Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?
Long-term consequences of cortisol excess are frequent despite appropriate treatment after cure of Cushing's syndrome. This might be due to diagnostic delay, often difficult to reduce in rare diseases. The identification of a genetic predisposing factor might help to improve early diagnosis by familial screening. Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Hypercortisolism in PBMAH is most often diagnosed between the fifth and sixth decades of life. The bilateral nature of the adrenocortical tumors and the occurrence of rare clear familial forms suggest a genetic origin. Indeed, a limited subset of PBMAH can be observed as part of multiple tumors syndromes due to alterations of the APC, Menin or Fumarate Hydratase genes. Rare variants of the phosphodiesterases PDE11A have been associated with PBMAH. The recent identification of ARMC5 germline alterations in 25-50% of PBMAH patients without obvious familial history or associated tumors opens new perspectives. ARMC5 alterations follow the model of a tumor suppressor gene: a first germline inactivating mutation of this 16p located gene is followed by a somatic secondary hit on the other allele (inactivating mutation or allelic loss). Functional studies demonstrate that ARMC5 controls apoptosis and steroid synthesis. The phenotype of index cases patients with the mutation seems more severe than the one of WT index cases. However, phenotype variability within a family is often observed. This review summarizes the genetics of PBMAH, focusing on ARMC5, which offer new perspectives for early diagnosis of Cushing's syndrome.
Institut National de la Santé et de la Recherche Médicale (INSERM) U1016 Centre National de la Recherche Scientifique (CNRS) UMR 8104, Institut Cochin, Université Paris-Descartes, 75014 Paris, France Department of Endocrinology Referral Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, 27 rue du Faubourg St Jacques, 75014 Paris, France.
Ludivine
L
Drougat
Institut National de la Santé et de la Recherche Médicale (INSERM) U1016 Centre National de la Recherche Scientifique (CNRS) UMR 8104, Institut Cochin, Université Paris-Descartes, 75014 Paris, France Department of Endocrinology Referral Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, 27 rue du Faubourg St Jacques, 75014 Paris, France.
Stéphanie
S
Espiard
Institut National de la Santé et de la Recherche Médicale (INSERM) U1016 Centre National de la Recherche Scientifique (CNRS) UMR 8104, Institut Cochin, Université Paris-Descartes, 75014 Paris, France Department of Endocrinology Referral Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, 27 rue du Faubourg St Jacques, 75014 Paris, France Institut National de la Santé et de la Recherche Médicale (INSERM) U1016 Centre National de la Recherche Scientifique (CNRS) UMR 8104, Institut Cochin, Université Paris-Descartes, 75014 Paris, France Department of Endocrinology Referral Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, 27 rue du Faubourg St Jacques, 75014 Paris, France jerome.bertherat@aphp.fr.
Jerôme
J
Bertherat
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D051186:Armadillo Domain Proteins; D003480:Cushing Syndrome / Q000175:diagnosis* / Q000235:genetics; D042241:Early Diagnosis; D005649:Fumarate Hydratase / Q000235:genetics; D017491:Genes, APC; D018095:Germ-Line Mutation; D006801:Humans; D009154:Mutation; D010727:Phosphoric Diester Hydrolases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*
C000590373:ARMC5 protein, human; D051186:Armadillo Domain Proteins; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C406737:PDE11A protein, human; D005649:Fumarate Hydratase