Clinical Characteristics And Gene Mutation Of Primary Bilateral Adrenocortical Hyperplasia

Objective:To investigate the clinical characteristics and treatment of primary bilateral adrenocortical hyperplasia,and to study the mutation of its pathogenic gene.Methods:18 patients with primary bilateral adrenocortical hyperplasia admitted to the Department of Urology,General Hospital of Tianjin Medical University from April2008 to March 2018 were collected,including 17 patients with primary bilateral macronodular adrenal hyperplasia(PBMAH),8 males and 9 females,aged 42-70 years,with an average age of 54.6 years;1 patient with primary pigmented nodular adrenocortical disease(PPNAD),female,14 years.During telephone or outpatient follow-up,the incidence of primary bilateral adrenocortical hyperplasia in the patients' families was counted and the family tree was drawn.The peripheral venous blood of 15 patients was collected for whole gene exome sequencing.The mutations of known pathogenic genes were searched and counted,and PCR sequencing was performed on 19 family members.Results:1.In 17 patients with PBMAH,24-UFC was elevated,and CT indicated that bilateral adrenal glands with diffuse enlargement and multiple nodules.16 cases of them presented with typical or atypical Cushing's syndrome and 1 case with subclinical Cushing's syndrome.5 had family history of PBMAH,and 1 had meningioma.1 patient with PPNAD had obvious symptoms of centripetal obesity and skin pigmentation.Her 24-UFC increased significantly,and abdominal CT showed no exact abnormalities in the shape,size and density of bilateral adrenal glands.2.17 patients with PBMAH underwent surgical treatment,14 of them underwent unilateral adrenalectomy,and their postoperative cortisol was reduced to the normal range.The longest follow-up period was 59 months,no further increase of cortisol was found;bilateral adrenalectomy and hormone replacement therapy were performed in 3 cases.All patients with PBMAH had stable postoperative control of hypertension and diabetes mellitus,and the abnormal manifestations such as bloodyface,fatigue,edema,alopecia and sleepiness disappeared.sexual dysfunction of 3male patients did not completely recover.One patient with PPNAD underwent right adrenalectomy,and a short postoperative period of low cortisol was observed,however,the UFC increased again 103 days after operation.3.All 14 PBMAH patients had mutations of ARMC5 gene,including 9missense mutations,5 frameshift mutations and 3 nonsense mutations;one case had GNAS gene mutation(c.1861 G > A).The mutation rate of c.2114C>T(p.Ala705Val)of ARMC5 gene was 100%,and the mutation frequency of this site was 76.5% in their families.The patient with PPNAD had splicing site mutation of PRKAR1 A gene(c-6-2a >G)and missense mutation of PDE11 A gene(c.551 g >A),her mother had PPNAD and PRKAR1 A heterozygous mutation.Conclusion:Primary bilateral adrenocortical hyperplasia is a rare cause of hypercortisolism and has obvious hereditary tendency.ARMC5 is the most common pathogenic gene of PBMAH,and c.2114C>T(p.la705val)is the most common mutation;PRKAR1A gene mutation is the main pathogenesis of PPNAD.Bilateral adrenalectomy is currently the most effective treatment for primary bilateral adrenocortical hyperplasia;however,for most patients with mild symptoms,unilateral adrenalectomy can effectively control hypercortisolism.