MCID: ACT092
MIFTS: 49

Acth-Independent Macronodular Adrenal Hyperplasia

Categories: Genetic diseases, Rare diseases, Endocrine diseases

Aliases & Classifications for Acth-Independent Macronodular Adrenal Hyperplasia

MalaCards integrated aliases for Acth-Independent Macronodular Adrenal Hyperplasia:

Name: Acth-Independent Macronodular Adrenal Hyperplasia 54 50 13 69
Adrenocorticotropic Hormone-Independent Macronodular Adrenal Hyperplasia 50 71
Corticotropin-Independent Macronodular Adrenal Hyperplasia 50 71
Acth-Independent Macronodular Adrenocortical Hyperplasia 50 71
Acth-Independent Macronodular Adrenal Hyperplasia 2 69
Acth-Independent Macronodular Adrenal Hyperplasia 1 71
Massive Macronodular Adrenocortical Disease 50
Primary Macronodular Adrenal Hyperplasia 50
Adrenal Cushing Syndrome Due to Aimah 71
Acth-Independent Cushing Syndrome 71
Aimah1 71
Aimah 50
Mmad 50

Characteristics:

OMIM:

54
Inheritance:
isolated cases

Miscellaneous:
adult onset (40 to 60 years old)
variable expressivity, some patients may be clinically asymptomatic


HPO:

32
acth-independent macronodular adrenal hyperplasia:
Onset and clinical course adult onset
Inheritance autosomal dominant inheritance sporadic


Classifications:



Summaries for Acth-Independent Macronodular Adrenal Hyperplasia

NIH Rare Diseases : 50 the following summary is from orphanet, a european reference portal for information on rare diseases and orphan drugs.orpha number: 189427disease definitionacth-independent macronodular adrenal hyperplasia (aimah) is a rare cause of cushing syndrome (cs; see this term) characterized by nodular enlargement of both adrenal glands (multiple nodules above 1 cm in diameter) that produce excess cortisol and features of adrenocorticotropic hormone (acth) independent cs (see this term).epidemiologyprevalence of endogenous cs is estimated at 1/26,000 and aimah represents less than 1% of the cases.clinical descriptionthe disease presents a bimodal age distribution with a rare subset presenting in the first years of life, particularly associated to mccune-albright syndrome (mas; see this term). most patients present in their 5th or 6th decade and the disease might be more prevalent in females. aimah most frequently presents as clinical or subclinical cs and signs usually become apparent only after several decades of life. however, in some patients the adrenal lesions are found incidentally, in the process of radiological investigation of another disease. the adrenal glands can be massively enlarged bilaterally with the presence of numerous macronodules; however diffuse adrenal enlargement without nodules has been described.etiologythe exact etiology is unknown but the adrenal overgrowth seen in aimah may be due to the expression of aberrant membrane receptors found in the adrenal cortex that regulate cortisol secretion and which are stimulated by gastric inhibitory polypeptide (gip), vasopressin, serotonin, catecholamines and luteinizing hormone (lh).diagnostic methodsdiagnosis is based on the clinical picture of cs, the demonstration of acth-independent hypercortisolism (decreased levels of acth in plasma, non suppressible cortisol level after dexamethasone administration), and bilateral adrenal nodular enlargement on radiological imaging. diagnosis is often difficult because hypercortisolism usually develops slowly over years, may be cyclical and is often associated with subtle cs. radiological imaging is helpful, but occasionally nodularity is indistinguishable from that in normal elderly persons. diagnosis can be confirmed by histological examination. hormonal investigations can demonstrate aberrant receptor expression with abnormal stimulation of cortisol secretion by various hormones such as gip in cases of food-dependent cs and gonadotropin-releasing hormone (gnrh) in cases of lh-dependent cs.differential diagnosisdifferential diagnoses include other causes of acth-independent cs (adrenal adenoma and carcinoma), acth-dependent cs including pituitary (cushing disease) or extra-pituitary tumors (ectopic acth secretion; see these terms), polycystic ovary syndrome and metabolic syndrome.genetic counselingaimah is most often reported as sporadic but there are increasing reports of familial cases with autosomal dominant transmission. as the genetics of this disease are largely unknown genetic counseling is not yet possible.management and treatmenttreatment can be medical if aberrant adrenal receptors are identified and can be blocked (i.e. with propranolol, somatostatin or gnrh analogs). if the blockade is not possible, treatment will be chosen depending on the level of steroid excess. unilateral adrenalectomy can be proposed for patients with a moderate increase in hormone production, while bilateral adrenalectomy is recommended for patients with significant overproduction. after bilateral adrenalectomy, glucocorticoid and mineralocorticoid replacement is required.prognosisprognosis after treatment is good but quality of life may be affected due to the long-term effects of hypercortisolemia. without treatment the disease is life-threatening as in the case of manifest hypercortisolism. in cases of moderate hypercortisolism, long-term morbidity is due to the increased cardiovascular and metabolic risk factors associated with mild cs.visit the orphanet disease page for more resources. last updated: 9/1/2012

MalaCards based summary : Acth-Independent Macronodular Adrenal Hyperplasia, also known as adrenocorticotropic hormone-independent macronodular adrenal hyperplasia, is related to acth-independent macronodular adrenal hyperplasia 2 and primary pigmented nodular adrenocortical disease, and has symptoms including failure to thrive, acne and nephrolithiasis. An important gene associated with Acth-Independent Macronodular Adrenal Hyperplasia is GNAS (GNAS Complex Locus), and among its related pathways/superpathways are Signaling by GPCR and Peptide ligand-binding receptors. The drugs Epinephrine and Racepinephrine have been mentioned in the context of this disorder. Affiliated tissues include adrenal gland, pituitary and ovary, and related phenotypes are behavior/neurological and endocrine/exocrine gland

UniProtKB/Swiss-Prot : 71 ACTH-independent macronodular adrenal hyperplasia 1: A rare adrenal defect characterized by multiple, bilateral, non- pigmented, benign, adrenocortical nodules. It results in excessive production of cortisol leading to ACTH-independent Cushing syndrome. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes.

OMIM : 54
ACTH-independent macronodular adrenal hyperplasia (AIMAH) is an endogenous form of adrenal Cushing syndrome characterized by multiple bilateral adrenocortical nodules that cause a striking enlargement of the adrenal glands. Although some familial cases have been reported, the vast majority of AIMAH cases are sporadic. Patients typically present in the fifth and sixth decades of life, approximately 10 years later than most patients with other causes of Cushing syndrome (Swain et al., 1998; Christopoulos et al., 2005). Approximately 10 to 15% of adrenal Cushing syndrome is due to primary bilateral ACTH-independent adrenocortical pathology. The 2 main subtypes are AIMAH and primary pigmented nodular adrenocortical disease (PPNAD, see 610489), which is often a component of the Carney complex (160980) and associated with mutations in the PRKAR1A gene (188830) on chromosome 17q23-q24. AIMAH is rare, representing less than 1% of endogenous causes of Cushing syndrome (Swain et al., 1998; Christopoulos et al., 2005). See also ACTH-independent Cushing syndrome (615830) due to somatic mutation in the PRKACA gene (601639). Cushing 'disease' (219090) is an ACTH-dependent disorder caused in most cases by pituitary adenomas that secrete excessive ACTH. (219080)

Related Diseases for Acth-Independent Macronodular Adrenal Hyperplasia

Graphical network of the top 20 diseases related to Acth-Independent Macronodular Adrenal Hyperplasia:



Diseases related to Acth-Independent Macronodular Adrenal Hyperplasia

Symptoms & Phenotypes for Acth-Independent Macronodular Adrenal Hyperplasia

Symptoms via clinical synopsis from OMIM:

54

Head And Neck- Face:
round face

Skeletal:
osteoporosis
decreased bone mineral density

Neurologic- Behavioral Psychiatric Manifestations:
depression
psychosis
agitation
mood changes
anxiety

Muscle Soft Tissue:
muscle wasting

Growth- Weight:
truncal obesity

Laboratory- Abnormalities:
increased serum cortisol
decreased serum acth
cortisol does not decrease on dexamethasone suppression test

Skeletal- Spine:
kyphosis

Skin Nails & Hair- Skin:
thin skin
easy bruising
striae

Cardiovascular- Vascular:
hypertension

Neurologic- Central Nervous System:
cognitive decline

Endocrine Features:
cushing syndrome
acth-independent hypercortisolemia
macronodular adrenal hyperplasia
enlarged adrenal glands

Neoplasia:
no progression to cancer


Clinical features from OMIM:

219080

Human phenotypes related to Acth-Independent Macronodular Adrenal Hyperplasia:

32 (show all 32)
id Description HPO Frequency HPO Source Accession
1 failure to thrive 32 hallmark (90%) HP:0001508
2 acne 32 frequent (33%) HP:0001061
3 nephrolithiasis 32 frequent (33%) HP:0000787
4 round face 32 hallmark (90%) HP:0000311
5 kyphosis 32 HP:0002808
6 fatigue 32 frequent (33%) HP:0012378
7 osteoporosis 32 HP:0000939
8 muscle weakness 32 frequent (33%) HP:0001324
9 thin skin 32 hallmark (90%) HP:0000963
10 depression 32 frequent (33%) HP:0000716
11 hypokalemia 32 frequent (33%) HP:0002900
12 infertility 32 frequent (33%) HP:0000789
13 osteopenia 32 HP:0000938
14 psychosis 32 HP:0000709
15 hypertension 32 frequent (33%) HP:0000822
16 diabetes mellitus 32 frequent (33%) HP:0000819
17 agitation 32 HP:0000713
18 mental deterioration 32 HP:0001268
19 truncal obesity 32 hallmark (90%) HP:0001956
20 mood changes 32 HP:0001575
21 anxiety 32 frequent (33%) HP:0000739
22 vestibular areflexia 32 hallmark (90%) HP:0008568
23 generalized hirsutism 32 frequent (33%) HP:0002230
24 striae distensae 32 frequent (33%) HP:0001065
25 macronodular adrenal hyperplasia 32 HP:0008231
26 skeletal muscle atrophy 32 HP:0003202
27 neoplasm 32 HP:0002664
28 bruising susceptibility 32 frequent (33%) HP:0000978
29 adrenocortical hypoplasia 32 hallmark (90%) HP:0008182
30 decreased circulating acth level 32 HP:0002920
31 menometrorrhagia 32 frequent (33%) HP:0400008
32 primary hypercorticolism 32 HP:0001579

UMLS symptoms related to Acth-Independent Macronodular Adrenal Hyperplasia:


agitation, generalized fatigue

MGI Mouse Phenotypes related to Acth-Independent Macronodular Adrenal Hyperplasia:

44
id Description MGI Source Accession Score Top Affiliating Genes
1 behavior/neurological MP:0005386 9.8 AVPR1A AVPR1B AVPR2 EDNRA GNAS MC2R
2 endocrine/exocrine gland MP:0005379 9.63 GNRH1 MC2R AVPR1A AVPR1B EDNRA GNAS
3 homeostasis/metabolism MP:0005376 9.5 AVPR1A AVPR1B AVPR2 EDNRA GNAS GNRH1
4 nervous system MP:0003631 9.17 AVPR1A AVPR1B EDNRA GNAS GNRH1 MC2R

Drugs & Therapeutics for Acth-Independent Macronodular Adrenal Hyperplasia

Drugs for Acth-Independent Macronodular Adrenal Hyperplasia (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):

(show all 18)
id Name Status Phase Clinical Trials Cas Number PubChem Id
1
Epinephrine Approved, Vet_approved Phase 2 51-43-4 5816
2 Racepinephrine Approved Phase 2
3 Adrenocorticotropic Hormone Phase 2
4 Epinephryl borate Phase 2
5
Mifepristone Approved, Investigational 84371-65-3 55245
6 Adrenergic Agents
7 Adrenergic Agonists
8 Adrenergic alpha-Agonists
9 Adrenergic beta-Agonists
10 Anti-Asthmatic Agents
11 Autonomic Agents
12 Bronchodilator Agents
13 Hormones
14 Mydriatics
15 Neurotransmitter Agents
16 Peripheral Nervous System Agents
17 Respiratory System Agents
18 Vasoconstrictor Agents

Interventional clinical trials:


id Name Status NCT ID Phase Drugs
1 Study of Efficacy and Safety of Osilodrostat in Cushing's Syndrome Recruiting NCT02468193 Phase 2 Osilodrostat
2 Study of Adrenal Gland Tumors Recruiting NCT00005927
3 Retrospective Chart Review Study of Korlym for the Treatment of ACTH Independent Cushing's Syndrome Enrolling by invitation NCT02663609

Search NIH Clinical Center for Acth-Independent Macronodular Adrenal Hyperplasia

Genetic Tests for Acth-Independent Macronodular Adrenal Hyperplasia

Anatomical Context for Acth-Independent Macronodular Adrenal Hyperplasia

MalaCards organs/tissues related to Acth-Independent Macronodular Adrenal Hyperplasia:

39
Adrenal Gland, Pituitary, Ovary, Cortex, Adrenal Cortex, Testes, Skin

Publications for Acth-Independent Macronodular Adrenal Hyperplasia

Articles related to Acth-Independent Macronodular Adrenal Hyperplasia:

(show all 26)
id Title Authors Year
1
Whole exome sequencing identifies mutation of EDNRA involved in ACTH-independent macronodular adrenal hyperplasia. ( 23754170 )
2013
2
Classification, diagnosis and treatment of ACTH-independent macronodular adrenal hyperplasia. ( 24069103 )
2013
3
Laparoscopic enucleation of macronodules in a patient with ACTH-independent macronodular adrenal hyperplasia 7 years after unilateral adrenalectomy: consideration of operative procedure. ( 23486077 )
2013
4
Phosphodiesterase 11A (PDE11A) gene defects in patients with acth-independent macronodular adrenal hyperplasia (AIMAH): functional variants may contribute to genetic susceptibility of bilateral adrenal tumors. ( 22996146 )
2012
5
Assessment of long-term efficacy and safety of metyrapone monotherapy in a patient with ACTH-independent macronodular adrenal hyperplasia. ( 22038492 )
2012
6
Genome-wide gene expression profiling identifies overlap with malignant adrenocortical tumours and novel mechanisms of inefficient steroidogenesis in familial ACTH-independent macronodular adrenal hyperplasia. ( 22383426 )
2012
7
Usefulness and limitations of unilateral adrenalectomy for ACTH-independent macronodular adrenal hyperplasia in a patient with poor glycemic control. ( 22790131 )
2012
8
A rare case of ACTH-independent macronodular adrenal hyperplasia associated with aldosterone-producing adenoma. ( 21297325 )
2011
9
A case of ACTH-independent macronodular adrenal hyperplasia associated with multiple endocrine neoplasia type 1. ( 21415556 )
2011
10
Aberrant expression of glucagon receptors in adrenal glands of a patient with Cushing's syndrome and ACTH-independent macronodular adrenal hyperplasia. ( 20529775 )
2010
11
Aberrant expression of multiple hormone receptors in ACTH-independent macronodular adrenal hyperplasia causing Cushing's syndrome. ( 20460422 )
2010
12
Unilateral adrenalectomy can be an alternative therapy for infantile onset Cushing' s syndrome caused by ACTH-independent macronodular adrenal hyperplasia with McCune-Albright syndrome. ( 20543510 )
2010
13
ACTH-independent macronodular adrenal hyperplasia. ( 19500767 )
2009
14
Role of unilateral aderenalectomy in ACTH-independent macronodular adrenal hyperplasia. ( 18825451 )
2009
15
Familial vasopressin-sensitive ACTH-independent macronodular adrenal hyperplasia (VPs-AIMAH): clinical studies of three kindreds. ( 19018784 )
2009
16
ACTH-independent macronodular adrenal hyperplasia: imaging findings of a rare condition : A case report. ( 17502981 )
2008
17
The role of unilateral adrenalectomy in ACTH-independent macronodular adrenal hyperplasia (AIMAH). ( 18214589 )
2008
18
Cushing's syndrome secondary to ACTH-independent macronodular adrenal hyperplasia. ( 18209860 )
2007
19
Ectopic expression of vasopressin V1b and V2 receptors in the adrenal glands of familial ACTH-independent macronodular adrenal hyperplasia. ( 16343095 )
2005
20
Clinical and subclinical ACTH-independent macronodular adrenal hyperplasia and aberrant hormone receptors. ( 16215323 )
2005
21
A case of ACTH-independent macronodular adrenal hyperplasia: simultaneous expression of several aberrant hormone receptors in the adrenal gland. ( 12940463 )
2003
22
Unilateral adrenalectomy improves insulin resistance and diabetes mellitus in a patient with ACTH-independent macronodular adrenal hyperplasia. ( 14709842 )
2003
23
An unusual case of Cushing's syndrome due to ACTH-independent macronodular adrenal hyperplasia. ( 12744099 )
2003
24
Is unilateral adrenalectomy an alternative treatment for ACTH-independent macronodular adrenal hyperplasia?: Long-term follow-up of four cases. ( 11834434 )
2002
25
A case of severe hypertension caused by ACTH-independent macronodular adrenal hyperplasia. ( 11936469 )
2002
26
Simultaneous bilateral laparoscopic adrenalectomy in ACTH-independent macronodular adrenal hyperplasia. ( 11389748 )
2001

Variations for Acth-Independent Macronodular Adrenal Hyperplasia

UniProtKB/Swiss-Prot genetic disease variations for Acth-Independent Macronodular Adrenal Hyperplasia:

71
id Symbol AA change Variation ID SNP ID
1 GNAS p.Arg201His VAR_003441 rs121913495
2 GNAS p.Arg201Ser VAR_017846 rs11554273

ClinVar genetic disease variations for Acth-Independent Macronodular Adrenal Hyperplasia:

6
id Gene Variation Type Significance SNP ID Assembly Location
1 GNAS NM_000516.5(GNAS): c.601C> T (p.Arg201Cys) single nucleotide variant Pathogenic/Likely pathogenic rs11554273 GRCh37 Chromosome 20, 57484420: 57484420
2 GNAS NM_000516.5(GNAS): c.602G> A (p.Arg201His) single nucleotide variant Pathogenic/Likely pathogenic rs121913495 GRCh37 Chromosome 20, 57484421: 57484421
3 GNAS NM_000516.5(GNAS): c.601C> A (p.Arg201Ser) single nucleotide variant Pathogenic rs11554273 GRCh37 Chromosome 20, 57484420: 57484420

Expression for Acth-Independent Macronodular Adrenal Hyperplasia

Search GEO for disease gene expression data for Acth-Independent Macronodular Adrenal Hyperplasia.

Pathways for Acth-Independent Macronodular Adrenal Hyperplasia

Pathways related to Acth-Independent Macronodular Adrenal Hyperplasia according to GeneCards Suite gene sharing:

id Super pathways Score Top Affiliating Genes
1
Show member pathways
13.62 AVPR1A AVPR1B AVPR2 EDNRA GNAS GNRH1
2
Show member pathways
12.97 AVPR1A AVPR1B AVPR2 EDNRA GNAS GNRH1
3
Show member pathways
12.43 AVPR1A AVPR1B EDNRA GNAS
4
Show member pathways
11.95 AVPR1A AVPR1B AVPR2 GNAS
5
Show member pathways
11.88 EDNRA GNAS MC2R
6
Show member pathways
11.53 AVPR1A AVPR1B EDNRA GNAS
7 11.29 EDNRA GNAS
8 11.1 AVPR2 GNAS
9 11.09 AVPR2 GNAS MC2R PDE11A
10 10.96 EDNRA GNAS

GO Terms for Acth-Independent Macronodular Adrenal Hyperplasia

Cellular components related to Acth-Independent Macronodular Adrenal Hyperplasia according to GeneCards Suite gene sharing:

id Name GO ID Score Top Affiliating Genes
1 integral component of plasma membrane GO:0005887 9.02 AVPR1A AVPR1B AVPR2 EDNRA MC2R

Biological processes related to Acth-Independent Macronodular Adrenal Hyperplasia according to GeneCards Suite gene sharing:

(show all 14)
id Name GO ID Score Top Affiliating Genes
1 G-protein coupled receptor signaling pathway GO:0007186 9.88 AVPR1A AVPR1B AVPR2 EDNRA GNAS MC2R
2 positive regulation of cytosolic calcium ion concentration GO:0007204 9.65 AVPR1A AVPR1B EDNRA
3 cellular response to hormone stimulus GO:0032870 9.61 AVPR1A AVPR1B AVPR2
4 signal transduction GO:0007165 9.56 AVPR1A AVPR1B AVPR2 EDNRA GNAS GNRH1
5 positive regulation of cAMP biosynthetic process GO:0030819 9.54 GNAS MC2R
6 activation of adenylate cyclase activity GO:0007190 9.54 AVPR2 EDNRA GNAS
7 renal water homeostasis GO:0003091 9.52 AVPR2 GNAS
8 telencephalon development GO:0021537 9.51 AVPR1A AVPR2
9 positive regulation of vasoconstriction GO:0045907 9.5 AVPR1A AVPR1B AVPR2
10 positive regulation of blood pressure GO:0045777 9.49 AVPR1A AVPR2
11 positive regulation of systemic arterial blood pressure GO:0003084 9.46 AVPR1A AVPR2
12 activation of phospholipase C activity GO:0007202 9.43 AVPR1A AVPR1B EDNRA
13 response to peptide GO:1901652 9.33 AVPR1A AVPR1B AVPR2
14 regulation of systemic arterial blood pressure by vasopressin GO:0001992 8.8 AVPR1A AVPR1B AVPR2

Molecular functions related to Acth-Independent Macronodular Adrenal Hyperplasia according to GeneCards Suite gene sharing:

id Name GO ID Score Top Affiliating Genes
1 G-protein coupled receptor activity GO:0004930 9.65 AVPR1A AVPR1B AVPR2 EDNRA MC2R
2 signal transducer activity GO:0004871 9.43 AVPR1A AVPR1B AVPR2 EDNRA GNAS MC2R
3 peptide binding GO:0042277 9.33 AVPR1A AVPR1B AVPR2
4 protein kinase C binding GO:0005080 9.32 AVPR1A AVPR1B
5 vasopressin receptor activity GO:0005000 8.8 AVPR1A AVPR1B AVPR2

Sources for Acth-Independent Macronodular Adrenal Hyperplasia

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
16 ExPASy
18 FMA
28 GO
29 GTR
30 HGMD
31 HMDB
32 HPO
33 ICD10
34 ICD10 via Orphanet
35 ICD9CM
36 IUPHAR
37 KEGG
38 LifeMap
40 MedGen
42 MeSH
43 MESH via Orphanet
44 MGI
46 NCI
47 NCIt
48 NDF-RT
51 NINDS
52 Novoseek
54 OMIM
55 OMIM via Orphanet
59 PubMed
60 QIAGEN
65 SNOMED-CT via HPO
66 SNOMED-CT via Orphanet
67 TGDB
68 Tocris
69 UMLS
70 UMLS via Orphanet
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