Endocrine Abstracts

JOINT2578

Introduction: Pseudohypoparathyroidism type 1b (PHP-1b) is characterized by resistance to parathyroid hormone (PTH), primarily in renal tissues, leading to hypocalcemia, hyperphosphatemia, and elevated PTH levels. In some cases, it may also present with resistance to thyroid- stimulating hormone. Features of Albright hereditary osteodystrophy are usually absent. This condition is caused by genetic and epigenetic imprinting defects of the GNAS locus on chromosome 20q13. 32. It is typically sporadic, although familial cases with autosomal dominant inheritance have been reported. We describe a novel deletion in the GNAS-AS1 and GNASXL transcripts, which has not been previously documented in the literature in a family with PHP-1b.

Clinical Case: A 36-year-old male presented with massive calcifications of the basal nuclei and thalami, along with dispersed calcifications in both cerebellar hemispheres, identified on a head CT scan conducted due to his complaints of vertigo and headache. Subsequent testing revealed severe hypocalcemia (5. 6 mg/dL) and elevated PTH levels (260. 8 pg/mL). His medical history included cataract surgery at a young age and complaints of paresthesias since adolescence. He was referred to the Endocrinology department, where pseudohypoparathyroidism was suspected. The patient started calcium and vitamin D supplementation, with correction of the hypocalcemia (Ca2+ 8. 9 mg/dL) and persistent elevated PTH (273 pg/mL). Given the clinical presentation and imaging findings, genetic testing for mutations in the STX16 and GNAS genes was performed, but results were negative. Subsequently, a methylation-specific MLPA test was requested, revealing a heterozygous deletion of the GNAS-AS1 and GNASXL transcripts, as well as a hypomethylation pattern in the DMR A/B region of the GNAS gene, attributed to the deletion of the maternal allele. To this date, this deletion has not been previously documented in the literature or in polymorphism databases. The patient was referred for genetic counselling where his family was evaluated: his sister exhibited the same deletion and clinical manifestations and his mother also have the same deletion, although she has no clinical symptoms and no analytical or imaging abnormalities. The genetic study of his aunt and cousin are pending.

Conclusion: PHP-1b is a rare endocrine disorder with genetic aetiology. While some mutations have been described, the identification of new mutations, such as the one presented in this case, may enhance our understanding of the underlying genetic mechanisms and facilitate future diagnoses.