。
Pseudohypoparathyroidism (PHP) is associated with compromised signal transductions via PTH receptor (PTH-R) and other G-protein-coupled receptors including GHRH-R. To date, while GH deficiency (GHD) has been reported in multiple patients with PHP-Ia caused by mutations on the maternally expressed GNAS coding regions and in two patients with sporadic form of PHP-Ib accompanied by broad methylation defects of maternally derived GNAS differentially methylated regions (DMRs), it has not been identified in a patient with an autosomal dominant form of PHP-Ib (AD-PHP-Ib) accompanied by an STX16 microdeletion and an isolated loss of methylation (LOM) at exon A/B-DMR. We studied 5 4/12-year-old monozygotic twins with short stature (both -3.4 SD) and GHD (peak GH values, <6.0 μg/L after arginine and clonidine stimulations). Molecular studies revealed maternally derived STX16 microdeletions and isolated LOMs at exon A/B-DMR in the twins, confirming the diagnosis of AD-PHP-Ib. GNAS mutation was not identified, and neither mutation nor copy number variation was detected in GH1, POU1F1, PROP1, GHRHR, LHX3, LHX4, and HESX1 in the twins. The results, in conjunction with the previous finding that GNAS shows maternal expression in the pituitary, suggest that GHD of the twins is primarily ascribed to compromised GHRH-R signaling caused by AD-PTH-Ib. Thus, resistance to multiple hormones including GHRH should be considered in AD-PHP-Ib.