SUN-382 Heterogeneous Clinical Presentation In Familial Cases Of Primary Macronodular Adrenal Hyperplasia (PMAH): The Influence Of Somatic Event Of ARMC5.

Abstract

Background: PMAH is a cause of adrenal hypercortisolism and it is a genetic disease linked to ARMC5 gene in most cases. Heterogenous phenotypes due to cortisol secretion and also due to different germline mutations in the ARMC5 have been described in around the world. The diversity of the molecular second hits in adrenal nodules may be able to justify different clinical outcome in the same family. We report two sisters with the same germline mutation and different clinical outcome. Case: A 45-year-old female patient presented with clinical evidence of hypercortisolism. Metabolic syndrome has been evidenced since the age of 35. Hormonal data confirmed an autonomous cortisol secretion. Abdominal CT revealed a bilateral enlargement of adrenal glands with multiples nodules (up to 2 cm, with 10 Housfield Units). 18F-FDG-PET/CT identified a slight SUV (left SUV 3.4 and right SUV 2.7). A heterozygous germline pathogenic variant of ARMC5 was identified at exon 1: c.165_166insG, p.Ile58Asnfs*45 at BTB (POZ) domain associated with a somatic LOH of the germline mutation. In 2013, the patient underwent Adrenal Sparing Surgery (ASS). She presented an excellent control of metabolic syndrome associated with adrenal insufficiency (AI) for 12 months. After 2 years a clinical recurrence of hypercortisolism was observed and confirmed by laboratory data. A new abdominal 18F-FDG-PET/CT and CT showed an increase of SUV and enlargement of the right residual adrenal gland (SUV - 3.4). The patient was submitted to a partial right adrenalectomy. Interesting, she did not present total or partial AI after the second surgical procedure. Inversely, her sister (46 years of age), with classical Cushing´s syndrome and carrier of same germline mutation (with similar hormonal data and SUV of 18F-FDG-PET/CT), presented a long-term remission of hypercortisolism after ASS. The analysis of somatic mutation of ARMC5 revealed a new event c.2082_2088delCCCGCTC, p.Pro695Serfs*20 in heterozygous status at exon 6. Analysis of PMAH sections HE stained showed a different pattern in the proportion and distribution of clusters of compact cells (60%) relative to clear spongiocytic cells. Her sister presented 13% of compact cells, similar to the PMAH pattern. Discussion: The macronodules of PMAH are composed of clear spongiocytic cells which preferentially express 3βHSD steroidogenic enzyme, and small or compact cells, which differentially express CYP17A1 steroidogenic enzyme and are located in dispersed clusters among the clear cells. CYP17A1 has both 17α-hydroxylase activity and 17,20-lyase activity. Conclusion: The somatic events of ARMC5 should be considered and could be involved in heterogeneous cortisol secretion and clinical presentation in familial cases with different outcome. Further familial cohorts and functional studies should increase our understanding of this challenged adrenal disorder.