Endocrinology and Diabetes Research Group, Hospital Universitario de Cruces, Universidad del País Vasco-Euskal Herriko Unibertsitatea, 48903 Barakaldo, Spain.
J Clin Endocrinol Metab. 2013 May;98(5):E996-1006. doi: 10.1210/jc.2012-4164. Epub 2013 Mar 26.
Recent advances in genetics and epigenetics have revealed an overlap between molecular and clinical features of pseudohypoparathyroidism (PHP) subtypes, broadening the previous spectrum of PHP genotype-phenotype correlations and indicating limitations of the current classification of the disease.
The aim of the study was to screen patients with clinical diagnoses of PHP type I or pseudo-PHP for underlying molecular defects and explore possible correlations between molecular findings and clinical features.
We investigated the GNAS locus at the molecular level in 72 affected patients (46 women and 26 men) from 56 nonrelated families. Clinical data were obtained for 63 of these patients (38 women and 25 men).
The molecular analysis showed that 35 patients carried structural mutations, 32 had loss of methylation, and 2 had a 2q37 deletion but did not reveal any (epi)mutation for 3 patients. Comparing these results and the clinical data, we observed that a younger age at diagnosis was associated with structural defects at the GNAS gene and epigenetic defects with a diagnosis later in life (9.19 ± 1.64 vs 24.57 ± 2.28 years, P < .0001).
This first global review of PHP in Spain highlights the importance of a detailed clinical and genetic study of each patient and the integrated analysis of the findings from the two approaches. It may also help geneticists and clinicians to raise the suspicion of PHP earlier, reach more accurate diagnoses, and provide patients with PHP and their families with useful genetic information and counseling, thereby improving outcomes and quality of life.
遗传学和表观遗传学的最新进展揭示了假性甲状旁腺功能减退症（PHP）亚型的分子和临床特征之间存在重叠，扩大了先前 PHP 基因型-表型相关性的范围，并表明当前疾病分类存在局限性。
本研究旨在筛选临床诊断为 PHP Ⅰ型或假性 PHP 的患者，以寻找潜在的分子缺陷，并探讨分子发现与临床特征之间的可能相关性。
我们在 56 个无亲缘关系的家族中对 72 名受影响的患者（46 名女性和 26 名男性）进行了 GNAS 基因座的分子水平检测。对其中 63 名患者（38 名女性和 25 名男性）进行了临床数据采集。
分子分析显示 35 名患者存在结构突变，32 名患者存在甲基化缺失，2 名患者存在 2q37 缺失，但有 3 名患者未发现任何（表观遗传）突变。将这些结果与临床数据进行比较，我们观察到，诊断时年龄较小与 GNAS 基因的结构缺陷有关，而诊断时年龄较大与表观遗传缺陷有关（9.19 ± 1.64 岁 vs 24.57 ± 2.28 岁，P <.0001）。
这是西班牙首例对 PHP 的全面综述，强调了对每位患者进行详细的临床和遗传研究以及对两种方法的研究结果进行综合分析的重要性。它还有助于遗传学家和临床医生更早地怀疑 PHP 的存在，做出更准确的诊断，并为 PHP 患者及其家属提供有用的遗传信息和咨询，从而改善预后和生活质量。
