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Disease Profile

Primary pigmented nodular adrenocortical disease

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)

PPNAD

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: 189439

Definition
Primary pigmented nodular adrenocortical disease (PPNAD) is a form of bilateral adrenocortical hyperplasia that is often associated with adrenocorticotrophin hormone (ACTH) independent Cushing syndrome (see this term) and is characterized by small to normal sized adrenal glands containing multiple small cortical pigmented nodules (less than 1 cm in diameter).

Epidemiology
The prevalence of endogenous Cushing syndrome (CS; see this term) is estimated at 1/26,000. PPNAD is responsible for less than 2% of cases. PPNAD is more frequent in females, especially after puberty.

Clinical description
Although the majority of cases are diagnosed in the 2nd and 3rd decades of life, a substantial proportion of patients present during early childhood (2-3 years). Patients with PPNAD often present with atypical CS, which is characterized by an asthenic, rather than obese, body habitus caused by severe osteoporosis, short stature and severe muscle and skin wasting. Patients with atypical CS have normal or near normal 24-hour urinary free cortisol production, but this is characterized by the absence of the normal circadian rhythmicity of cortisol. In adolescents and children with PPNAD, the disease frequently presents with periodic CS in which normal cortisol production is interrupted by days or weeks of hypercortisolism.

Etiology
More than 90% of reported cases of PPNAD occur as one of the manifestations of Carney complex (CNC; see this term). Although rare, familial cases of isolated PPNAD have also been reported. The condition is inherited in an autosomal dominant manner and can be associated with mutations in the PRKAR1A, PDE11A and PDE8B genes.

Diagnostic methods
Diagnosis is first based on confirmation of hypercortisolism (24hr urinary free cortisol, late night salivary cortisol, low-dose and high-dose dexamethasone-suppression test and assessment of midnight plasma cortisol). The second step is plasma ACTH detection to distinguish ACTH-independent CS (values lower than 5-10 pg/ml) from ACTH-dependent CS (see these terms). In some cases, nodules are visible on adrenal gland computed tomography (CT) or magnetic resonance imaging (MRI). The combination of atrophy and nodularity gives the glands an irregular contour, which is distinctly abnormal and diagnostic, especially in younger patients. Patients with PPNAD should also be screened for CNC and its potentially serious components.

Differential diagnosis
Differential diagnoses are ACTH-dependent CS, including pituitary (Cushing disease) or extra-pituitary tumors (ectopic ACTH secretion) and the other causes of ACTH-independent CS including adrenal adenoma and carcinoma (see these terms).

Genetic counseling
Genetic testing for mutations of PRKAR1A, PDE11A and PDE8B genes may be discussed to detect affected patients in families with identified mutations. Genetic counseling may be offered in families with these mutations.

Management and treatment
Bilateral adrenalectomy is the most common treatment for CS due to PPNAD followed by life-long cortisol and mineralocorticoid supplementation.

Prognosis
Without treatment, CS due to PPNAD can be life-threatening.

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
Adrenal hyperplasia
Enlarged adrenal glands
0008221
30%-79% of people have these symptoms
Diabetes mellitus
0000819
Fatigue
Tired
Tiredness

[ more ]

0012378
Hypogonadism
Decreased activity of gonads
0000135
Increased susceptibility to fractures
Abnormal susceptibility to fractures
Bone fragility
Frequent broken bones
Increased bone fragility
Increased tendency to fractures

[ more ]

0002659
Muscle weakness
Muscular weakness
0001324
Short stature
Decreased body height
Small stature

[ more ]

0004322
Skeletal muscle atrophy
Muscle degeneration
Muscle wasting

[ more ]

0003202
Slender build
Thin build
0001533
5%-29% of people have these symptoms
Myopathy
Muscle tissue disease
0003198
Percent of people who have these symptoms is not available through HPO
Agitation
0000713
Anxiety
Excessive, persistent worry and fear
0000739
Autosomal dominant inheritance
0000006
Bruising susceptibility
Bruise easily
Easy bruisability
Easy bruising

[ more ]

0000978
Decreased circulating ACTH level
0002920
Depressivity
Depression
0000716
Hypertension
0000822
Increased circulating cortisol level
0003118
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
Onset
Age symptoms begin
0003674
Osteopenia
0000938
Osteoporosis
0000939
Paradoxical increased cortisol secretion on dexamethasone suppression test
0003466
Pigmented micronodular adrenocortical disease
0001580
Primary hypercortisolism
0001579
Psychosis
0000709
Round face
Circular face
Round facial appearance
Round facial shape

[ more ]

0000311
Striae distensae
Stretch marks
0001065
Thin skin
0000963
Truncal obesity
0001956

Diagnosis

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing Resources

  • Orphanet lists international laboratories offering diagnostic testing for this condition.

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.

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. 
    OMIM: Primary pigmented nodular adrenocortical disease-1
    OMIM: Primary pigmented nodular adrenocortical disease-2
    OMIM: Primary pigmented nodular adrenocortical disease-3
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Primary pigmented nodular adrenocortical disease. Click on the link to view a sample search on this topic.