ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This brief and concise Consensus statement by the French Society of Endocrinology (SFE) and French Society of Pediatric Endocrinology & Diabetology (SFEDP), describes a systematic review and provides recommendations for the use of genetic screening in Cushing’s syndrome (CS).

Comment: The etiology of CS may involve both germline genetic alterations (detectable in leukocyte DNA) and somatic mutations (present only in tumor DNA). Two main pathways are altered in adrenal tumorigenesis: the catenin pathway and the cAMP/PKA pathway. Activation of the catenin pathway is involved mainly in adrenal tumors, particularly non-functional adenomas associated with moderate autonomous cortisol secretion and adrenocortical carcinomas (1, 2). Endogenous CS is due either to an ACTH-dependent source, most commonly pituitary adenomas (PAs), described as Cushing disease (CD), or less often ectopic CRH and/or ACTH secretion, or ACTH-independent (adrenal-related) hypercortisolemia (3).

Consideration of genetic evaluation follows identification of the type of CS. Germline mutations (typically in tumor-suppressor genes) in patients with ACTH-independent CS may explain more than half of the cases depending on the specific adrenal pathology (3). Tumor suppressor genes are inactivated according to Knudson’s theory (4). An initial germline loss-of-function mutation (predisposition) is followed by a later somatic mutation (i.e., in the tumor), which may be a point mutation but is more often a gene deletion, resulting in “loss of heterozygosity” (4).

Given the rarity of genetic forms of Cushing’s disease, there are currently insufficient data to recommend family genetic screening for isolated Cushing’s disease, particularly in case of AIP mutations identified mainly in a sporadic context. For other genetic alterations responsible for CS, family genetic screening should be carried out according to the recommendations specific to each pathology. Thanks to recent technological advances, more and more genes are being identified as associated with Cushing’s syndrome. Germline mutations are observed in around 50% of Cushing’s syndrome of adrenal origin, depending on etiology, although this still concerns fewer than 5% of cases of Cushing’s disease. Genetic testing is currently recommended in all cases of bilateral adrenal disease, as well as in all familial and/or pediatric forms of Cushing’s syndrome of adrenal or pituitary origin. However, for a number of genes responsible for Cushing’s syndrome, it is unclear whether taking these genetic alterations into account would modify the management of patients and their families.

References: 1. Berthon A, Stratakis CA. From beta-catenin to ARM-repeat proteins in adrenocortical disorders. Horm Metab Res. 2014; 46(12): 889-96.2. Espiard S, Ragazzon B, Bertherat J. Protein kinase A alterations in adrenocortical tumors. Horm Metab Res. 2014; 46(12): 869-75.3. Tatsi C, Flippo C, Stratakis CA. Cushing syndrome: Old and new genes. Best Pract Res Clin Endocrinol Metab. 2020; 34(2): 101418.4. Chernoff J. The two-hit theory hits 50. Mol Biol Cell. 2021; 32(22): rt1.