SAT-740 - Diagnostic Challenges in A Clinical Case of Persistent Hypocalcemia

Background:
Hypocalcemia in the general population is commonly caused by hypoparathyroidism and vitamin D deficiency. It has not been recorded elsewhere that there is a patient with pseudohypoparathyroidism with a negative GNAS genetic testing.

Clinical

Case:
Hypocalcemia is a commonly encountered metabolic abnormality in clinical practice; however, hypocalcemia resulting from pseudohypoparathyroidism (PHP) is a relatively rare entity that typically requires genetic testing to confirm the underlying mutation. This case is particularly unique because, despite a clinical presentation highly suggestive of PHP type Ia, genetic testing failed to identify a causative mutation. We present the case of an 18-year-old male with no significant past medical history who developed critically severe, symptomatic hypocalcemia (5.9 mg/dL, n: 8.5 - 10.5 mg/dL) in the setting of markedly elevated parathyroid hormone levels (283 pg/mL, n: 15 - 65 pg/mL) and associated hyperphosphatemia (6.4 mg/dL, n: 2.4 - 4.4 mg/dL). The patient was also found to have decreased vitamin D levels at 26.7 ng/mL (normal: 30 - 100 ng/mL), though these were within the insufficient rather than severely deficient range. Despite appropriate vitamin D supplementation, hypocalcemia persisted, and parathyroid hormone levels remained elevated. Genetic testing for mutations in the GNAS1 gene was performed but yielded negative results. This case highlights an unusual presentation of persistent hypocalcemia in which common etiologies have been thoroughly evaluated yet remain inconclusive. It underscores the need to consider alternative genetic mechanisms or less well-characterized mutations that may contribute to parathyroid hormone resistance and calcium dysregulation in similar clinical settings.

Conclusions:
Given the above-mentioned results, the patient demonstrates persistent hypocalcemia with a strong clinical suspicion for PHP despite negative GNAS genetic testing. While GNAS mutations account for the majority of PHP cases, there is growing evidence that alterations in other genes involved in PTH signaling and imprinting can produce a similar biochemical and clinical phenotype. Specifically, mutations or epigenetic alterations involving STX16, PRKAR1A, and PDE4D have been described in association with PHP or related disorders, including PHP type 1B and acrodysostosis. However, access to comprehensive genetic or epigenetic testing for these variants remains limited, which may hinder definitive molecular diagnosis in affected patients.

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