Context: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, indicating limitations of the current classification of the disease.Objectives: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.Patients and Methods:We investigated the GNAS locus at the molecular level in 72 affected patients (46 women; 26 men), from 56 non-related families. Clinical data were obtained for 63 of these patients (38 women; 25 men).Results:The molecular analysis showed 35 patients carried structural mutations, 32 had loss of methylation, and 2 had 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 those diagnosed later in life (9.19±1.64 vs. 24.57±2.28 years, p <0.0001).Conclusions: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 PHP patients and their families with useful genetic information and counseling, thereby to improving outcomes and quality of life.