Pseudohypoparathyroidism type 1A and Albright hereditary osteodystrophy: a comprehensive review of molecular pathogenesis, clinical manifestations, and therapeutic approaches
DOI:
https://doi.org/10.18203/2320-6012.ijrms20252056Keywords:
Pseudohypoparathyroidism type 1A , Albright hereditary osteodystrophy , GNAS gene mutation, Hormone resistance, Hypocalcemia, Brachydactyly, Endocrine disorders, Imprinted gene disorderAbstract
Pseudohypoparathyroidism type 1A (PHP1A) is a rare genetic disorder characterized by end-organ resistance to parathyroid hormone (PTH) due to heterozygous inactivating mutations in the GNAS gene. Patients frequently exhibit the phenotypic features of Albright hereditary osteodystrophy (AHO), including short stature, brachydactyly, subcutaneous ossifications, and obesity. Despite advances in molecular genetics, the clinical management of PHP1A remains challenging due to its multisystemic involvement. This review aims to elucidate the molecular mechanisms underlying PHP1A, delineate its clinical and biochemical characteristics, and discuss current and emerging therapeutic strategies. A systematic literature review was conducted, analyzing peer-reviewed articles from PubMed, Scopus, and OMIM databases focusing on PHP1A, AHO, and related disorders. PHP1A arises from maternal transmission of GNAS mutations, leading to impaired Gsα protein function and subsequent hormonal resistance. The AHO phenotype is present in most cases, with additional endocrine abnormalities such as hypothyroidism and growth hormone deficiency commonly reported. Early diagnosis is essential to mitigate complications, including severe hypocalcemia and neurocognitive impairments. Treatment involves calcium and vitamin D supplementation, though targeted therapies remain under investigation. PHP1A with AHO represents a complex multisystem disorder necessitating a multidisciplinary approach. Further research into genotype-phenotype correlations and novel therapeutic interventions is warranted to improve patient outcomes.
Metrics
References
Mantovani G, Bastepe M, Monk D, de Sanctis L, Thiele S, Usardi A, et al. Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement. Nat Rev Endocrinol. 2018;14(8):476-500. DOI: https://doi.org/10.1038/s41574-018-0042-0
Danzig J, Li D, Jan de Beur S, Levine MA. High-throughput Molecular Analysis of Pseudohypoparathyroidism 1b Patients Reveals Novel Genetic and Epigenetic Defects. J Clin Endocrinol Metab. 2021;106(11):e4603-20. DOI: https://doi.org/10.1210/clinem/dgab460
Milioto A, Reyes M, Hanna P, Kiuchi Z, Turan S, Zeve D, et al. Lack of GNAS Remethylation During Oogenesis May Be a Cause of Sporadic Pseudohypoparathyroidism Type Ib. J Clin Endocrinol Metab. 2022;107(4):e1610-9. DOI: https://doi.org/10.1210/clinem/dgab830
Kiuchi Z, Reyes M, Jüppner H. Preferential Maternal Transmission of STX16-GNAS Mutations Responsible for Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B): Another Example of Transmission Ratio Distortion. J Bone Miner Res. 2021;36(4):696-703. DOI: https://doi.org/10.1002/jbmr.4221
Reyes M, Kagami M, Kawashima S, Pallotta J, Schnabel D, Fukami M, et al. A Novel GNAS Duplication Associated With Loss-of-Methylation Restricted to Exon A/B Causes Pseudohypoparathyroidism Type Ib (PHP1B). J Bone Miner Res. 2021;36(3):546-52. DOI: https://doi.org/10.1002/jbmr.4209
Kiuchi Z, Reyes M, Hanna P, Sharma A, DeClue T, Olney RC, et al. Progression of PTH Resistance in Autosomal Dominant Pseudohypoparathyroidism Type Ib Due to Maternal STX16 Deletions. J Clin Endocrinol Metab. 2022;107(2):e681-7. DOI: https://doi.org/10.1210/clinem/dgab660
Bastepe M, Gensure RC. Hypoparathyroidism and Pseudohypoparathyroidism. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, et al. Endotext. MDText.com, Inc.; South Dartmouth (MA). 2024.
Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Pseudohypoparathyroidism - epidemiology, mortality and risk of complications. Clin Endocrinol (Oxf). 2016;84(6):904-11. DOI: https://doi.org/10.1111/cen.12948
Mantovani G, Elli FM. Inactivating PTH/PTHrP Signaling Disorders. Front Horm Res. 2019;51:147-59. DOI: https://doi.org/10.1159/000491045
Jüppner H. Molecular Definition of Pseudohypoparathyroidism Variants. J Clin Endocrinol Metab. 2021;106(6):1541-52. DOI: https://doi.org/10.1210/clinem/dgab060
Long XD, Xiong J, Mo ZH, Dong CS, Jin P. Identification of a novel GNAS mutation in a case of pseudohypoparathyroidism type 1A with normocalcemia. BMC Med Genet. 2018;19(1):132. DOI: https://doi.org/10.1186/s12881-018-0648-z
Nakamoto JM, Zimmerman D, Jones EA, Loke KY, Siddiq K, Donlan MA, et al. Concurrent hormone resistance (pseudohypoparathyroidism type Ia) and hormone independence (testotoxicosis) caused by a unique mutation in the G alpha s gene. Biochem Mol Med. 1996;58(1):18-24. DOI: https://doi.org/10.1006/bmme.1996.0027
Mazoni L, Apicella M, Saponaro F, Mantovani G, Elli FM, Borsari S, et al. Pseudohypoparathyroidism: Focus on Cerebral and Renal Calcifications. J Clin Endocrinol Metab. 2021;106(8):e3005-20. DOI: https://doi.org/10.1210/clinem/dgab208
Qi Z, Li Z, Gao Q, Dong L, Lin J, Peng K, et al. Characterizing Cerebral Imaging and Electroclinical Features of Five Pseudohypoparathyroidism Cases Presenting with Epileptic Seizures. Behav Neurol. 2022;2022:8710989. DOI: https://doi.org/10.1155/2022/8710989
Huang S, He Y, Lin X, Sun S, Zheng F. Clinical and genetic analysis of pseudohypoparathyroidism complicated by hypokalemia: a case report and review of the literature. BMC Endocr Disord. 2022;22(1):98. DOI: https://doi.org/10.1186/s12902-022-01011-9
Germain-Lee EL. Management of pseudohypoparathyroidism. Curr Opin Pediatr. 2019;31(4):537-49. DOI: https://doi.org/10.1097/MOP.0000000000000783
Downloads
Published
How to Cite
Issue
Section
