Introduction
Cushing syndrome is a collection of symptoms and signs brought on by prolonged and excessive exposure to glucocorticoids, whether as a result of endogenous endocrinopathies or, more frequently, external pharmaceutical sources. Adrenocorticotropin hormone, uncommon tumors that secrete the corticotropin-releasing hormone, or autonomous cortisol production from the adrenal glands without the help of adrenocorticotropin hormone can all cause endogenous Cushing syndrome. For most cases of adrenocorticotropic hormone-independent Cushing syndrome, solitary cortisol-producing adenomas are responsible. Cortisol-producing adenomas have been discovered to be caused by mutations in the gene encoding the protein kinase A catalytic subunit (cortisol-producing adenomas).
In both primary bilateral macronodular adrenal hyperplasia and micronodular adrenocortical disease, somatic mutations of the gene encoding phosphodiesterase 8B have been reported. In cortisol-producing adenomas, somatic PRKAR1A and GNAS (guanine nucleotide-binding protein, alpha-stimulating) mutations have been discovered (cortisol-producing adenomas). The somatic mutation of the protein kinase cAMP-activated catalytic subunit (PRKACA, which codes for the C subunit of PKA) was found to be present in roughly 40 percent of cortisol-producing adenomas in 2014, according to numerous studies. The loss of contact with the R subunits is the result of every PRKACA mutation discovered in cortisol-producing adenomas to date, which elevates overall PKA activity.
How Does Chronic Exposure to Glucocorticoid Affect the Body?
Numerous consequences are brought on by prolonged exposure to glucocorticoids, such as:
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Visceral obesity (abdominal fat that is deeply buried).
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Dyslipidemia (abnormally high blood lipids or cholesterol).
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Hypertension (excessive blood pressure against the arterial walls).
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Diabetes mellitus (high blood glucose level).
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Osteoporosis (a disorder that causes brittle, weakened bones).
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Myopathy (muscle fiber malfunction results in muscle weakness).
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Recurrent infections (recurring infections are typically brought on by an underlying) immunosuppressive condition).
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Altered mental status (an alteration of mental state).
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Thrombosis (blood clots that obstruct veins or arteries cause this condition).
Rarely, overt corticosteroid (OCS) is distinguished by pathognomonic illness symptoms such as:
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Buffalo hump (buildup of fat on the back of the neck).
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Moon face (fat deposits cause the face to appear rounded).
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Pink or purple skin striae (stretch marks are the indented streaks).
Mild autonomous cortisol excess is the term used to describe mild hormonal indicators of cortisol overproduction without syndrome-specific clinical symptoms. However, strong evidence demonstrates that even mild hypercortisolism is linked to metabolic, skeletal, and cardiovascular issues. Affected by adrenal incidentalomas in 0.2 percent to 2 percent of adults, mild autonomous cortisol excess is the most prevalent type of hormonal excess.
What Are the Genes Associated With Cortisol-Producing Adenomas?
The development of next-generation sequencing has made it possible to identify somatic mutations that lead to cortisol-producing adenomas producing cortisol on their own. The PRKACA gene, which is responsible for the catalytic subunit of protein kinase A, is the most frequently changed gene associated with overt Cushing syndrome cases thus far (PKA). Somatic hot spot mutations in PRKACA activate PKA in a constitutive manner, phosphorylating downstream substrates and boosting cortisol synthesis. Catenin (CTNNB1), the stimulatory G protein's - subunit (GNAS), and the gene encoding the PKA type I- regulatory subunit are additional genes in cortisol-producing adenomas that are affected (PRKAR1A). However, it is still unknown what causes more than 50 percent of cortisol-producing adenomas to be genetic.
How Are Cortisol-Driver Somatic Mutations Distributed in Cortisol-Producing Adenomas?
In 56 of the 78 cortisol-producing adenomas (71.8 percent), the CYP17A1-HSD3B2 IHC-guided targeted amplicon sequencing method discovered known cortisol-producing adenoma-related somatic alterations. Immunohistochemistry results for cortisol-producing adenoma with known gene mutations (CTNNB1, PRKACA, and GNAS) revealed a high expression of CYP17A1 and HSD3B2. According to targeted amplicon sequencing, the gene with the most frequent mutations was CTNNB1 (33/78; 42.3 percent). GNAS (7/78; 9.0 percent) and PRKACA (16/78; 20.5 percent) are followed.
The most frequently mutated gene in cortisol-producing adenomas from overt Cushing syndrome patients (Cushing syndrome patients cortisol-producing adenoma) was PRKACA (14/32, 43.8 percent), according to mutation patterns between the two adrenal Cushing syndrome subtypes. On the other hand, CTNNB1 (26/46, 56.5 percent) exhibited the highest genetic abnormalities in cortisol-producing adenomas from mild autonomous cortisol excess patients. The majority of the PRKACA and CTNNB1 mutations were found at the known cortisol-dysregulating mutational hot sites in cortisol-producing adenomas, p.L206R, and p.S45P, respectively. All guanine nucleotide-binding protein, alpha-stimulating mutations (n = 7) were found in cortisol-producing adenomas from females, and 71.4 percent of these mutations were found in mild autonomous cortisol-excess cortisol-producing adenomas. Five of the six Guanine nucleotide-binding protein, alpha-stimulating mutations occurred at the position 201 recognized hot spot arginine residue.
What Is Adrenocorticotropic Hormone Independent Cushing Syndrome?
The pituitary gland, a little gland near the brain's base, produces the adrenocorticotropic hormone. Another hormone called cortisol is produced under the direction of the adrenocorticotropic hormone. The adrenal glands, two tiny glands positioned above the kidneys, produce cortisol. The doctor will then assess the blood level of adrenocorticotropic hormone if these tests reveal elevated cortisol levels. Cortisol levels are high, and adrenocorticotropic hormone levels are normal or elevated in Cushing's illness. If these findings are made, then an MRI (magnetic resonance imaging) scan of the pituitary gland will be done to identify any malignancies.
Adrenocorticotropic hormone-dependent and adrenocorticotropic hormone-independent etiologies can cause endogenous Cushing syndrome; the latter accounts for 15 percent to 20 percent of cases and is typically brought on by unilateral adrenal adenomas or adrenal carcinomas coupled with autonomous adrenal cortisol release. Bilateral adrenocortical lesions, such as bilateral primary pigmented nodular adrenocortical disease (PPNAD), bilateral adrenocorticotropic hormone-independent macronodular adrenal hyperplasia (AIMAH), unilateral functional adenoma with a contralateral non-functional mass, and bilateral adrenocortical tumors, are occasionally the cause of adrenocorticotropic hormone-independent Cushing syndrome.
Conclusion
As seen in growth hormone-producing pituitary adenoma and lethal thyroid adenoma, constitutive activation of the PKA pathway causes tumor formation and endocrine over function. The most common reason for adrenocorticotropic hormone-independent Cushing syndrome is cortisol-producing adenoma. In addition to the usual clinical picture, overt Cushing syndrome is linked to serious comorbidities and higher mortality. Intriguingly, patients with PRKACA mutations present younger at diagnosis have higher cortisol levels and lower tumor sizes than cortisol-producing adenomas without mutations. The adenoma size appears to be bigger than described for the PRKACA mutation, but the present patient also had an overt Cushing syndrome and was young at the time of diagnosis. This may align with the additional oncogenic role PRKACB has been assigned.
