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The molecular genetics of adrenal cushing
Patricia Vaduva1,2[D . Jerome Bertherat1,3
Received: 18 July 2024 / Accepted: 26 September 2024 / Published online: 10 October 2024 @ The Author(s), under exclusive licence to Hellenic Endocrine Society 2024
Abstract
Adrenal Cushing represents 20% of cases of endogenous hypercorticism. Unilateral cortisol-producing adenoma (CPA), a benign tumor, and adrenocortical carcinoma (ACC), a malignant tumor, are more frequent than bilateral adrenal nodular diseases (primary bilateral macronodular adrenal hyperplasia (PBMAH) and primary pigmented nodular adrenal disease (PPNAD)).
In cortisol-producing adrenal tumors, the signaling pathways mainly altered are the protein kinase A and Wnt/ß-catenin pathways. Studying components of these pathways and exploring syndromic and familial cases of these tumors has histori- cally enabled identification of many of the predisposing genes. More recently, pangenomic sequencing revealed alterations in sporadic tumors.
In ACC, mainly due to TP53 alterations causing Li-Fraumeni syndrome, germline predisposition is frequent in chil- dren, while it is rare in adults. Pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, MSH6, and PMS2, which cause Lynch syndrome or alterations of IGF2 and CDKN1C (11p15 locus) in Beckwith-Wiedemann syndrome, can also cause ACC. Rarely, ACC is described in other hereditary tumor syndromes due to germline pathogenic variants in MEN1 or APC and, in very rare cases, NF1, SDH, PRKAR1A, or BRCA2. Concerning ACC somatic alterations, TP53 and genetic or epigenetic alterations at the 11p15 locus are also frequently described, as well as CTNNB1 and ZNRF3 pathogenic variants.
CPAs mainly harbor somatic pathogenic variants in PRKACA and CTNNB1 and, less frequently, PRKAR1A, PRKACB, or GNAS1 pathogenic variants. Isolated PBMAH is due to ARMC5 inactivating pathogenic variants in 20 to 25% of cases and to KDM1A pathogenic variants in food-dependent Cushing. Syndromic PBMAH may be due to germline pathogenic variants in MEN1, APC, or FH, causing type 1 multiple endocrine neoplasia, familial adenomatous polyposis, or hereditary leiomyomatosis-kidney cancer syndrome, respectively. PRKAR1A germline pathogenic variants are the main alteration causing PPNAD (isolated or part of Carney complex).
Keywords Adrenocortical carcinoma · Cortisol-producing adenoma · Primary bilateral macronodular adrenal hyperplasia · Primary pigmented nodular adrenal disease · Molecular genetics · Adrenal cushing
☒ Jerome Bertherat
1 Genomic and Signaling of Endocrine Tumors team, INSERM U1016, CNRS UMR8104, Cochin Institute, Paris Cité University, Paris 75005, France
2 Department of Endocrinology, Diabetes and Nutrition, Rennes University Hospital, Rennes 35000, France
3 Department of Endocrinology, Reference center for rare adrenal diseases, Cochin Hospital, APHP, Paris 75014, France
Introduction
Endogenous Cushing’s syndrome is due in around 20% of cases to adrenal gland diseases, encompassing adenomas, carcinomas, and bilateral adrenal tumors [1, 2]. Adrenal tumors are relatively common, affecting 3 to 10% of the general population, but most of them are not responsible for cortisol hypersecretion [3].
Among adrenal incidentalomas, less than 5% are pri- mary adrenal malignant tumors (adrenocortical carcinoma, ACC), while around 85% are adrenal adenomas and hyper- plasia, among which 20 to 50% have mild autonomous cortisol secretion (MACS) and 1 to 4% are responsible for
overt Cushing [4]. Over the past decade, steroid assay by mass-spectrometry techniques has revealed that most of the tumors considered as clinically inactive do, in fact, produce some steroids [5]. In ACC steroids, secretion is variable, ranging from androgens and/or cortisol and their precursors secretion to no steroid secretion.
Among the adrenal causes of Cushing’s syndrome, cor- tisol-secreting benign and malignant unilateral tumors are more frequent than bilateral adrenal nodular diseases [6, 7]. Moreover, women are more likely to develop Cush- ing’s syndrome associated with an adrenal tumor (benign or malignant), although no clear pathophysiological explana- tion has been identified to date [8].
Adequate diagnosis and management of adrenal cortisol- producing tumors is essential as morbidity due to adrenal Cushing is high, this mainly attributable to the occurrence of diabetes, hypertension, thrombosis, and osteoporosis. Mor- tality is also high in adrenocortical carcinoma, but mainly due to tumor growth and metastasis [9]. However, adrenal
Cushing’s syndrome leads to twice as many deaths as com- pared to those among the general population due to cardio- vascular and cerebrovascular events and infections. Even among patients with MACS, a recent meta-analysis showed higher mortality compared to patients with nonfunctioning adrenal tumors [10].
The emergence of molecular genetics, studying the struc- ture and function of genes at a molecular level, opened a new field in identifying genetic alterations and understand- ing inheritance patterns in adrenal tumors. In cortisol-pro- ducing benign adrenal tumors, the main signaling pathway altered is the protein kinase A (PKA) pathway as regards both unilateral adenomas and bilateral adrenal disease [11, 12] (Fig. 1). The Wnt/B-catenin pathway is mainly alter- nated in sporadic adrenocortical carcinoma and non-overt- cortisol secreting ACA [13, 14] (Fig. 2).
Stimulatory ligand (MC2R / aberrant receptor)
1
GPCR
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Adenylyl cyclase (AC)
GIPR
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β/γ
stimulatory a-subunit
as
as
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Activates AC
ATP
CAMP
PDE
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R
R
PKA
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AMP
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C
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CREB
ARMC5
pCREB
Cortisol
4
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KDMIA
Cell proliferation
FH
Met
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Cell cycle
MEN1
Illustration created with BioRender.com
GF2
1
Wnt
ZNRF3
LRP
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Frizzled
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Dishevelled
PI3K
Raf
GSK-3₿
CKla
AKT
MEK
Axin
APC
menin
ß-Catenin
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mTOR
ERK
CDKN2A
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CDK4
ß-Catenin
TCF/LEF
Gene transcription
MDM2
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p53
RB1
G1
ATRX
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DAXX
TERT
cell cycle
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G2
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CyclinE
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DNA repair proteins
Adrenocortical carcinoma (ACC)
Germline
ACC is a rare tumor and a cause of Cushing’s syndrome, although germline predisposition is frequent, found in up to 80% of childhood ACC and probably around 5% of adult ACC. It has been identified in several tumor susceptibility syndromes (Table 1), Li-Fraumeni syndrome having been the first described [15].
Li-Fraumeni syndrome (LFS) is characterized by pre- disposing to a high risk for early-onset cancer (e.g., breast cancer, sarcoma, brain tumors, leukemia, and ACC); it is inherited in an autosomal dominant manner and is due to germline pathogenic variants in the TP53 tumor suppressor gene [15-17]. Pathogenic variants of TP53 are frequently found in children (up to 90%), but more rarely in adult ACC
(<5%) [18-21], and are mostly point alterations with 70% missense and 20% nonsense or splice variants [22] (Table 1). The prevalence of LFS is particularly high in southern Bra- zil due to a founder germline pathogenic variant (p.R337H) affecting 0.3% of this population; it predisposes mainly to ACC and breast cancer [23-25]. De novo pathogenic vari- ants of TP53 occur in around 20% of people diagnosed with LFS [26].
Another predisposing syndrome is the Beckwith-Wiede- mann syndrome, an overgrowth disorder characterized by macrosomia, macroglossia, organomegaly, developmental abnormalities, embryonal tumors, and ACC; it is due to genetic or epigenetic alteration of the imprinted 11p15.5 region [27, 28]. This locus includes the IGF2 and CDKN1C genes that undergo parental imprinting (Table 1).
Besides BWS and LFS, which are responsible for the majority of childhood tumors, ACC was recently described
| Tumor type | Gene (pathogenic variants, except º/* ) | Isolated / Syndromic disease | Associated phenotype |
|---|---|---|---|
| Adrenocortical carcinoma | TP53 CDKN1C IGF2 | Li-Fraumeni syndrome Beckwith-Wiedemann syndrome Beckwith-Wiedemann syndrome | Soft-tissue sarcoma, breast cancers, brain tumors, leukaemia Exomphalos, macroglossia, macrosomia, hemihypertrophy |
| MLH1, MSH2, MSH6, PMS2 | Lynch syndrome | Colorectal, endometrial, small bowel and upper tract urothelial cancers; more rarely sebaceous tumors, ovarian and pancreatic cancers | |
| Primary bilat- eral macronod- ular adrenal hyperplasia | MEN1 APC | Type 1 Multiple endocrine neoplasia Familial adenomatous polyposis | Parathyroid, pituitary or pancreas tumors Multiple adenomatous polyps and colon/rectum cancer, more rarely periampullary cancer, thyroid tumors and hepatoblastoma |
| NF1 | Type 1 neurofibromatosis | Multiple café au lait macules, intertriginous freckling, multiple cutaneous neurofibromas, optic nerve/central nervous system gliomas, malignant peripheral nerve sheath tumors ... | |
| SDH | Hereditary pheochromocytoma and paraganglioma | Pheochromocytoma and/or paraganglioma | |
| PRKAR1A | Carney complex | Spotty skin pigmentation (lentiginosis), myxoma (cardiac, cuta- neous, mucosa, breast), large-cell calcifying sertoli cell tumors, thyroid tumors and other endocrine or non-endocrine tumors | |
| BRCA2 | Hereditary breast and ovarian cancer | Breast and/or ovarian cancer | |
| ARMC5 KDM1A | Isolated Isolated | ||
| MEN1 | Type 1 multiple endocrine neoplasia | Parathyroid, pituitary or pancreatic tumors | |
| APC | Familial adenomatous polyposis | Multiple adenomatous polyps and colon/rectum cancer, more rarely periampullary cancer, thyroid tumors and hepatoblastoma | |
| FH | Hereditary leiomyomatosis-kidney cancer | Leiomyomatosis, kidney cancer | |
| GNAS1º | McCune Albright syndrome | Polyostotic fibrous dysplasia, café-au-lait skin pigmentation, autonomous endocrine hyperfunction | |
| Primary pig- mented nodular adrenocortical disease | PRKAR1A PRKACA* | Isolated or part of Carney complex Isolated or part of Carney complex | Spotty skin pigmentation (lentiginosis), myxoma (cardiac, cuta- neous, mucosa, breast), large-cell calcifying sertoli cell tumors, thyroid tumors and other endocrine or non-endocrine tumors |
In bold, gene alteration frequently causing the disease
· postzygotic alteration
* copy number gain
as being part of other tumor susceptibility syndromes such as Lynch syndrome and multiple endocrine neoplasia type 1 (MEN1). Apart from ACC, Lynch syndrome confers an increased risk for digestive, urothelial, ovarian, and pan- creatic cancers [29]. It is predominantly due to germline pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, MSH6, and PMS2 and follows an autosomal dominant inheritance pattern (Table 1). Inactivating patho- genic variants of MEN1 are found in about 90% of families affected by multiple endocrine neoplasia type 1: they pres- ent mainly parathyroid, endocrine, pancreas, and pituitary tumors. ACC is rarely observed in MEN1 patients, whereas benign adrenocortical tumors are common [30] (Table 1).
ACC has been described in several other hereditary tumor syndromes due to germline pathogenic variants in the APC, NF1, SDH, PRKAR1A or BRCA2 genes, but these account for less than 1% of cases [31-34] (Table 1).
Given the high burden of germline alterations in ACC, affecting around 10% of patients, systematic screening for TP53 pathogenic variants is recommended in children [35], while it is suggested among adults, in addition to screening for genes associated with Lynch syndrome [36].
Somatic
In order to identify somatic genetic alterations in ACC, can- didate gene approaches targeting the already known germ- line predisposition genes have been used. This has enabled identification of somatic alterations of the TP53 gene in around 25% of sporadic ACC [37, 38] and alterations in the 11p15 locus in almost 90% of cases [39, 40] (Table 2). More rarely, alteration of the MEN1, APC, NF1, or MMR genes have been described (Table 2).
In addition to these loci that can be altered at germinal and somatic levels, specific alterations of actors of the Wnt/
| Table 2 Somatic alterations to adrenocortical tumors | |
|---|---|
| Tumor type | Gene (pathogenic variants) |
| Adrenocortical carcinoma | TP53 |
| CDKN1C | |
| IGF2 | |
| CTNNB1 | |
| ZNRF3 | |
| MLH1, MSH2, MSH6, PMS2 | |
| MEN1 | |
| APC | |
| NF1 | |
| CDKN2A, RB1, CDK4 | |
| TERT, TERF2, ATRX, DAXX | |
| Cortisol-producing adenoma | PRKACA |
| CTNNB1 | |
| PRKACB | |
| PRKAR1A | |
| GNAS1 | |
beta-catenin pathway have been described. Somatic acti- vating pathogenic variants in the CTNNB1 gene, encoding beta-catenin, were found in around 25% of sporadic ACC [13, 14] and alterations (mainly homozygous deletions) of the ZNRF3 gene, encoding for the E3-ubiquitin ligase, mutually exclusive with CTNNB1 pathogenic variants, are seen in up to 20% of patients with ACC [41-43] (Table 2).
Moreover, in sporadic ACC, pangenomic sequencing showed alterations in cell-cycle-related genes of CDKN2A, RB1, and CDK4, and telomere maintenance related genes such as TERT, TERF2, ATRX, and DAXX (Table 2).
Unilateral cortisol-producing adenoma (CPA)
In cortisol-producing adenomas, no germinal genetic altera- tions have been described to date. CPAs are often due to somatic alterations of the protein kinase A (PKA) holoen- zyme, leading to activation of the latter pathway.
Activating somatic pathogenic variants of the PRKACA gene, encoding the catalytic subunit a of the PKA, were thus the first alteration described in CPA (this achieved in 2014 by four independent teams [12, 44-46] (Table 2)), being found in around 40% of CPA patients. These variants were specifically seen in patients with overt Cushing’s syndrome and were either absent or very rare in other adrenocortical lesions [47]. All PRKACA missense variants identified in CPA, excepting one (p.E32V), were located in a hotspot region (mainly represented by the p.L206R variant): they were seen to alter the interaction between the catalytic and regulatory subunits of the PKA, thus destabilizing the holo- enzyme [48, 49]. In addition to PRKACA pathogenic vari- ants, a somatic pathogenic variant in the PRKACB gene, encoding the catalytic subunit ß of PKA, was found in a
patient with CPA, which led to severe hypercorticism [50]. Moreover, inactivating pathogenic variants of PRKAR1A, encoding the regulatory subunit 1 A of the PKA or loss of heterozygosity (LOH) at the PRKAR1A locus in 17q, have been described in CPA [48, 51].
Apart from leading to constitutive activation of PKA sig- naling, somatic activating pathogenic variants of the GNAS1 gene, encoding the Gs protein alpha-subunit, also seem to be responsible for CPA [52]. GNAS1 alterations inactivate GTPase activity, leading to adenylate cyclase activation.
Activation of the Wnt/B-catenin pathway was also reported in about 40% of adrenocortical adenomas, most of them harboring somatic pathogenic variants of the CTNNB1 gene [14] (Table 2). This constitutive ß-catenin activation due to CTNNB1 pathogenic variants is the most frequent molecular alteration identified in both benign adrenocorti- cal tumors (non-secreting adenomas and, more rarely, CPA or aldosterone producting adenomas) and ACC [53].
Bilateral cortisol-producing nodular disease
Besides ACC and CPA, adrenal Cushing’s syndrome may be due to bilateral benign tumors. The latter are separated into two main groups according to a cut of 1 cm for the nod- ules’ diameter size [54]. Thus, in the case of infracentimetric nodules, the term used is micronodular adrenal hyperplasia (MiAH), its most common form being primary pigmented nodular adrenal disease (PPNAD) and, in the case of supra- centimetric modules, the term used is macronodular hyper- plasia, occurring mainly in the form of primary bilateral macronodular adrenal hyperplasia (PBMAH).
Genetic alterations found in these bilateral tumors are exclusively germinal. Most of them are specific to each disease (described below), but pathogenic variants of the PDE11A and PDE8B genes, encoding for phosphodies- terases (PDEs), have been described in both PBMAH and PPNAD [55, 56].
Primary bilateral macronodular adrenal hyperplasia (PBMAH)
Primary bilateral macronodular adrenal hyperplasia (PBMAH) is the most common cause of bilateral adrenal Cushing, but remains rare and represents less than 1% of endogenous Cushing’s syndrome cases [57-59]. However, nowadays, more and more diagnoses of PBMAH are being made thanks to investigation of patients with bilateral adre- nal incidentalomas associated with mild autonomous corti- sol secretion (MACS), suggesting a higher prevalence than that previously reported [60].
Recently, the 2022 World Health Organization (WHO) pathological classification of adrenal tumors introduced a new term, bilateral macronodular adrenocortical disease (BMAD), to describe this disease, the latter development being associated with the discovery of several new genetic alterations promoting tumor development [61, 62].
Clinical forms of PBMAH can easily be correlated with specific germline genetic alterations, leading to syndromic or isolated forms of the disease. Several genetic tumor predisposition syndromes are associated with PBMAH, namely, type 1 multiple endocrine neoplasia due to germ- line pathogenic variants of the MEN 1 gene, familial adeno- matous polyposis due to germline pathogenic variants of the APC gene, or hereditary leiomyomatosis-kidney cancer syndrome due to germline pathogenic variants of the FH gene [63-65] (Table 1). Moreover, PBMAH may be part of McCune Albright syndrome, due to post-zygotic activating pathogenic variants of the GNAS 1 gene [66] (Table 1).
Isolated PBMAH is the most common form of the dis- ease with several gene alterations involved. The bilateral adrenal involvement and the description of familial cases of PBMAH lead to the suspicion of genetic alteration causing isolated PBMAH. The first predisposing gene of this form to be described was ARMC5, a tumor suppressor gene located at the 16p11.2 locus [67] (Table 1). In addition to the germi- nal pathogenic event (mostly frameshift or nonsense vari- ants) inactivating one allele of ARMC5, a second somatic hit, specific to each adrenal nodule (point pathogenic variant or LOH), has been reported. Other studies subsequently con- firmed the causative role of ARMC5 alterations in PBMAH development, both in familial or apparently sporadic pre- sentation [68, 69]. Overall, pathogenic variants of ARMC5 are found in around 20 to 25% of PBMAH cases [70-73]. Functional studies showed that inactivation of ARMC5 in human adrenocortical cancer decreases steroidogenesis but, at the same time, ARMC5 pathogenic variants reduce apop- tosis [67, 71]. Thus, the increased number of adrenocorti- cal cells due to the impaired apoptosis overcompensates the reduced steroidogenic capacity of each cell, leading to a global excess in cortisol production.
In addition to ARMC5, pathogenic variants of the KDM1A gene have been found to be responsible for isolated PBMAH, these alterations being mutually exclusive [74] (Table 1). KDM1A, also known as LSD1, located in 1p36.12, encodes lysine demethylase type 1 A. As regards ARMC5, biallelic inactivation of KDM1A occurs in PBMAH, as expected for a tumor suppressor gene [75]. KDM1A inactivation causes food-dependent Cushing or glucose-dependent insulino- tropic peptide (GIP)-dependent PBMAH related to GIPR ectopic expression. The precise mechanism of regulation of GIPR expression by KDM1A is yet to be explored, but it could involve epigenetic regulation of gene expression and
several cellular pathways via different mechanisms, includ- ing protein-protein interactions, protein stability, regulation of subcellular localization, or promoter binding [76].
Besides PBMAH due to GIPR ectopic expression, other illegitimate membrane receptors have been described in this disease in around 80% of cases. The aberrant expression of G protein-coupled hormone receptors (GPCRs) in PBMAH, leading to increased secretion of cortisol in response to vari- ous hormonal stimuli, has been extensively studied. The fol- lowing stimulating ligands, binding to GPCRs, apart from GIP, have been described: LH/HCG responsible for Cush- ing’s syndrome during pregnancy and after menopause [60], B-adrenergic receptors (B-AR), vasopressin (V2-V3-vaso- pressin receptor), serotonin (5-HT7 receptor), and glucagon [77]. Prevalence of cortisol response to these illegitimate receptors is similar in patients with ARMC5 pathogenic variants and in wild-type patients [67, 71], this may suggest that still unknown genetic alterations may be responsible for these PBMAH forms.
More anecdotally, in some rare cases of PBMAH, inac- tivating variants of ACTH receptor (MC2R) were reported, which could cause a loss of ligand binding and responsive- ness, leading to autonomous cortisol secretion. Finally, whole exome sequencing studies reported the involvement of other potential causal genes, including DOT1L (coding for a histone H3 lysine methyl-transferase), HDAC9 (coding for a histone deacetylase), and the endothelin receptor type A (EDNRA) gene in patients with PBMAH [78].
Primary pigmented nodular adrenal disease (PPNAD)
Germline inactivating pathogenic variants in the PRKAR1A gene, encoding the regulatory subunit la of the protein kinase A (PKA), located in 17q22-24, are detected in around 70-80% of patients with PPNAD [11, 79] (Table 1). PRKAR1A defects result in activation of the cAMP/PKA pathway, leading to cell proliferation and steroidogenesis [80]. PRKAR1A is a tumor suppressor gene and its variants can be found in isolated PPNAD or when PPNAD is part of Carney complex, which is an association of endocrine and non-endocrine tumors.
PRKAR1A pathogenic variants (more than 100 have been described to date) are spread all along the coding sequence of the gene and even in the flanking intronic sequence (affecting splicing). Most of them are “private,” identified in only one or a few families. De novo pathogenic variants are described in sporadic cases, being found in less than 30% of patients [11]. Around 80% of PRKAR1A variants lead to a premature stop codon, causing degradation of the mutant mRNA by nonsense mediated mRNA decay (NMD), resulting in no mRNA translation into protein [81]. At the
somatic level, the loss of the second allele is frequently observed [82]. However, some missense or splice variants or short in-frame insertions/deletions translate into a mutant protein with altered or truncated sequence, thus escaping NMD (20%). Since this defective mutant protein can exert a dominant negative effect on the wild-type protein, the somatic allelic loss of the wild-type allele is not systemati- cally required [80, 83].
In addition, copy number gain of the 19p region, includ- ing the PRKACA gene, was identified in patients with Cushing’s syndrome and bilateral adrenal disease, with pathological features compatible with those of PPNAD [12, 84]. Functional studies in the case of PRKACA duplication showed a gain of function, with higher protein levels and activation of cAMP/PKA signaling.
Involvement of the Wnt/beta catenin pathway was also suspected in patients with PPNAD, with some somatic CTNNB1 pathogenic variants reported and beta-catenin accumulation in some tumors [13].
Genetic screening
Even though currently there are no general international guidelines for the screening of genetic alterations in cor- tisol- producing adrenal tumors, some recommendations can be given for specific situations and based on the recent French Consensus statement for the diagnosis of Cushing’s syndrome: Genetics of Cushing’s syndrome [85]. ystematic screening for a genetic cause in the case of a unilateral adre- nocortical tumor is recommended in children, and, in par- ticular, screening for TP53 alterations in the case of ACC. In addition, some authors recommend the screening of germ- line predispositions in adults, using gene panel, including TP53 and Lynch syndrome related genes, taking advantage of the new targeted Next Generation Sequencing (NGS) technologies. In the case of bilateral cortisol- producing tumors, it is recommended that all individuals be screened, ideally using a gene panel including the most frequently implicated genes, namely, ARMC5 in adults with PBMAH, PRKAR1A in children or adults with PPNAD, and GNAS in children with neonatal Cushing’s syndrome. Moreover, when a germline alteration is found in an individual present- ing with an adrenal tumor, whatever its type, genetic coun- seling should be offered to all first degree relatives, inviting them to systematically undergo screening for this alteration.
Conclusion
With the advent of next-generation sequencing technolo- gies and pangenomic approaches, new genetic altera- tions in cortisol-producing adrenal tumors are constantly being detected. Thus, besides historical germline altera- tions causing syndromic forms of adrenal tumors ACC or PBMAH (i.e., TP53, IGF2, CDKN1C, and MMR genes in ACC; MEN1, APC, and FH in PBMAH, and PRKAR1A in PPNAD), somatic pathogenic variants can now explain many sporadic forms of these diseases (i.e., CTNNB1 and ZNRF3 in ACC, ARMC5 and KDM1A in PBMAH, and PRKACA and CTNNB1 in CPA). Furthermore, integrated genomics have proven valuable for identification of new germline predisposing genes in bilateral nodular adreno- cortical diseases. These developments can improve patient management and open up new avenues of research for new treatments.
Declarations
Conflict of interest None to declare.
Ethical approval Not applicable.
Informed consent Not applicable.
Competing interest The authors declare no Competing Interests for this review.
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