Endocrine Abstracts

Introduction: Pseudohypoparathyroidism (PHP) is an orphan disease caused by a mutation in the GNAS gene encoding the α-subunit of G-protein. PHP is characterized by multihormonal resistance. A correlation between the genotype and phenotype of patients with GNAS mutations hasn’t yet been described.

Clinical Case: Patient T., 19 years old male, admitted to our Centre with general weakness and overweight. Hypocalcemia, hyperphosphatemia, increased serum PTH, TSH and psychomotor retardation were first detected at the age of 8 months, however, the diagnosis was clinically made at age of 2 years. The patient’s elder brother died at the age of 4 years for unknown reason (symptoms consistent with PHP), the mother, elder sister and her 2 daughters were healthy. From 2003 to 2008, the patient received alfacalcidol 1.2 mg daily without normocalcemia achievement. Further alfacalcidol was replaced with cholecalciferol 25,000 IU daily. At the same time, levothyroxine was prescribed. At the age of 4 years, the patient was diagnosed with diabetes insipidus followed by desmopressin therapy. At admission, T.’s consciousness was clear, however, he was partially oriented in space and time. T. had II stage obesity (BMI - 36.73 kg/m²). There were a posture disturbance, shortening of the metatarsal bones of 1,2,4,5 fingers of both hands, shortening and deformation of 4 toes (phenotype of Albright hereditary osteodystrophy). Laboratory tests revealed normocalcemia - 2.16 mmol/l (2.15-2.55), normophosphatemia - 1.33 mmol/l (0.74-1.52), normocalciuria - 3.7 mmol/d (2.5-8), increased serum PTH -102.4 pg/ml (15-65). 25(OH) vitamin D was above 150 ng/ml. We temporarily discontinued cholecalciferol and prescribed alfacalcidol 0.75 mg daily with achievement of normocalcemia, normophosphatemia. Brain MRI visualized symmetrical zones of calcification in the subcortical nuclei and nuclei dentati of cerebellum. Nephrocalcinosis/nephrolithiasis were excluded. Given the lack of evidence for the diabetes insipidus a trial withdrawal of desmopressin was carried out, and the plasma and urine osmolality, blood serum electrolytes remained within the laboratory reference range. The typical MRI signal of the neurohypophysis was preserved. GNAS gene sequencing showed a novel heterozygous mutation, whose pathogenicity was proved.

Conclusion: PHP is caused by complex genetic and epigenetic defects. As a result, the path to diagnosis can be long and difficult. Determining the pathogenicity of novel GNAS mutations will improve understanding of gene function and expected clinical manifestations.