Multiple hormonal resistance and metabolic disorders in pseudogypoparatiosis

Pseudohypoparathyroidism is a rare group of clinically and genetically heterogeneous diseases caused by the inactivation of the PTH-signaling pathway. The main component of the disease is resistance to PTH, causing a disturbance of calcium-phosphorus metabolism. With pseudohypoparathyroidism, there may also be a development of insensitivity to thyrotropic and gonadotropic hormones of the pituitary gland and the formation of characteristic clinical features in the form of subcutaneous calcifications, brachidactyly, obesity, stuntedness, mental retardation. This article describes the clinical case of pseudohypoparathyroidism in a 35-year-old woman with classic phenotypic hypoparathyroidism with hereditary Albright osteodystrophy and a proven mutation in the GNAS gene, and discusses the spectrum of metabolic disorders of the disease.

1. Albright F, Burnett, C, Smith, P. H, Parson, W. Pseudo-hypoparathyroidism--an example of ‘Seabright-Bantam syndrome’: report of three cases. Endocrinology. 1942;30:922–32.

2. Levine MA, Downs RW, Jr., Singer M, et al. Deficient activity of guanine nucleotide regulatory protein in erythrocytes from patients with pseudohypoparathyroidism. Biochem. Biophys. Res. Commun.1980;94(4):1319-1324.

3. Patten JL, Johns DR, Valle D, et al. Mutation in the Gene Encoding the Stimulatory G Protein of Adenylate Cyclase in Albright's Hereditary Osteodystrophy. N. Engl. J. Med. 1990;322(20):1412-1419. doi: 10.1056/nejm199005173222002.

4. Elli FM, Linglart A, Garin I, et al. The Prevalence ofGNASDeficiency-Related Diseases in a Large Cohort of Patients Characterized by the EuroPHP Network. J. Clin. Endocr. Metab. 2016;101(10):3657-3668. doi: 10.1210/jc.2015-4310.

5. Fernández-Rebollo E, Lecumberri B, Gaztambide S, et al. Endocrine Profile and Phenotype-(Epi)Genotype Correlation in Spanish Patients with Pseudohypoparathyroidism. J. Clin. Endocr. Metab.2013;98(5):E996-E1006. doi: 10.1210/jc.2012-4164.

6. Sano S, Nakamura A, Matsubara K, et al. (Epi)genotype-Phenotype Analysis in 69 Japanese Patients With Pseudohypoparathyroidism Type I. Journal of the Endocrine Society. 2018;2(1):9-23. doi: 10.1210/js.2017-00293.

7. Mantovani G. Pseudohypoparathyroidism: Diagnosis and Treatment. J. Clin. Endocr. Metab.2011;96(10):3020-3030. doi: 10.1210/jc.2011-1048.

8. Thiele S, Mantovani G, Barlier A, et al. From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network. European journal of endocrinology / European Federation of Endocrine Societies. 2016;175(6):P1-P17. doi: 10.1530/eje-16-0107.

9. Saleem S, Aslam H, Anwar M, et al. Fahr’s syndrome: literature review of current evidence. Orphanet J. Rare Dis. 2013;8(1):156. doi: 10.1186/1750-1172-8-156.

10. Otheman Y, Khalloufi H, Benhima I, Ouanass A. Manifestations neuropsychiatriques révélant une pseudohypoparathyroïdie avec un syndrome de Fahr. L'Encéphale. 2011;37(1):54-58. doi: 10.1016/j.encep.2010.03.001.

11. Farfel Z, Friedman E. Mental deficiency in pseudohypoparathyroidism type I is associated with Ns-protein deficiency. Ann. Intern. Med. 1986;105(2):197-199.

12. Mouallem M, Shaharabany M, Weintrob N, et al. Cognitive impairment is prevalent in pseudohypoparathyroidism type Ia, but not in pseudopseudohypoparathyroidism: possible cerebral imprinting of Gs? Clin. Endocrinol. (Oxf.). 2007;0(0):070907132242011-??? doi: 10.1111/j.1365-2265.2007.03025.x.

13. Perez KM, Lee EB, Kahanda S, et al. Cognitive and behavioral phenotype of children with pseudohypoparathyroidism type 1A. Am. J. Med. Genet. A. 2018;176(2):283-289. doi: 10.1002/ajmg.a.38534.

14. Chen M, Berger A, Kablan A, et al. Gsα Deficiency in the Paraventricular Nucleus of the Hypothalamus Partially Contributes to Obesity Associated with Gsα Mutations. Endocrinology. 2012;153(9):4256-4265. doi: 10.1210/en.2012-1113.

15. Roizen JD, Danzig J, Groleau V, et al. Resting Energy Expenditure Is Decreased in Pseudohypoparathyroidism Type 1A. J. Clin. Endocr. Metab. 2016;101(3):880-888. doi: 10.1210/jc.2015-3895.

16. 1Carel JC, Le Stunff C, Condamine L, et al. Resistance to the Lipolytic Action of Epinephrine: A New Feature of Protein GsDeficiency. J. Clin. Endocr. Metab. 1999;84(11):4127-4131. doi: 10.1210/jcem.84.11.6145.

17. Chen M, Shrestha YB, Podyma B, et al. Gsα deficiency in the dorsomedial hypothalamus underlies obesity associated with Gsα mutations. J. Clin. Invest. 2016;127(2):500-510. doi: 10.1172/jci88622.