Table 2.
Characteristics and presentation of patients with genetic syndromes associated with Cushing syndrome.
| Genetic syndrome | Type of CS | Gene(s) | Gene locus | Approximate frequency of CS in patients with the genetic syndrome | Clinical presentation |
|---|---|---|---|---|---|
| Multiple Endocrine Neoplasia type 1 (MEN1) | Cushing disease, ACTH-independent CS or ectopic CS | MEN1 | 11q13.1 | Cushing disease: 1% ACTH-independent CS: 2.5–5.5% | Tumors of anterior pituitary gland, parathyroid glands, pancreatic islet cells and others |
| Multiple Endocrine Neoplasia type 2A/2B (MEN2A/2B) | Cushing disease or ectopic CS | RET | 10q11.21 | Rare case reports | Medullary thyroid carcinoma with pheochromocytoma and hyperparathyroidism (MEN2A) or mucosal neuromas and intestinal ganglioneuromas (MEN2B) |
| Multiple Endocrine Neoplasia type 4 (MEN4) | Cushing disease | CDKN1B | 12p13.1 | 1 case reported | MEN1-like syndrome |
| Familial Isolated Pituitary Adenomas (FIPA) | Cushing disease | AIP (15–30% of cases) | 11q13.2 | 5% of FIPA patients | Presence of at least two family members with PAs, with or without other abnormalities |
| Carney complex (CNC) | ACTH-independent CS, rare cases of Cushing disease | PRKAR1A | 17q24.2 | ACTH-independent CS: 60% CD: Rare case reports | Myxomas, spotty skin pigmentation, endocrine overactivity and other tumors |
| McCune-Albright (MAS) | ACTH-independent CS, rare cases of Cushing disease | GNAS | 20q13.32 | Up to 7% | Polyostotic fibrous dysplasia, café-au-lait macules, and precocious puberty, and other endocrine disorders |
| Beckwith-Wiedemann syndrome (BWS) | ACTH-independent CS, rare cases of Cushing disease | IGF2, H9 and CDKI | 11p15 | Rare case reports | Hemihypertrophy, macrosomia, macroglossia, predisposition to embryonic tumors and others |
| Li-Fraumeni syndrome (LFS) | ACTH-independent CS | TP53 | 17p13.1 | 6–13% of patients (frequency referring to adrenocortical carcinomas) | Predisposition to various tumors at early age, including soft tissue sarcoma, osteosarcoma, brain tumors, breast cancer, melanoma and others |
| DICER1 | Cushing disease | DICER1 | 14q32.13 | Rare | Pleuropulmonary blastomas, cystic nephromas, Sertoli-Leydig cell tumors, multinodular goiter, and other tumors |
| 3 P association (3PA) | Cushing disease | SDHx, VHL, MEN1, RET and MAX | Various | 1 case reported | 3Ps: Pituitary adenomas, Pheochromocytomas and/or Paragangliomas |
| Tuberous sclerosis (TS) | Cushing disease | TSC1, TSC2 | 9q34.13 (TSC1) 16p13.3 (TSC2) | Rare case report | Hamartomas, epilepsy and mental retardation |
| USP8 germline syndrome | Cushing disease | USP8 | 15q21.2 | 1 patient reported (100% penetrance hypothesized) | Cushing disease, developmental delay, dysmorphic features, skin defects, chronic lung disease, chronic kidney disease, dilated cardiomyopathy with congestive heart failure (CHF) and others |