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Disease Profile

ACTH-independent macronodular adrenal hyperplasia

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

All ages

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ICD-10

E24.8

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

AIMAH; Massive macronodular adrenocortical disease; MMAD;

Categories

Congenital and Genetic Diseases; Endocrine Diseases; Female Reproductive Diseases;

Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 189427

Definition
A rare cause of Cushing syndrome (CS) 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.

Epidemiology
Prevalence of endogenous CS is estimated at 1/26,000 and Cushing syndrome due to macronodular adrenal hyperplasia (CSMAH) represents less than 1% of the cases.

Clinical description
The 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. CSMAH 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.

Etiology
The exact etiology is unknown but the adrenal overgrowth seen in CSMAH 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 methods
Diagnosis 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 diagnosis
Differential 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 counseling
CSMAH 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 treatment
Treatment 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.

Prognosis
Prognosis 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.

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Failure to thrive
Faltering weight
Weight faltering

[ more ]

0001508
Macronodular adrenal hyperplasia
0008231
Round face
Circular face
Round facial appearance
Round facial shape

[ more ]

0000311
Thin skin
0000963
Truncal obesity
0001956
30%-79% of people have these symptoms
Bruising susceptibility
Bruise easily
Easy bruisability
Easy bruising

[ more ]

0000978
Depressivity
Depression
0000716
Diabetes mellitus
0000819
Fatigue
Tired
Tiredness

[ more ]

0012378
Generalized hirsutism
Excessive hairiness over body
0002230
Hypertension
0000822
Menometrorrhagia
0400008
Muscle weakness
Muscular weakness
0001324
Nephrolithiasis
Kidney stones
0000787
Osteoporosis
0000939
5%-29% of people have these symptoms
Meningioma
0002858
Percent of people who have these symptoms is not available through HPO
Adult onset
Symptoms begin in adulthood
0003581
Agitation
0000713
Anxiety
Excessive, persistent worry and fear
0000739
Decreased circulating ACTH level
0002920
Kyphosis
Hunched back
Round back

[ more ]

0002808
Mental deterioration
Cognitive decline
Cognitive decline, progressive
Intellectual deterioration
Progressive cognitive decline

[ more ]

0001268
Mood changes
Moody
0001575
Neoplasm
0002664
Osteopenia
0000938
Primary hypercortisolism
0001579
Psychosis
0000709
Skeletal muscle atrophy
Muscle degeneration
Muscle wasting

[ more ]

0003202
Somatic mutation
0001428
Sporadic
No previous family history
0003745
Striae distensae
Stretch marks
0001065

Learn more

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on ACTH-independent macronodular adrenal hyperplasia. This website is maintained by the National Library of Medicine.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.