Case report: compound heterozygous PTH1R variant(s) in a patient with inactivating PTH/PTHrP signalling disorder type 1 (iPPSD1).

Abstract

Objectives: Inactivating parathyroid hormone (PTH)/PTHrP Signalling Disorder Type 1 (iPPSD1) is a rare genetic condition caused by loss-of-function mutations in the PTH1R gene, presenting with PTH resistance and variable skeletal and dental manifestations. The gene is catalogued under OMIM *168468. Compound heterozygous variants are exceptionally rare and associated with severe phenotypes.

Case presentation: We report a 9-year-old female from the Indian subcontinent presenting with primary failure of tooth eruption, dental anomalies, valgus deformity, and PTH resistance with subclinical hypothyroidism. Whole exome sequencing identified novel compound heterozygous variants in exons 8 and 9 of the PTH1R gene (NM_002820.4: c.557G>A [p.Arg186His] and c.686delC [p.Phe230fs*6], confirmed in trans), confirmed by Sanger sequencing and absent from major population databases.

Conclusions: This is the first reported case of a compound heterozygous PTH1R variant in the Indian population, expanding the known allelic spectrum of iPPSD1 and highlighting the importance of genetic diagnosis in guiding clinical management. Early molecular diagnosis enabled appropriate multidisciplinary management.