Multihormonal resistance in patients with pseudohypoparathyroidism

Identified by Fuller Albright in 1942, pseudohypoparathyroidism is the first described condition of tissue resistance to a hormone. The patients revealed a curious phenotype: short stature, overweight, brachymetacarpia and brachymetatatarsia, subcutaneous ossifications, mental retardation. The low values of serum calcium were resistant to the administration of parathyroid extracts. At surgery or autopsy, the parathyroid glands were present and even hypertrophic. The condition could be related not to an abnormal parathormone receptor (PTH), but to a defect of the Gs proteins linking the receptor to the effector unit producing cAMP. A loss-of-function mutation of the GNAS gene encoding Gs explains the disease with a different expression depending on whether the condition is transmitted by the father or the mother (parental imprinting mechanism). The ubiquity of binding proteins explains why resistance is not reserved for the receptivity of PTH, particularly in the kidney, causing hypocalcemia, hyperphosphatemia and lack of activation of 25-hydroxycholecalciferol. Resistance also hinders, to varying degrees, action of PTHrP (in the embryo), TSH (and TRH), gonadotropins, growth hormone and GH-RH, leptin, calcitonin. . . It also explains the alterations observed in melanogenesis, olfactory, gustative, visual, and auditory sensoriality. Different phenotypes have been reported, including pseudo-pseudohypoparathyroidism without Albright's osteodystrophy and pseudo-hypohyperparathyroidism with bone involvement similar to primary hyperparathyroidism.(c) 2023 l'Academie nationale de medecine. Published by Elsevier Masson SAS. All rights reserved.