Endocrine and molecular biological studies in a German family with Albright hereditary osteodystrophy

We examined a German family with five members affected by Albright hereditary osteodystrophy (AHO). The only patient with pseudohypoparathyroidism type Ia (PHP-Ia) presented clinically with latent tetany, mental retardation, round face, short stature, brachymetacarpia and calcifications of subcutaneous tissue, heart and brain, whereas all other four members with pseudopseudohypoparathyroidism (pseudo-PHP) showed only subcutaneous calcifications and brachymetaphalangia. The PHP-Ia patient exhibited hypocalcaemia, hyperphosphataemia, elevated immunoreactive parathyroid hormone (PTH), and a blunted response of cyclic adenosine monophosphate (cAMP) in plasma and urine to synthetic 1-38 hPTH. In addition, latent primary hypothyroidism was found. In contrast, all tested healthy family members as well as the patients with pseudo-PHP exhibited normal calcium metabolism including cAMP response to exogenous PTH. In Northern blot experiments all patients with AHO, regardless whether affected by PHP-Ia or pseudo-PHP, revealed significantly reduced mRNA levels coding for the alpha subunit of the G protein that stimulates adenylyl cyclase (Gs alpha), when compared with healthy family members. In contrast, there was no significant difference between healthy and affected subjects with regard to the levels of the mRNA coding for the alpha subunit of Gi alpha-2, the main inhibitory G protein of adenylyl cyclase. The results indicate that reduced expression of Gs alpha is a useful genetic marker in some families with AHO, regardless whether patients are affected by PHP-Ia or by pseudo-PHP.