Pseudohypoparathyroidism (PHP) covers a heterogeneous group of disorders, which have in common resistance to
parathyroid hormone (PTH). However, they differ in many aspects such as site of the defect in signal transduction, clinical picture (with or without Albright's hereditary osteodystrophy (AHO)), extension of
hormone resistance, and the tissue activity of
protein Gs. PHP type Ic, a rare subtype, is characterized by resistance to several
hormones, the presence of AHO, and normal activity of
protein Gs. We present the case of a patient with PHP type Ic. Although resistance to TSH was suggested at the age of 12 months, diagnosis was made when she presented with
hypocalcemia and resistance to PTH. Resistance to GH was also detected, and partial resistance to
gonadotropins became clear after puberty. We demonstrated a defective lipolytic response to
epinephrine, suggesting a role of this resistance in the pathogenesis of her
morbid obesity. In view of the difficulties in the management of
overweight in this disorder, treatment with a
cannabinoid receptor type 1 (CB1) antagonist was started, and it proved to be highly effective, lowering the patient's body mass index from 40.5 to 33.5, which was quite impressive. We propose that an underactive
melanocortin-4 receptor, which is found in certain patients with PHP, leads to upregulation of the
CB1 receptor and consequently to a good response to treatment with CB1 antagonists. Another interesting finding was the GNAS mutation that was identified in this patient. A
nonsense mutation resulted in a truncated Gsa that was able to stimulate
adenylyl cyclase efficiently, but could not bind to receptors in a normal way.