Presentation: Patient with primary bilateral macronodular adrenal hyperplasia

A 39-year-old man is referred to the endocrine clinic with typical signs and symptoms of Cushing syndrome, i.e. hypertension and diabetes – its classical complications. He is found to have high levels of morning cortisol and this was not suppressed at overnight dexamethasone test. He had low levels of ACTH (adrenocorticotropic hormone) and DHEAS (dehydroepiandrosterone sulphate). Abdominal computed tomography (CT) revealed multiple bilateral irregular macronodular adrenal masses. He has no family history of adrenal disease or other endocrinopathies. A genetic test identified a pathogenic ARMC5 variant.

Genomic testing should be considered in every patient with bilateral adrenal masses and cortisol excess, independent of a confirmed or relevant family history of adrenal disease or other endocrinopathies, severity of the clinical phenotype, or presence of a syndromic presentation. Patients typically present with the following characteristics:

• radiological imaging suggestive of bilateral macronodular adrenal hyperplasia or bilateral adrenal adenomas; and
• biochemical and clinical evidence of ACTH-independent overt Cushing syndrome; and/or
• biochemical evidence of autonomous (ACTH-independent) cortisol secretion, i.e. mild autonomous cortisol secretion (MACS).

National Genomic Test Directory testing criteria for primary pigmented nodular adrenocortical disease (R160) are:

• primary pigmented nodular adrenocortical disease; or
• clinical diagnosis of ACTH-independent Cushing syndrome of unknown aetiology.

National Genomic Test Directory testing criteria for Carney complex (R156) are:

• two or more of the features from the list below (with histological confirmation where relevant); or
• one feature from the list below (with histological confirmation where relevant) and an affected first-degree relative:
  • spotty skin pigmentation with typical distribution (lips, conjunctiva, vaginal and penile mucosa);
  • myxoma (cutaneous and mucosal);
  • cardiac myxomas;
  • breast myxomatosis or fat-suppressed MRI suggestive of this finding;
  • PPNAD or paradoxical positive response of urinary glucocorticosteroid excretion to dexamethasone administration during Liddle’s test;
  • acromegaly due to GH-producing adenoma or hyperplasia;
  • large cell calcifying Sertoli cell tumour (LCCSCT) or characteristic calcification on testicular ultrasound;
  • thyroid carcinoma or multiple, hypoechoic nodules on thyroid ultrasound in a young patient;
  • psammomatous melanotic schwannomas (PMS);
  • blue nevus, epithelioid blue nevus;
  • breast ductal adenoma; and
  • osteochondromyxoma.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• For patients who meet test directory eligibility criteria, select one of the following:
  • R160 Primary pigmented nodular adrenocortical disease panel.
    • This panel currently comprises the following genes: ARMC5, PRKAR1A, PDE11A, PDE8B. The test involves small gene panel sequencing and exon-level copy number variation (CNV) detection.
  • R156 Carney complex.
    • This panel involves PRKAR1A single gene testing. For more information, see Patient with Carney complex.
• None of the tests described above include whole genome sequencing, so you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms.
• The majority of tests are DNA-based, and an EDTA sample (typically a purple-topped tube) is required. The sample is best stored at 4°C until it can be posted to the genomic laboratory.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

References:

• Bertherat J, Bourdeau I, Bouys L and others. ‘Clinical, Pathophysiologic, Genetic, and Therapeutic Progress in Primary Bilateral Macronodular Adrenal Hyperplasia‘. Endocrine Reviews 2022: volume 44, issue 4, pages 567–628. DOI: 10.1210/endrev/bnac034
• Cavalcante IP, Berthon A, Fragoso MC and others. ‘Primary bilateral macronodular adrenal hyperplasia: definitely a genetic disease‘. Nature Reviews Endocrinology 2022: issue 18, pages 699–711. DOI: 10.1038/s41574-022-00718-y

For patients

• Patient: Cushing’s syndrome