A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: from genetic characterization to clinical phenotype.
ARMC5 mutations have recently been identified as a common genetic cause of primary bilateral macronodular adrenal hyperplasia (PBMAH). We aimed to assess the prevalence of ARMC5 germline mutations and correlate genotype with phenotype in a large cohort of PBMAH patients. A multicenter study was performed, collecting patients from different endocrinology units in Italy. Seventy-one PBMAH patients were screened for small mutations and large rearrangements in the ARMC5 gene: 53 were cortisol-secreting (two with a family history of adrenal hyperplasia) and 18 were non-secreting cases of PBMAH. Non-mutated and mutated patients' clinical phenotypes were compared and related to the type of mutation. A likely causative germline ARMC5 mutation was only identified in cortisol-secreting PBMAH patients (one with a family history of adrenal hyperplasia and ten apparently sporadic cases). Screening in eight first-degree relatives of three index cases revealed four carriers of an ARMC5 mutation. Evidence of a second hit at somatic level was identified in five nodules. Mutated patients had higher cortisol levels (p = 0.062), and more severe hypertension and diabetes (p < 0.05). Adrenal glands were significantly larger, with a multinodular phenotype, in the mutant group (p < 0.01). No correlation emerged between type of mutation and clinical parameters. ARMC5 mutations are frequent in cortisol-secreting PBMAH and seem to be associated with a particular pattern of the adrenal masses. Their identification may have implications for the clinical care of PBMAH cases and their relatives.
Endocrinology Unit, Department of Medicine DIMED, Padova University Hospital, Padua, Italy.
N M
NM
Albiger
Endocrinology Unit, Department of Medicine DIMED, Padova University Hospital, Padua, Italy.
D
D
Regazzo
Endocrinology Unit, Department of Medicine DIMED, Padova University Hospital, Padua, Italy.
B
B
Rubin
Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, IRCCS, Padua, Italy.
A M
AM
Ferrara
Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, IRCCS, Padua, Italy.
S
S
Rizzati
Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, IRCCS, Padua, Italy.
E
E
Taschin
Endocrinology Unit, Department of Medicine DIMED, Padova University Hospital, Padua, Italy.
F
F
Ceccato
Division of Endocrinology, Ancona University Hospital, Polytechnic University of Marche, Ancona, Italy.
G
G
Arnaldi
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.|Neuroendocrinology Research Laboratory, Istituto Auxologico Italiano IRCCS, Milan, Italy.
F
F
Pecori Giraldi
Endocrinology, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Roma, Rome, Italy.
A
A
Stigliano
Endocrinology, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Roma, Rome, Italy.
L
L
Cerquetti
Endocrinology and Metabolism Unit, S. Maria della Misericordia University Hospital, Udine, Italy.
F
F
Grimaldi
Department of Internal Medicine, General Hospital, Montebelluna, Treviso, Italy.
E
E
De Menis
Endocrinology Unit, Department of Medicine DIMED, Padova University Hospital, Padua, Italy.
M
M
Boscaro
Minimally Invasive Endocrine Surgery Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy.
M
M
Iacobone
Department of Biology, University of Padova, Via U. Bassi 58/B, 35128, Padua, Italy. gianluca.occhi@unipd.it.
G
G
Occhi
Endocrinology Unit, Department of Medicine DIMED, Padova University Hospital, Padua, Italy.
C
C
Scaroni
D000311:Adrenal Glands / Q000473:pathology*; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D051186:Armadillo Domain Proteins; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D025521:Tumor Suppressor Proteins / Q000235:genetics*
C000590373:ARMC5 protein, human; D051186:Armadillo Domain Proteins; D025521:Tumor Suppressor Proteins
ARMC5; Cushing’s syndrome; Genotype to phenotype correlation; Primary bilateral macronodular adrenal hyperplasia