Pseudohypoparathyroidism (PHP) is a rare inherited syndrome frequently associated with Albright's hereditary osteodystrophy (AHO). We conducted a multicenter study including 71 PHP children and 77 relatives. Erythrocyte Gsalpha biological activity was measured in each patient (normal range 85-110%). 61 patients were classified into four subtypes based on clinical and endocrine data and Gsalpha activity: 45 PHP Ia, 8 PHP Ib, 2 PHP II, and 6 PHP Ic. PHP Ia had decreased Gsalpha (58 +/- 9%), PHP Ib patients had PTH resistance, no AHO and normal Gsalpha (96 +/- 9%), PHP Ic patients had PTH resistance, AHO and no decreased Gsalpha (97 +/- 13%). The 10 remaining patients were considered to have pseudo-pseudohypoparathyroid (Pseudo-PHP) and were divided into two subtypes. One subtype had decreased Gsalpha and the second subtype had normal Gsalpha activity. The heterogeneous expression of Pseudo-PHP and thyrotropin resistance, which preceded parathyroid hormone resistance in 24% of the children, suggested that PHP might be a gradually evolving disease. GRF resistance was found in 4 out of 9 children investigated. The pedigree analysis showed PHP Ia had a dominant mode of inheritance with increased severity through generations. Pedigree analysis did not support a genomic imprinting hypothesis. Two children out of 9 had a chromosome 2 abnormality. This study confirms that Gsalpha activity is a significant marker in the diagnosis and classification of PHP.