A Novel Clinical Presentation of PROP1-Associated Combined Pituitary Hormone Deficiency with Severe Thrombosis: A Case Report

A 40-year-old woman with a clinical diagnosis of combined pituitary hormone deficiency (CPHD-2) (OMIM# #262600), and recurrent thrombosis underwent whole-exome sequencing, which identified a likely pathogenic variant in the PROP1 (Prophet of Pit1) gene and Variant of Unknown Significance (VUS) in the PROC gene. The PROP1 gene encodes as a “later acting transcription factor” in pituitary development and encodes a paired-like homeodomain transcription factor that is necessary for expression of the POUF domain transcription factor 1. The Protein C (PROC) gene encodes protein C, a vitamin K-dependent anticoagulant that regulates blood coagulation by inactivating coagulation factors Va and VIIIa. Mutations in the PROP1 gene can cause CPHD-2, which may manifest as short stature, hypothyroidism, growth retardation, delayed and incomplete secondary sexual development with infertility. This is due to deficiencies in thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH), and growth hormone (GH). Pathogenic variants in PROC cause protein C deficiency, an inherited thrombophilia that predisposes affected individuals to venous thromboembolism. We report a case where a lady presented with short stature, C-spine fusion, short and stiff neck, multiple pituitary hormone deficiencies (LH, FSH, TSH, GH and Prolactin) and recurrent lower limb arterial thrombosis. She had primary amenorrhea, for which treatment was initiated at the age of 22 years. Genetic testing by exome sequencing enabled an accurate diagnosis of the underlying aetiology, with genotype – phenotype correlation which led to better disease management.