Xu Xiaoqin, Shen Yingxiao, Yang Wei, Wei Haiyan, Chen Ting, Chen Linqi, Wang Zhihua, Yao Hui, Zhang Jianping, Chen Ruimin, Sun Yan, Dong Guanping, Huang Ke, Levine Michael A, Fu Junfen, Wu Wei
Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China.
Department of Endocrinology, Genetics and Metabolism, Henan Children's Hospital, Zhengzhou Children's Hospital, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, China.
Eur J Endocrinol. 2025 May 30;192(6):776-786. doi: 10.1093/ejendo/lvaf120.
We assessed pediatric patients with clinically diagnosed pseudohypoparathyroidism (PHP), pseudopseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH) for genetic and epigenetic defects in GNAS and characterized their clinical features.
We enrolled a total of 87 patients in our study, 70 patients underwent genetic analysis. We compared the clinical manifestations according to the previously reported inactivating PTH/PTHrP signaling disorder (iPPSD) classification combined with conventional clinical classification.
We identified pathogenic variants within exons 1-13 of GNAS in 31 patients (iPPSD2), with the majority presenting as PHP1A, and 2 cases each of PPHP and POH. GNAS imprinting defects were found in 39 patients (iPPSD3), with the clinical types including 11 cases of PHP1A and 28 cases of PHP1B. Sluggish height growth and hypocalcemia-related symptoms were common presenting complaints in PHP1A, while hypocalcemia-related symptoms were typical in PHP1B. Both iPPSD2 and iPPSD3 patients had variable manifestations of Albright hereditary osteodystrophy (AHO), but heterotopic ossification was limited to iPPSD2. We compared the clinical characteristics of these iPPSD2 patients presented as PHP1A in different cohorts. The AHO phenotypes varied among the 4 cohorts. Three PHP1A patients were treated with recombinant human growth hormone and showed improved height and growth rates.
Our findings suggest that molecular screening can be highly specific in patients with parathyroid hormone resistance. Furthermore, we found significant overlap in the clinical features between patients with iPPSD2 and iPPSD3, suggesting that a combination of molecular genetic diagnosis and clinical evaluation may be the better approach for fully understanding GNAS inactivation defects disorders.
我们评估了临床诊断为假性甲状旁腺功能减退症（PHP）、假性假性甲状旁腺功能减退症（PPHP）和进行性骨化性纤维发育不良（POH）的儿科患者，以检测GNAS基因的遗传和表观遗传缺陷，并对其临床特征进行了描述。
我们共纳入了87例患者进行研究，其中70例患者接受了基因分析。我们根据先前报道的失活性甲状旁腺激素/甲状旁腺激素相关蛋白信号传导障碍（iPPSD）分类结合传统临床分类比较了临床表现。
我们在31例患者（iPPSD2）中发现了GNAS外显子1-13内的致病变异，其中大多数表现为PHP1A，PPHP和POH各2例。在39例患者（iPPSD3）中发现了GNAS印记缺陷，临床类型包括11例PHP1A和28例PHP1B。身高增长缓慢和低钙血症相关症状是PHP1A常见的主诉，而低钙血症相关症状在PHP1B中较为典型。iPPSD2和iPPSD3患者均有不同表现的Albright遗传性骨营养不良（AHO），但异位骨化仅限于iPPSD2。我们比较了不同队列中表现为PHP1A的这些iPPSD2患者的临床特征。4个队列中的AHO表型各不相同。3例PHP1A患者接受了重组人生长激素治疗，身高和生长速度有所改善。
我们的研究结果表明，分子筛查对甲状旁腺激素抵抗患者具有高度特异性。此外，我们发现iPPSD2和iPPSD3患者的临床特征存在显著重叠，这表明分子遗传学诊断与临床评估相结合可能是全面了解GNAS失活缺陷疾病的更好方法。
