Clinical genetics - Special cases What are the Molecular genetics & Clinical genetics of Cushing syndrome? - Special cases Dr. Carling, Editorial note: Do not start reading about adrenal tumors here. These are rare conditions, and the likelihood that you have what is known as a “Inherited Genetic Tumor-Susceptibility Syndrome” is very low. However, special genetic cases of adrenal tumors do occur, and I have personally focused my scientific efforts on this area since I was in my early 20s as a medical student (Yes, I know, decades ago now...). So, I know about these rare diseases, how they can be diagnosed, managed, and treated. Also, importantly, nowadays, genetic testing is widely available, but again underutilized because of lack of knowledge, occasional fear. However, genetic testing, if positive can make us treat tumors and cure them in the patients, but also their children and other family members, even before they occur, and a negative test can bring enormous relief and save the patient and family members unnecessary and costly imaging scans and tests. Risk assessment and management Tumors that arise from adrenocortical cells are often benign adrenocortical adenomas but adrenocortical carcinomas (ACC) do rarely occur. No clear environmental risk factors have been identified for either adrenocortical adenoma or adrenal cancer. Both adrenocortical adenoma and adrenal cancer are associated with tumor susceptibility syndromes including MEN1, Carney complex, McCune-Albright syndrome, Gardner’s syndrome, Beckwith-Wiedemann syndrome, and neurofibromatosis type 1. Adrenal masses presenting in children, adolescents, and young adults have a higher chance to be manifestations of one of these syndromes and carry a higher risk for malignancy. Most adrenocortical adenomas and adrenal cancer s are non-functional, meaning they do not cause detectable hormone excess. Most adrenal lesions are discovered incidentally on imaging obtained for another reason. These have been termed adrenal “incidentalomas”. Adrenal lesions may also be discovered during the workup of an endocrine disorder. Patients with biochemical evidence of hypercortisolism, hyperaldosteronism, and catecholamine excess should have the adrenal glands imaged with either thin-slice (“adrenal-protocol”) abdominal CT with and without IV contrast or multiplanar MRI. (Read more about adrenal imaging here.) All patients with a newly discovered adrenal incidentaloma (a tumor found without signs and symptoms of adrenal hormone overproduction) should undergo biochemical screening for clinical and subclinical Cushing syndrome as they are the most commonly associated endocrine abnormalities. Testing for Cushing syndrome is done as described above (here) Patients with incidentalomas who also have known hypertension or hypokalemia should be evaluated for an aldosteronoma by measuring plasma aldosterone to renin activity ratio. Testing for primary hyperaldosteronism is done as described above (here). If a pheochromocytoma is suspected, plasma free metanephrines and normetanephrines should be measured. Elevated levels should be confirmed with 24-hour collection of urine fractionated metanephrines and catecholamines (Read more here). Testing for sex hormone excess is typically not indicated, although the European Society of Endocrinology recommends testing for DHEA-S, androstenedione, 17-hydroxyprogesterone, testosterone for women, and estradiol for men and post-menopausal women if there are clinical signs of virilization or suspicion for adrenal cancer (Read about ACC: Adrenocortical carcinoma here). Adrenocortical carcinoma is associated with over half of cases with elevated sex hormone or sex hormone-precursor levels. Biopsy of an adrenal lesion is not recommended unless there is suspicion that it may be a metastasis from another primary cancer. In this case, pheochromocytoma must be ruled out prior to the biopsy. Disease-specific Epidemiology The reported incidence of adrenal incidentalomas varies between 2-3% of the general population based on the inclusion criteria of the study and whether it was a surgical or nonsurgical series. The true incidence of adrenal adenomas is unclear as screening for such masses is not routine. Extrapolation from autopsy studies indicates about a 2% incidence of adrenal masses while radiological studies have reported up to 10% frequency in elderly population. Adrenal masses in childhood are very rare and typically syndromic (meaning a “Inherited Genetic Tumor-Susceptibility Syndrome”). Most incidentalomas will be found to be benign adenomas— adrenocortical carcinoma is a rare disease with only about 1-2 cases per 1 million patients per year. Many genetic abnormalities have been discovered in adrenocortical adenomas and Adrenal Cancers. Many of these studies have been performed by Dr. Carling and his colleagues. Somatic mutations of β-catenin (CTNNB1) have been associated with all 3 forms of adrenocortical adenoma as well as Adrenal Cancer. Mutations of PRKACA and GNAS have been identified in Cortisol-producing adrenal adenoms. These genes encode for proteins involved in the protein kinase A pathway that regulates ACTH (adrenocorticotropic hormone; the pituitary hormone controlling the cortisol release from the adrenals) response and cortisol production. NFAs are less well-studied given that they are rarely symptomatic and do not usually require treatment. NFAs with CTNNB1 mutations have been found to be larger on average. Germline mutations in PRKAR1A, PDE11A, and PDE8B have been found to be associated with adrenal micronodular hyperplasia. Although some have proposed an adenoma-to-carcinoma pathway linking adrenocortical adenomas and carcinomas, this has not been proven and is still a subject of controversy. Adrenal Cancer tends to harbor a myriad of somatic genetic aberrations including aneuploidy and hypermethylation. Defects in IGF signaling, especially very high levels of IGF2, are also associated with adrenal Cancer, as evidenced by the increased risk of adrenal Cancer in Beckwith-Wiedemann syndrome. Mutations of genes in the Wnt/β-catenin pathway such as CTNNB1 and ZNRF3, as well as other cell-cycle regulatory genes including TP53 and RB1 are commonly found in adrenal cancer. Disease-specific Approach to Risk Assessment, Counseling, and Testing As many as 5-10% of Adrenal Cancers harbor germline mutations and are part of an “Inherited Genetic Tumor-Susceptibility Syndrome”. As adrenal cancer can be the presenting tumor of these syndromes, it is important to identify syndromic patients in order to screen them for other associated tumors. Adrenal cancer presenting in childhood is highly suspicious for a genetic syndrome. 50-80% of children with adrenal cancer will be found to have a germline TP53 mutation and be diagnosed with Li-Fraumeni syndrome. Up to 3% of adrenal cancers are associated with DNA mismatch repair mutations and Lynch syndrome. 1-2% of adrenal cancers are associated with MEN1. Syndromes less often associated with adrenal cancer include familial adenomatous polyposis, Beckwith-Wiedemann, neurofibromatosis type 1, and Carney complex. The discovery of a high prevalence of germline TP53 mutations in patients with adrenal cancer has led to the recommendation that all patients diagnosed with adrenal cancer undergo testing for a TP53 mutation regardless of family history. Similarly, it has been suggested that adrenal cancer patients be screened for DNA mismatch repair mutations. Some authors advocate for multigene panels to evaluate for germline mutations in all patients diagnosed with adrenal cancer. The discovery of a germline mutation in a patient should prompt evaluation of other at-risk members of the family. Hereditary Cancer Syndromes Li-Fraumeni Syndrome LFS is caused by pathogenic mutations in the tumor suppressor gene TP53 that predisposes to sarcomas, leukemias, brain cancers, breast cancers, lung cancers, and choroid plexus tumors in addition to adrenocortical cancers. It is estimated to have a prevalence of 1:20,000 to 1:1,000,000 and is higher in certain areas such as Southern Brazil due to founder’s effect. 50-80% of all children with adrenal cancer will be found to have LFS but only 3-10% of children with LFS will develop adrenal cancer. The risk for adrenal cancer in LFS appears to decrease with age. Affected children are also at risk for developing precocious puberty and Cushing syndrome secondary to hormone excess. Classic Li-Fraumeni syndrome is diagnosed by molecular genetic testing for a pathogenic TP53 mutation or clinically by the presence of all 3 diagnostic criteria: sarcoma diagnosed before age 45, first-degree relative with any cancer before age 45, and first- or second-degree relative with any cancer before age 45 or sarcoma at any age. LFS should also be suspected in women with early-onset breast cancer who tested negative for BRCA1 and BRCA2 pathogenic variants and any individual who meets the Chompret criteria for TP53 testing. Patients who meet any 1 of the 3 Chompret criteria below has at least a 20% chance of testing positive for a TP53 mutation: diagnosis of a tumor belonging to the LFS tumor spectrum before age 46 with a first- or second-degree relative also with a LFS tumor (except breast) diagnosed before age 56; diagnosis of multiple tumors (except breast), two of which belong to the LFS tumor spectrum, the first of which presented before age 46; and diagnosis of adrenal cancer or choroid plexus tumor. Lynch syndrome Lynch syndrome is due to defects in the DNA mismatch repair proteins PMS2, MSH2, MSH6, and MLH1. It has an estimated prevalence of 1 in 440 amongst the general population and is most often associated with colorectal cancers and endometrial cancers. While adrenal cancer has been associated with Lynch syndrome, the risk that a patient with Lynch syndrome will develop adrenal cancer remains very low. Beckwith-Wiedemann syndrome Beckwith-Wiedemann syndrome (BWS) is associated with abnormal IGF2 signaling caused by alteration of gene transcription in the “BWS critical region” on chromosome 11p15.5. About 85% of cases are sporadic. BWS may be caused by gene mutations or methylation and imprinting abnormalities within the BWS critical region. When the specific genetic or genomic abnormality is not known, investigational testing can involve DNA methylation studies, single-gene testing, copy number analysis, karyotyping and multigene panels. There are no consensus clinical diagnostic criteria for BWS. It is characterized by macrosomia, macroglossia, hemihyperplasia, metabolic abnormalities, visceromegaly and renal abnormalities. Individual phenotypes vary, and a patient may have many or only a few of the above features. BWS is associated with several types of neoplasia, most commonly Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma and adrenocortical tumors. Up to 1% of children with BWS develop adrenal cancer, but the adrenal tumors in BWS may also be benign adenomas and cysts. The risk of developing any BWS tumor ranges from 4-21% and is highest in early childhood. This risk decreases with age and tumors are rarely diagnosed after the age of 8. MEN1 MEN1 is rarely associated with adrenocortical tumors. Adrenal manifestations can occur in the form of benign enlargement, adrenocortical adenoma or adrenal cancer. About 1-2% of adrenal cancer are associated with MEN1 gene mutations. Most MEN1 patients with adrenal cancer will already have other signs and symptoms of MEN1 such as hyperparathyroidism, pituitary or gastro-enteropancreatic tumors. Adrenal tumors in MEN1 are most frequently non-functioning. There have been case reports of MEN1 patients with benign adrenal tumors who later developed adrenal cancer, suggesting an adenoma to carcinoma transformation. Please read further at here and at our sister sites parathyroid.com and thyroidcancer.com about MEN1 and MEN2, and how they can develop parathyroid tumors and medullary thyroid cancer. Carney Complex Primary pigmented nodular adrenal disease is common in patients with CNC and causes clinically evident Cushing syndrome in about 70% of affected females and 45% of affected males before age 45. Cushing syndrome may be atypical in these patients due to only intermittent production of cortisol, and it is recommended that patients be evaluated with diurnal cortisol levels or dexamethasone-stimulation test and adrenal imaging rather than urine cortisol levels alone. For additional information on CNC-associated tumors, see Carney Complex under “Non-medullary Thyroid Cancer”. Clinical Management of Patients at Increased Risk Li-Fraumeni Syndrome There are no consensus guidelines for screening of adrenal cancer in LFS, but some have advocated for abdominal ultrasounds and biochemical testing (17-OH-progesterone, androstenedione, testosterone, DHEA-S, 24-hour urine cortisol) every 3-4 months starting from birth until age 40. Any tumors that are discovered should be managed according to the usual guidelines regarding that tumor. However, adjuvant radiation should be avoided if the benefit is unclear as it may increase the risk for developing other malignancies. MEN1 Screening for adrenal tumors can be performed concurrently with GEP-NETs with cross-sectional abdominal imaging every 3-5 years. Adrenal tumors detected in MEN1 patients should be managed similarly to an incidentaloma and undergo complete endocrine workup with a higher baseline suspicion for malignancy. Additional guidelines for the management of patients with MEN1 syndrome can be found at our sister site parathyroid.com. Beckwith-Wiedemann syndrome Patients with BWS should undergo routine surveillance following diagnosis. A baseline whole-body MRI or CT should be obtained at time of diagnosis. Abdominal ultrasounds should be obtained every 3-4 months until age 4 to evaluate for any visceral tumors. Serum AFP should be measured every 6 weeks to 4 months until age 4. Kidney and adrenal ultrasounds should be continued every 3-4 months until age 8 to evaluate for Wilms and adrenal tumors. Lynch syndrome and FAP Although patients with Lynch syndrome or FAP may have higher than average risk for developing adrenal tumors, their risk remains sufficiently low that no dedicated screening recommendations exist for adrenal tumors.