Key words
adrenal hyperplasia - Cushing syndrome - genetics - Carney complex - cyclic AMP - PPNAD - PMAH
Introduction
Adrenocorticotropin (ACTH)-independent, primary adrenocortical tumors and
hyperplasias are neoplasms of the adrenal cortex that arise due to perturbations in
various key molecular pathways; for benign tumors cyclic AMP (cAMP)-signaling is the
main pathway ([Fig. 1]) [1]. Traditionally, ACTH-independent
adrenocortical tumors and hyperplasias were classified into three major categories
as adenomas, hyperplasias, and carcinomas [2].
This classification is non-specific for several reasons. First, it does not factor
the various genetic defects and hormone functionality of these lesions. Second,
causative genes in the predisposition and/or development of these lesions
are increasing in number owing to the rapid adoption of genetic technologies in
routine clinical practice and translational research. Third, these lesions may arise
in the context of familial or syndromic conditions, which require careful
phenotyping and genetic counseling of at risk individuals or their relatives. Thus,
a more robust and specific classification system is required.
Fig. 1 The cyclic AMP-signaling pathways in primary adrenocortical
cortisol-producing neoplasms. The G-protein coupled receptor for ACTH
(ACTHR), also known as melanocortin 2 receptor (MC2R), is a
seven-transmembrane receptor that undergoes extensive conformational changes
in response to its ligand, ACTH. This leads to activation of adenylyl
cyclase (AC) through the G proteins and the generation of cyclic AMP,
activating protein kinase A (PKA), a holoenzyme that consists of a tetramer
of two homo- or heterodimers regulatory subunits (R1α, R1β,
R2α and R2β), and catalytic subunits (Cα,
Cβ, Cγ and PRKX) that are encoded by the respective genes.
This in turn enables phosphorylation of PKA targets, including gene
expression to mediate cell growth, differentiation and hormone production
(e. g., cortisol and its pre-cursors). Genetic alterations in key
genes of the cAMP-signaling pathway leads to the formation of various
primary adrenocortical lesions. AC: Adenylyl cyclase; C: Catalytic subunit
of protein kinase A; cAMP: Cyclic AMP; CREB: Cyclic AMP response element
binding protein, a transcription factor; GPCR: G-protein-coupled receptor;
Gsα, stimulatory subunit α of the G-protein; PDE11A:
Phosphodiesterase 11A; PKA: cAMP-dependent protein kinase; R: Regulatory
subunit.
The various types of adrenocortical tumors and hyperplasias, their histology and
genetics are described in [Table 1].
Translational research of primary adrenocortical hyperplasias have identified key
molecular pathways involved in tumor formation ([Fig. 1]) [3]
[4]. The initial discovery of disease-causing
activating variants in GNAS, which encodes the alpha subunit (Gsα) of
the stimulatory guanine nucleotide-binding protein ([Fig. 1]) in primary adrenocortical hyperplasia
of patients with McCune–Albright syndrome (MAS), was critical in
establishing that cAMP signaling is involved in adrenocortical tumorigenesis, if not
in all, at least in cortisol-producing lesions [5]
[6]
[7]. Other early genetic discoveries included
defects of the regulatory subunit type 1-α (RIα) of protein kinase A
(PRKAR1A) and protein kinase cAMP-activated catalytic subunit beta
(PRKACB) [8] in Carney complex
(CNC) [9], phosphodiesterases (PDE11A,
PDE8B) in isolated micronodular adrenal hyperplasia (iMAD) [10], potassium voltage-gated channel subfamily
J member 5 (KCNJ5) in aldosterone-producing adenomas (APA) [11], and armadillo repeat containing 5
(ARMC5) in primary bilateral macronodular adrenocortical hyperplasia
(PBMAH) [12]. In this review, we discuss the
genetic and molecular mechanisms responsible for the formation of ACTH-independent
adrenocortical hyperplasias and propose a new genetic classification given the most
recent advances in gene discovery and to aid the clinician in the diagnosis and
counseling of these conditions.
Table 1 Classification and characteristics of primary
adrenocortical hyperplasia.
|
Adrenocortical lesions
|
Genes (locus)
|
Histolopathology
|
Characteristics
|
|
PBMAH
|
ARMC5 (16p11.2) MEN1 (11q13)
FH (1q42.3–43)
APC (5q22.2)
PDE11A (2q31.2) PDE8B (5q13.3)
GNAS (20q13)
PRKACA duplication (19p13.1)
|
Nodules or macroadenomatous, > 1 cm, with
(type 1) or without (type 2) internodular atrophy Hyperplasia
with dominant nodule
|
Middle age, mild hypercortisolism and/or
mineralocorticoid excess Associated with MEN-1, FAP, MAS, HLRCS,
isolated (AD) Most lesions have aberrant GPCRs (vasopressin,
serotonin, catecholamines, GIP, luteinizing hormone) PMAH carry
the ability of intra-adrenal production of ACTH with an
autocrine/paracrine effect on glucocorticoid or
mineralocorticoid production
|
|
PBAD
|
GNAS (20q13; mosaic)
|
Distinct adenomas (> 1 cm), with
occasional microadenomas and internodular atrophy
|
Infants and very young children MAS
|
|
FDCS (GIP-dependent)
|
GIPR gene (19q13.32) duplication
|
Large adenomas and/or macronodules
|
Isolated or familial aberrant GPCRs (GIPR), low fasting cortisol,
hypercortisolism post-meals
|
|
i-PPNAD
|
PRKAR1A (17q22–24) PRKACA duplications
(19p13.1)
|
Microadenomatous (< 1 cm) hyperplasia
with pigmentation
|
Children and young adults Lentiginosis in few cases
|
|
c-PPNAD
|
PRKAR1A (17q22–24, CNC1 locus)
2p16 (CNC2
locus, unknown gene)
|
Microadenomatous (< 1 cm) hyperplasia
with (mostly) internodular atrophy and pigmentation
|
Children, young and middle aged adults Disease at a younger age
and a higher frequency of myxomas, schwannomas, and thyroid and
gonadal tumors than patients without PRKAR1A variants.
In-frame deletion of exon 3 and the c.708+1G>T
appears to confer a more severe CNC phenotype, while the splice
variant c.709(-7–2)del6 and the initiation alternating
substitution c.1A>G/p.M1Vp has been associated
with incomplete penetrance of CNC, as seen in i-PPNAD CNC1: The
hot spot c.491–492delTG is most closely associated with
lentigines, cardiac myxoma, and thyroid tumors when opposed to
all other PRKAR1A variants Expressed RIα mutant
protein present with more severe and aggressive CNC-phenotype
CNC2: Sporadic disease later in life with a lower frequency of
myxomas, schwannomas, thyroid and LCCSCT
|
|
iMAD
|
PDE11A (2q31.2) PDE8B (5q13)
PRKACA (19p13.1) 2p16 (unknown gene)
|
Microadenomatous (<1 cm) hyperplasia with
internodular hyperplasia and limited or absent pigmentation
|
Mostly children and young adults
Cyclical
hypercortisolism
May be associated with a paradoxical
rise of glucocorticoid excretion during the Liddleʼs test
Isolated or AD
|
APC: Adenomatous polyposis coligene; c-PPNAD: CNC-associated primary
pigmented nodular adrenocortical disease; CNC: Carney complex; FAP: Familial
adenomatous polyposis; FDCS: Food-dependent Cushing syndrome; GNAS: Gene
coding for the stimulatory subunit α of the G-protein (Gsα);
GPCR: G-protein-coupled receptor; HLRCS: Hereditary leiomyomatosis and renal
cancer syndrome; i-MAD: Isolated micronodular adrenocortical disease;
i-PPNAD: Isolated PPNAD; LCCSCT: Large cell calcifying Sertoli cell tumor;
MAS: McCune–Albright syndrome; MEN1: Multiple endocrine neoplasia
type 1; PBAD: Primary bimorphic adrenocortical disease; PBNMAH: Primary
bilateral macronodular adrenocortical hyperplasia; PDE8B: Phosphodiesterase
8B gene; PDE11A: Phosphodiesterase 11A gene; PRKAR1A: Protein kinase,
cAMP-dependent, regulatory, type I, α gene.
Molecular Pathways in Primary Adrenocortical Hyperplasias
Molecular Pathways in Primary Adrenocortical Hyperplasias
The major molecular pathway that is perturbed in primary adrenocortical
cortisol-producing neoplasms is the cAMP-signaling pathway ([Fig. 1]). Briefly, The G-protein coupled
receptor for ACTH (ACTHR), also known as melanocortin 2 receptor (MC2R), is a
seven-transmembrane receptor that undergoes extensive conformational changes in
response to its ligand, ACTH ([Fig. 1]). This
leads to activation of adenylyl cyclase (AC) through the G proteins and the
generation of cyclic AMP, activating protein kinase A (PKA), a holoenzyme that
consists of a tetramer of two homo- or heterodimers regulatory subunits
(R1α, R1β, R2α and R2β), and catalytic subunits
(Cα, Cβ, Cγ and PRKX) that are encoded by the respective
genes [13]. This in turn enables
phosphorylation of PKA targets, including gene expression to mediate cell growth,
differentiation and hormone production (e. g., cortisol and its
pre-cursors). As shown in [Fig. 1], genetic
alterations in key genes of the cAMP-signaling pathway leads to the formation of
various primary adrenocortical lesions.
Classification of Primary Adrenocortical Hyperplasia
Classification of Primary Adrenocortical Hyperplasia
In 2007, a comprehensive classification of ACTH-independent adrenocortical
hyperplasia was proposed [2]. On
histopathology, these lesions are grossly divided into micro-
(<1 cm) and macro-nodular (>1 cm) disease, a
classification that primarily relies on the size of nodules [2]. Although size has biologic relevance [2], reliance on size alone may lead to
erroneous classification of these nodules, as smaller or larger nodules can co-exist
and/or be seen in either disease states. Additional tissue markers may help
in the differentiation of the two processes, including the presence or absence of
internodular hyperplasia or atrophy of the surrounding cortex (as in PBMAH) and
pigmentation of the nodule or cortex (as in PPNAD) [2]. The most specific pigmentation is lipofuscin, a light to dark brown
autofluorecent granularity of adrenal tissue which represents lysosomal residual
bodies containing end products of oxidative damage to lipids [14]. Additional characteristics of these
lesions includes sparing of the adrenal medulla and the persistence of cells that
are probably derived from fetal adrenal precursors in the micronodular forms [15].
Macronodular adrenocortical hyperplasia
PBMAH is the most common subtype of macronodular adrenocortical hyperplasia. This
condition is often bilateral and affects the adult population [16]. First described in 1964 [17], PBMAH has been referred to by many
names which continues to pose confusion in medical literature, including massive
macronodular adrenocortical disease (MMAD), bilateral macronodular adrenal
hyperplasia (BMAH), ACTH-independent macronodular adrenocortical hyperplasia
(AIMAH), autonomous macronodular adrenal hyperplasia (AMAD), primary
macronodular adrenal hyperplasia (PMAH), ACTH-independent massive bilateral
adrenal disease (AIMBAD), and “giant” or “huge”
macronodular adrenal disease [18].
Asynchronous involvement of only one adrenal gland in PBMAH is rare [19]. After the recent discovery of a local
intra-adrenal secretion of ACTH with an autocrine/paracrine effect on
glucocorticoid secretion [20]
[21] the term PBMAH has been favored, as a
form of pituitary ACTH-independent hyperplasia.
On imaging, PBMAH is characterized by bilateral adrenal enlargement that is often
multilobular. On pathology, PbMAH is represented by a dominant or multiple
yellowish nodules (similar in color to normal adrenal tissue) with intervening
hyperplasia or atrophy, consisting of lipid-rich and poor cells that form
several island-like structures, devoid of dark pigmentation [17]. On histology, PBMAH can be divided
into two types: Type 1 manifests with multiple nodules or discrete adenomas of
various sizes (but typically over 1 cm) and internodular atrophy, while
those with Type 2 have diffuse hyperplasia without internodular atrophy [22]. The combined weight of both adrenals
in PBMAH ranges from 55–90 grams [16]
[23].
PBMAH is a clinically heterogeneous disorder that is often associated with
subclinical glucocorticoid and/or mineralocorticoid secretion in adults
over a number of years. PBMAH may also manifest clinically with overt Cushing
syndrome, associated with cortisol (or its precursor steroids) and/or
other steroid hormone (including aldosterone) excess [22]
[24]. Glucocorticoid and other steroid
hormone secretion may be mediated by non-mutated but aberrantly expressed
receptors through vasopressin, serotonin, catecholamines, gastric inhibitory
polypeptide (GIP), luteinizing hormone, or autocrine/paracrine ACTH
stimulation [25]
[26]
[27]
[28].
PBMAH was initially mostly reported as a sporadic disease but was found to be
inherited in a dominant manner in several families. Recently, the tumor
suppressor ARMC5 was implicated in 20–50% of apparent
sporadic and familial PBMAH cases, where both alleles carried one germline and
one somatic disease-causing variant each [12]
[19]
[29]
[30]. A second somatic event is required
to mediate tumorigenesis and polyclonal nodularity, either 16p loss of
heterozygosity or a somatic hit in ARMC5
[31]. Interestingly, each nodule in PBMAH
may harbor a ‘private’ disease-causing variant, thus tissues
have defects that completely inactivate ARMC5
[31].
Other genetic defects have been implicated in the pathogenesis of PBMAH,
including the somatic activating variant of GNAS at codon Arg (201)
without features of MAS [22]
[32], the germline p.R867G variant of
PDE11A in a patient with familial PBMAH [22], the several disease-causing germline
variants of PDE8B
[33], and germline variants in FH,
MEN1, and APC in the context of familial syndromes as detailed
below in this review [22]
[32]. Very rarely, patients with familial
PBMAH may carry germline duplications of PRKACA resulting in copy number
gains [34]
[35]. Possible disease-causing variants of
the MC2R gene have also been reported in PBMAH [36]. A number of genomic/transcript
abnormalities have been reported in PBMAH, including losses in 20q13 and 14q23
[7], overexpression of WISP2, BCL2, E2F1, EGF,
c-KIT, MYB, PRKACA, and CTNNB1, which implicates
various aberrant oncogenic pathways in nodular polyclonality and growth [37]. Chromatin deregulation of DOT1L
and HDAC9, implicated in regulating gene transcription and cell
proliferation have also been implicated in the pathogenesis of PBMAH [38].
Other rare subtypes of ACTH-independent macronodular adrenocortical hyperplasia
include primary bimorphic adrenocortical disease (PBAD, as seen in MAS) and
food-dependent Cushing syndrome (FDCS, also known as GIP-dependent Cushing
syndrome). PBAD due to MAS is a congenital disorder that presents in the
infantile period with severe hypercortisolism due to nodular adrenocortical
hyperplasia with sharply defined zones of cortical atrophy that give the cortex
a bimorphic appearance [5]
[39]. PBAD is caused by constitutive
activation of the cAMP-signaling pathway from postzygotic gain-of-function
variants in GNAS, within exon 8 of the Gsα subunit ([Fig. 1]) [7]. Moreover, the differential diagnosis of hypercortisolism in
patients with MAS also includes bilateral “atypical” adenomas
[40], isolated bilateral hyperplasia
[41], and hyperplasia with spontaneous
resolution [42] or improvement after
unilateral adrenalectomy [43]
[44].
In a rare form of FDCS, glucocorticoid excess is driven by aberrant
glucose-dependent insulinotropic polypeptide receptor (GIPR) expression that
arise from somatic duplications (within the adrenal lesions) in chromosome
region 19q13.32 containing the GIPR locus [45]. GIP-dependent PBMAH should be
distinguished from FDCS. The differential histopathologic characteristics and
features of these lesions are summarized in [Table 1].
Micronodular adrenocortical hyperplasia
Of the micronodular variety, PPNAD which is congenital and often bilateral is the
most common subtype. PPNAD is either pigmented (c-PPNAD) as seen in CNC, or
isolated (i-PPNAD); this condition has also been referred to non-specific
nomenclatures, including micronodular adrenal disease and microadenomatosis or
primary adrenocortical nodular dysplasia with foci of eosinophilic giant cells
[46]. The term PPNAD was coined by Dr
J. Aidan Carney (Mayo Clinic, Rochester, Minnesota, United States) in 1984 [47]. PPNAD presents as multiple, small,
pigmented nodules (~6 mm in size) with internodular cortical
atrophy [18]. Unlike in PMAH, the adrenal
glands in PPNAD have several pathognomonic features including abnormal adrenal
contour on imaging, smaller in size than in PBMAH (15–25 grams), darkly
pigmented (brown or black nodules) and there is usually internodular cortical
atrophy (reflecting atrophy of the ‘normal’ ACTH-dependent
cortex) [18]. c-PPNAD is inherited in an
autosomal dominant manner and has been linked to three major loci: c-PPNAD is
primarily caused by inactivating variants in PRKAR1A (CNC1 locus) [9]. Rarely, CNC is caused by a yet to be
identified gene that is mapped to chromosome 2 (CNC2 locus on 2p16) [48]. Activation of the cAMP pathway in
PPNAD leads to upregulation of serotonin (5-HT) synthesizing enzyme tryptophan
hydroxylase (TPH) and its receptors (5-HT4, 5-HT6, and 5-HT7).
It should be noted that CNC may also be caused by PRKACB amplification
(CNC3 locus) [8]; PRKACB codes for
the PKA catalytic subunit beta (Cβ) ([Fig. 1]). Defects in PRKACB have not been linked to PPNAD
despite its association with other manifestations of CNC.
iMAD represents a distinct and rare disorder of the adrenal glands that manifests
with hypercortisolism of very early onset [2]. First described in 2004, iMAD is regarded as a separate entity
from PPNAD, with earlier onset of clinical manifestations, cyclicity of
hypercortisolism, and clinically manifesting in isolation; however, these two
entities share several features including micronodularity, paradoxical rise of
glucocorticoid excretion during the Liddleʼs test (1 mg overnight and
low and high dose dexamethasone suppression tests) [49], and autosomal dominant inheritance in
some cases [50]
[51]. On pathology, iMAD is characterized
by multiple small yellow-to-dark brown nodules surrounded by a cortex with a
uniform appearance, which leads to capsular deficits resulting in extra-adrenal
cortical excrescences and moderate diffuse cortical hyperplasia [2]
[51]
[52]. This disease is highly
heterogeneous, and disease-causing variants in PDE11A
[52]
[53], PDEB8
[10]
[52], or germline duplications of
PRKACA
[34]
[35]
[54] have been implicated in its
pathogenesis. Micronodular adrenocortical hyperplasias mainly produce cortisol
and/or its pre-cursors, although non-cortisol producing lesions exist
(unpublished data) but have not been extensively studied [15].
Familial Syndromes Associated with Primary Adrenocortical Hyperplasia
Familial Syndromes Associated with Primary Adrenocortical Hyperplasia
Several monogenic disorders have been associated with the development of primary
adrenocortical hyperplasias ([Table 2]). The
following section briefly enlists these conditions.
Table 2 Familial syndromes associated with primary adrenocortical
hyperplasias.
|
Familial syndromes
|
Gene (locus)
|
Mode of inheritance
|
Major features
|
|
Carney complex
|
PRKAR1A (17q22–24, CNC1 locus)
2p16 (CNC2
locus, gene unknown)
PRKACB (1p31.1, CNC3 locus)
|
AD
|
-
PPNAD
-
Cardiac myxomas
-
Pigmented skin lesions (lentiginosis and blue nevi)
-
Somatotroph-pituitary adenomas
-
LCCSCT
-
Benign thyroid nodules, differentiated thyroid cancer
-
Melanocytic schwannomas
|
|
Multiple Endocrine Neoplasia Type 1
|
MEN1 (11q13)
|
AD
|
|
|
Familial Adenomatous Polyposis
|
APC (5q22.2)
|
AD
|
-
Large pre-cancerous colorectal polyps in the second and
third decade of life
-
Adrenocortical tumors, including adrenocortical cancer
and PBMAH
-
Papillary thyroid carcinomas
-
Lipomas
-
Pancreatic carcinomas
|
|
Hereditary Leiomyomatosis and Renal Cell Cancer
|
FH (1q42.3–43)
|
AD
|
|
APC: Adenomatous polyposis coligene; c-PPNAD: CNC-associated primary
pigmented nodular adrenocortical disease; CNC: Carney complex; FAP: Familial
adenomatous polyposis; FDCS: Food-dependent Cushing syndrome; GNAS: Gene
coding for the stimulatory subunit α of the G-protein (Gsα);
GPCR: G-protein-coupled receptor; HLRCS: Hereditary leiomyomatosis and renal
cancer syndrome; i-MAD: Isolated micronodular adrenocortical disease;
i-PPNAD: Isolated PPNAD; LCCSCT: Large cell calcifying Sertoli cell tumor;
MAS: McCune–Albright syndrome; MEN1: Multiple endocrine neoplasia
type 1; PBAD: Primary bimorphic adrenocortical disease; PBMAH: Pimary
bilateral macronodular adrenocortical hyperplasia; PDE8B: phosphodiesterase
8B gene; PDE11A: phosphodiesterase 11A gene; PRKAR1A: Protein kinase,
cAMP-dependent, regulatory, type I, α gene.
Carney Complex (CNC)
CNC is an autosomal dominant multiple neoplasia syndrome arising from genetic
alterations in three loci, PRKAR1A (which codes for R1α subunit of
PKA and is known as the CNC1 locus), 2p16 (CNC2), and PRKACB amplification
(CNC3 locus) [55]. Most disease-causing
variants are caused by inactivating variants in R1α of PKA that are spread
along the whole coding sequence [9]
[56]. The clinical manifestations of CNC
include PPNAD (more than 60% of patients with CNC have clinically detectable
PPPNAD), cardiac myxomas, various pigmented skin lesions, growth-hormone excess due
to somatotroph-pituitary hyperplasia, benign large cell calcifying Sertoli cell
tumor of the testis, thyroid lesions and melanocytic schwannomas. CNC does not
predispose to macronodular adrenocortical hyperplasia.
Multiple Endocrine Neoplasia Type 1 (MEN-1)
Multiple Endocrine Neoplasia Type 1 (MEN-1)
MEN-1 is an autosomal dominant condition that arises from heterozygous
disease-causing inactivating germline variants of MEN1 (11q13) [57]. The clinical manifestations of MEN-1
include primary hyperparathyroidism (>95%), skin lesions
(>90%), pituitary adenomas (45%), and neuroendocrine
meoplasms (>30%). Adrenal enlargement are seen in approximately
20.4% (146/715) of patients with MEN-1. MEN-1 may predispose to
PBMAH (10.1% of the cohort) [22]
[58]. It is not known if MEN-1 predisposes to
micronodular adrenocortical hyperplasia.
Familial Adenomatous Polyposis (FAP)
Familial Adenomatous Polyposis (FAP)
FAP is an autosomal dominant condition that arise from the tumor suppressor gene
APC. The clinical manifestations include large pre-cancerous colorectal
polyps, primary adrenocortical lesions including PBMAH, papillary thyroid
carcinomas, lipomas, and pancreatic carcinomas. PBMAH is an infrequent manifestation
of FAP [22]. It is not known if FAP
predisposes to micronodular adrenocortical hyperplasia.
Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCS)
Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCS)
HLRCC is an autosomal dominant condition arising from disease-inactivating variants
of the mitochondrial enzyme fumarate hydratase (FH). Clinical manifestations
include hereditary leiomyomatosis, renal cancer, and adrenal lesions. HLRCC
predisposes to PMAH and/or adrenocortical adenomas that can be
non-functional [22]
[59]
[60], although the first demonstration of
FH’s involvement in adrenocortical tumors was in a patient with
PBMAH and mostly subclinical hypercortisolism [59].
Carney Triad (CT)
CT is a sporadic condition from an unknown genetic defect with a female predominance.
In CT, patients harbor a recurrent aberrant DNA methylation of the promoter region
of the SDHC gene [61]. This condition
predisposes to hamartomatous lesions in various organs (such as pulmonary
chondromas), gastrointestinal stromal tumors, pheochromocytoma, and esophageal
leiomyoma [62]. CT is the only known adrenal
condition that has among its clinical manifestations both adrenocortical and
medullary involvement; in fact, adrenal lesions are the fourth component of this
condition, which includes PMAH and/or adrenocortical adenomas that are
mostly non-functional [63].
Genetic Classification, Testing and Counseling of Patients with Familial Primary
Adrenocortical Hyperplasias
Genetic Classification, Testing and Counseling of Patients with Familial Primary
Adrenocortical Hyperplasias
Advances in the field of genetics and genomics has substantially progressed and
informed our understanding of the molecular pathogenesis of sporadic and familial
forms of primary adrenocortical hyperplasias. In keeping with the growing list of
genes implicated in the pathogenesis of these lesions, and to better serve genetic
testing and counseling of affected or at risk patients, a gene-based classification
in which patients are grouped based on the presence of disease-causing germline
variants or other genetic alterations is required ([Fig. 2]). This classification will highlight the causative genes, which
may aid with prioritizing genetic testing and/or counseling of affected
family members. Additionally, this approach may decrease the risk of misclassifying
familial cases as sporadic. An example of such a classification system includes
listing the implicated gene name before the type of hyperplasia, such as
ARMC5-PBMAH, MEN1-PBMAH, PRKAR1A-CNC, and
PDE11A-iMAD ([Fig. 2]). As there are
yet unidentified molecular cause(s) of these adrenocortical hyperplasias [15], we anticipate a growing number of genes
implicated in these disorders over the next decades and a robust, flexible and easy
to follow classification system is thus required.
Fig. 2 Gene-based diagnostic algorithm for primary adrenocortical
hyperplasias.
Since most familial forms of adrenocortical hyperplasias are inherited in an
autosomal dominant manner, establishing a causative gene is important for
understanding the disease mechanisms, mode of inheritance and usefulness of cascade
screening. Although the genotype-phenotype correlation is often times unpredictable,
providing specific screening and counseling could decrease a patient’s
anxiety towards this uncertainty, decrease genetic discrimination and ensure
appropriate disease surveillance. Genetic screening may begin as early as infancy in
at risk individuals, especially in CNS or iMAD from MAS. A successful patient
counseling model should incorporate the patient’s values and attitudes
toward their disease, while underscoring the risks and benefits of genetic screening
and counseling, psychosocial interventions and service delivery [64].
In the context of ARMC5-PBMAH or PDE11A-iMAD/PBMAH, the penetrance is
decreased and first-degree relatives that are carriers may not be affected.
Therefore, all first-degree relatives with a known carrier state should be referred
for genetic counseling and phenotype-directed biochemical screening per established
clinical guidelines. Family screening of ARMC5, as with the other genes as
listed in [Table 1] and [2], will allow early detection of carriers,
and prospective follow up. Genetic testing should be offered when an individual is
free to refuse or accept the test according to their wishes and moral beliefs.
Children should not be tested for these low penetrant genes unless there is clinical
evidence of disease.
Conclusions
The identification of several genetic causes of primary adrenocortical hyperplasias,
primarily in the cAMP-signaling pathways, have paved the way for large-scale
clinical and molecular studies and future research. The traditional classification
as adenomas, hyperplasias and carcinomas is non-specific and has added confusion to
the nomenclature of these lesions. In this new era of personalized care and
genetics, a gene-based classification that is more specific is required to assist in
the understanding of their disease processes, hormonal functionality and signaling
pathways. Additionally, a gene-based classification carries implications for
treatment, genetic counseling and screening of asymptomatic family members.
Author and Contributors
All authors contributed equally to the conception or design of the work; or the
acquisition, analysis, or interpretation of data for the work; and drafting the work
or revising it critically for important intellectual content; and final approval of
the version to be published; and agreement to be accountable for all aspects of the
work in ensuring that questions related to the accuracy or integrity of any part of
the work are appropriately investigated and resolved.
