Exploring genetic complexity: Pseudo hypoparathyroidism mimicking cystic fibrosis

Abstract

Cystic fibrosis (CF) is a genetic disorder caused by pathogenic variants in the CFTR gene, primarily affecting the respiratory, gastrointestinal, and endocrine systems. However, due to overlapping clinical features with other genetic and metabolic disorders, differentiating CF from alternative diagnoses remains challenging. Pseudohypoparathyroidism (PHP), a rare endocrine disorder characterized by parathyroid hormone (PTH) resistance, leading to hypocalcemia, hyperphosphatemia, and skeletal abnormalities, further complicates the process of differentiating CF from other genetic conditions featuring respiratory symptoms.

We present a 10-year-old male with recurrent respiratory infections, chronic cough, growth impairment, and hypotonia, initially suspected of having CF. Whole-exome sequencing (WES) identified a variant of uncertain significance (VUS) in CFTR (Exon 1, p. Ser4Leu) but a likely pathogenic variant in GNAS (Exon 5, p. Val128Ala), confirming PHP. This case not only highlights the complexity of genetic disorders with overlapping phenotypes but also underscores the need for continuous learning and adaptation in the face of such complexity. The crucial role of next-generation sequencing (NGS) in refining diagnoses further emphasizes this point.

This case underscores the importance of considering alternative genetic etiologies in patients with CF-like symptoms. A multidisciplinary approach integrating genetic, biochemical, and clinical assessments is essential for accurate diagnosis and optimal management. This case also highlights the need for further research to explore respiratory involvement in PHP, an area that remains largely unexplored.