Endocrine Abstracts

JOINT2415

Background: ACTH-dependent Cushing Syndrome is associated with increased morbidity and mortality. Diagnostic evaluation may be challenging, especially in the acute setting. We present a case of severe ACTH-dependent Cushing Syndrome attributed to a corticotroph pituitary adenoma (Cushing’s Disease, CD) coexisting with an unspecified syndromic cause of GH deficiency and potential hypopituitarism.

Case Presentation: A 39-year-old woman with decompensated heart failure with reduced ejection fraction was admitted to hospital with severe hypertension, hypokalaemia, and hyperglycaemia. The patient reported generalised weakness, oedema and appearance of wide purple striae, starting two months before her admission. On physical examination, she presented with short stature (1.35m), clinodactyly, low-set ears and micrognathia. Upon questioning, she reported primary amenorrhea and short-term treatment with rGH at the time of adolescence, but no medical records could be retrieved. Of note, she had normal breast development. During her hospitalisation she was admitted to the ICU twice due to acute respiratory failure in the presence of ARDS and later due to acute hemorrhagic pancreatitis. Upon imaging, multiple prevalent spinal fractures were noted. Due to the high clinical suspicion of CS, she was referred for endocrine consultation. After full recovery from acute illness, ACTH-dependent Cushing’s Syndrome was confirmed, and pituitary MRI revealed a macroadenoma (max diameter 2 cm) with cavernous sinus invasion. She was started on the novel steroidogenesis inhibitor osilodrostat and teriparatide for osteoporosis, while awaiting neurosurgery. After 4 months of treatment, she had clinical and biochemical remission of hypercortisolism with significant improvement of the related comorbidities. Evaluation of hypothalamus-pituitary axes revealed low gonadotropin, GH and IGF-1 levels. Further testing for the presence of concurrent genetic syndrome was performed. Pelvic ultrasound revealed hypoplastic uterus and ovaries; standard karyotype analysis and array comparative genomic hybridization excluded the diagnosis of Turner Syndrome. Subsequent whole exome sequencing analysis revealed a mutation of VUS in the CDH23 gene (c.1339A>G CDH23 gene), which is implicated in both familiar and sporadic pituitary tumours occurrence. Additionally, further trio-exome sequencing analysis detected a likely pathogenic variant in PAX6 (c.728_731delAAAA) and VUS in SOX2 (c.382C>T), genes encoding transcription factors implicated in pituitary development.

Conclusion: Pituitary insufficiency co-existing with a corticotroph macroadenoma is a rare finding. Whether there is an association between the two entities remains an unresolved issue. Despite recent advances, a genetic cause remains unidentified in many cases of hypopituitarism. Future research to discover additional implicated genes will provide better understanding on the molecular pathways implicated in pituitary development.