Cushing's syndrome due to bilateral nodular adrenal hyperplasia AND primary adrenal insufficiency

Carried by: FIRENDO

References:

Clinician(s): Pr Jérôme BERTHERAT, Pr Pascal BARAT

Biologist(s): Pr Eric PASMANT, Dr. Florence ROUCHER-BOULEZ

Presentation

Bilateral nodular adrenal hyperplasia is a rare cause of Cushing’s syndrome (excessive secretion of adrenal steroids). It includes two diagnostic categories: pigmented micronodular adrenal dysplasia (PPNAD) and bilateral macronodular adrenal hyperplasia (PBMAH).

Congenital primary adrenal insufficiency, a life-threatening condition, is linked to a deficiency in steroid hormones due to adrenal cortex dysfunction. Symptoms appear in the first few months of life, sometimes during childhood, and can be more or less specific: hypoglycaemia, salt loss, dehydration.

Criteria before considering a discussion in MDM-FMG

Cushing’s syndrome due to bilateral nodular adrenal hyperplasia:

Diagnostic criteria and hormonal and imaging investigations are detailed in the National Diagnostic and Care Programme (PNDS) for Cushing’s syndrome
Biologically proven ACTH-independent Cushing’s syndrome (CLU, midnight F, DXM suppression test, baseline ACTH and/or after CRH)
If patient has undergone surgery: confirmation of histological diagnosis of PPNAD or PBMAH
If patient has not undergone surgery: adrenal imaging reviewed in a multidisciplinary team meeting to obtain expert agreement on the diagnosis of Cushing’s syndrome due to bilateral adrenal involvement
Genetic testing for PRKAR1A, ARMC5, PRKACA, MENIN (NGS panel)

Primary Adrenal Insufficiency:

Characterisation of PAI:
- Age at diagnosis, family history and consanguinity, associated extra-adrenal manifestations
- In all patients: Na+, K+, ACTH, renin, cortisol, DHEAS, 17OH-Progesterone, (FSH, LH, T, E2, adrenal ultrasound)
- In all boys >3 years of age: very long chain fatty acids
- In cases of suspected autoimmune disease and depending on age: anti-adrenal or anti-21OH antibodies
- (In girls or 46XY with DSD: karyotype if ultrasound does not confirm normal ovaries and Müllerian structures, AMH)
Inconclusive analysis of first-line genes:
- In 2024: 23 genes in a short read panel ideally containing SRY to highlight phenotypic-chromosomal sex discordance: AAAS ABCD1 AIRE CDKN1C CYP11A1 DHCR7 GPX1 LGR4 MC2R MCM4 MRAP NGLY1 NNT NR0B1 NR5A1 POLE PRDX3 SAMD9 SGPL1 STAR TXNRD2 WNT4 ZNRF3
- Sanger: CYP11B2, CYP11B1, HSD3B2, CYP21A2 if hormonal test suggest such an enzyme block