Table 4.
Genetic disorders associated with adrenal tumors
| Genetic disorder | Affected gene (mode of inheritance) | Adrenal involvement | Extra-adrenal manifestations |
|---|---|---|---|
| Genetic disorders associated with pheochromocytomas | |||
| Von-Hippel-Lindau disease type 2 | VHL (autosomal dominant) | Pheochromocytomas are diagnosed in 10%-20% of patients and are often bilateral (~40%). Malignant cases have been reported. | • Hemangioblastomas of the brain and spine. • Retinal angiomas. • Renal cell cancer. • Pancreatic neuroendocrine neoplasms. • Pancreatic serous cystadenomas. • Endolymphatic sac tumors of the middle ear. • Papillary cystadenomas of the epididymis and broad ligament. |
| Multiple endocrine neoplasia syndrome type 2 | RET (autosomal dominant) | Pheochromocytomas are common (~50% of cases), often bilateral (~60%), and rarely malignant. |
MEN2A: • Medullary thyroid carcinoma. • Hyperparathyroidism. • Cutaneous lichen amyloidosis. • Hirschsprung disease. MEN2B: • Medullary thyroid carcinoma. • Mucocutaneous neuromas of the tongue, lips, and eyelids. • Marfanoid habitus. • Decreased upper/lower body ratio. • Kyphoscoliosis/lordosis. • Joint laxity. • Myelinated corneal nerves. • Intestinal ganglioneuromas, associated with constipation and megacolon. |
| Paraganglioma syndrome type 1 | SDHD (autosomal dominant; maternal imprinting) | Pheochromocytomas are found in 10%-25% of cases and can be bilateral. Malignancy is uncommon. | • Paragangliomas. • Renal cell cancer. • Pituitary adenomas. • GISTs. |
| Paraganglioma syndrome type 4 | SDHB (autosomal dominant) | Pheochromocytomas are found in ~25% of cases and can be bilateral. Malignancy is common (>40%). | • Paragangliomas. • Renal cell cancer. • Pituitary adenomas. • GISTs. • Pulmonary chondromas. |
| Paraganglioma syndrome type 5 | SDHA (autosomal dominant) | Pheochromocytomas are rare (very low penetrance). Bilateral disease and malignancy have been reported. | • Paragangliomas. • Pituitary adenomas. • GISTs. • Pulmonary chondromas. |
| MAX mutation | MAX (autosomal dominant) | Pheochromocytomas are often bilateral (60%-70%) and can be malignant (10%-25%). | Paragangliomas. |
| TMEM127 mutation | TMEM127 (autosomal dominant) | Pheochromocytomas are often bilateral (~40%). Moderate risk of malignancy (~10%). | Renal cell cancer. |
| Pheochromocytoma/paraganglioma-somatostatinoma-polycythemia syndrome | EPAS1 (somatic mosaicism) | Pheochromocytomas have been described. | • Paragangliomas. • Polycythemia. • Somatostatinoma. • Retinal abnormalities. • Organ cysts. |
| Genetic disorders associated with both pheochromocytomas and adrenocortical tumors | |||
| Neurofibromatosis type 1 | NF1 (autosomal dominant) | • Pheochromocytomas are diagnosed in 0.1%-6% of cases. They can be bilateral (~15%) and malignant (3%-12%). • poradic cases of adrenocortical carcinoma have been reported. |
• Central nervous system gliomas (especially of the optic pathway). • Café-au-lait spots. • Freckling. • Neurofibromas (can have malignant transformation). • Lisch nodules. • Short stature. • Scoliosis. • Cognitive deficits. • Seizures. • Macrocephaly. • Paragangliomas (rare). • Rhabdomyosarcomas. • GISTs. • Juvenile myelomonocytic leukemia. • Breast cancer. • Congenital heart disease. |
| Hereditary leiomyomatosis and renal cell cancer | FH (autosomal dominant) | • Adrenal masses have been observed in ~8% of cases. • Patients can present with bilateral adrenal tumors (~15%). Cases of ACTH-independent Cushing syndrome have been described. • Pheochromocytomas are rare. They can be bilateral and carry a moderate/high risk of malignancy. |
• Renal cell cancer. • Cutaneous leiomyomas. • Uterine leiomyomas. • Paragangliomas. |
| Beckwith-Wiedemann syndrome | Chromosome 11p15.5 region. Mostly sporadic disease. Familial transmission occurs in ~15% of cases. |
Adrenal involvement has been described only in children: • Adrenocortical adenomas and hyperplasia (including association with androgen and cortisol excess) are common. • Numerous cases of adrenal cysts. • Some cases of adrenocortical carcinomas. • Sporadic cases of pheochromocytoma (including bilateral disease). |
• Several childhood cancers, including Wilms tumor, hepatoblastoma, rhabdomyosarcoma, neuroblastoma. • Macrosomia. • Omphalocele. • Macroglossia. |
| Genetic disorders associated with adrenocortical carcinomas only | |||
| Li-Fraumeni syndrome | TP53 (autosomal dominant) | Accounts for 3%-7% of adrenocortical carcinoma cases in adults (50%-80% in children). Adrenocortical carcinoma is often the presenting malignancy of the syndrome. | Numerous malignancies, including brain, breast, and lung cancer, sarcomas, leukemias, choroid plexus tumors. |
| Lynch syndrome | MLH1, MSH2, MSH6, PMS2, EPCAM (autosomal dominant) | Accounts for 3% of adrenocortical carcinoma cases in adults. | • Numerous malignancies, including colorectal, endometrial, small bowel, genitourinary system, pancreatobiliary system, ovarian, stomach, brain, prostate. • Sebaceous skin neoplasms. • Keratoacanthomas. |
| Carney complex | PRKAR1A (autosomal dominant) | Cases of adrenocortical carcinomas reported. ACTH-independent Cushing syndrome secondary to primary pigmented nodular adrenocortical disease is much more common. | • Lentiginous skin pigmentation. • Cutaneous myxomas. • Thyroid nodules (including cancer). • Growth hormone hypersecretion, with or without evidence of pituitary adenoma/hyperplasia. • Cardiac myxomas. • Schwannomas. • Large cell calcifying Sertoli cell tumors (males). • Ovarian cysts and tumors. • Benign breast tumors. |
| Birt-Hogg-Dubé syndrome | FLCN (autosomal dominant) | Cases of adrenocortical tumors with uncertain malignant potential (oncocytomas) have been reported. | • Skin fibrofolliculomas. • Pulmonary cysts and spontaneous pneumothorax. • Renal oncocytomas. • Renal cell cancer. |
| Genetic disorders associated with both adrenocortical carcinomas and adenomas | |||
| Multiple endocrine neoplasia syndrome type 1 | MEN1 (autosomal dominant) | Adrenocortical tumors have been reported in ~10% of cases and can be bilateral (~15%). The risk of malignancy is high (~15%). Hormone hypersecretion is found in ~15% of cases (mainly primary aldosteronism and ACTH-independent Cushing syndrome). Cases of pheochromocytoma have been described, but this is an extremely rare occurrence. |
• Primary hyperparathyroidism. • Pituitary adenomas. • Neuroendocrine neoplasms. • Lipomas. • Facial angiofibromas. • Collagenomas. |
| Familial adenomatous polyposis | APC (autosomal dominant) | Adrenocortical adenomas have been described in 7%-13% of patients (including bilateral tumors in ~20% of cases). Rare cases of adrenocortical carcinomas have been reported. | • Colorectal polyps and cancer. • Upper gastrointestinal polyps. • Desmoid tumors. • Brain tumors. • Thyroid nodules and cancer. • Hepatoblastomas. |
| Genetic disorders associated with adrenocortical adenomas only | |||
| PBMAH from ARMC5 mutations | ARMC5 (autosomal dominant) | Most cases of PBMAH are sporadic. Germline mutations of ARMC5 are found in ~25% of all case of PBMAH. However, ~50% of those with PBMAH and severe Cushing syndrome and ~80% of those with a clear family history of PBMAH have a germline mutation. | Meningiomas have been described in patients harboring ARMC5 mutations. |
| Carney triad | Mostly unknown. Germline variants of SDHA, SDHB, or SDHC have been found in ~10% of cases. | It is sporadic and affects mostly young women. Adrenocortical adenomas have been described in 20% of cases (mostly nonfunctioning tumors). |
Triad: paragangliomas + GISTs + pulmonary chondromas. Other manifestations: esophageal leiomyomas. |
| Partial glucocorticoid resistance associated with bilateral adrenal hyperplasia | Heterozygous mutations of NR3C1, encoding for the glucocorticoid receptor | Mutations have been identified in 5% of patients with bilateral adrenal incidentalomas combined with hypertension and/or MACS. Patients with mutations: • Were younger and had a lower prevalence of hypertension than nonmutated patients. • All but one failed the 1-mg DST. • All but 1 had higher urinary free cortisol excretion than nonmutated patients. • All but 1 had normal or high ACTH levels. • Had lower potassium (<4 mEq/L), renin, and aldosterone (<2.7 ng/dL) levels than patients without mutations. |
Patients typically lack clinical hypercortisolism or hyperandrogenism and present incidentally with bilateral adrenal enlargement. The combination of low potassium, low aldosterone, elevated urinary free cortisol, and abnormal 1-mg DST are clues to the diagnosis. |
Abbreviations: 1-mg DST, 1-mg overnight dexamethasone suppression test; ARMC5, Armadillo Repeat Containing 5 gene; GIST, gastrointestinal stromal tumor; MACS, mild autonomous cortisol secretion; PBMAH, primary bilateral macronodular adrenal hyperplasia.