SLP Report: Endocrine - Cushing Syndrome in Children PDF

BIOMEDICAL SCIENCE FACULTY OF HEALTH SCIENCE UNIVERSITI KEBANGSAAN MALAYSIA YEAR 3 SEMESTER 3 SESSION 2023/2024 NNNB 3352 ENDOCRINE BIOCHEMISTRY DISEASES SLP REPORT TITLE : ENDOCRINE - CUSHING S...

BIOMEDICAL SCIENCE FACULTY OF HEALTH SCIENCE UNIVERSITI KEBANGSAAN MALAYSIA YEAR 3 SEMESTER 3 SESSION 2023/2024 NNNB 3352 ENDOCRINE BIOCHEMISTRY DISEASES SLP REPORT TITLE : ENDOCRINE - CUSHING SYNDROME IN CHILDREN LECTURER’S NAME : DR. NURUL FARHANA JUFRI GROUP 5 NO NAME MATRIC NO 1 ALEXANDER ROMAN ETOR A189208 2 NURUL ADILA BINTI SYARIF A188750 3 AGNES GOH CHU EN A187754 4 THEENISCHA A/P MAGESWARAN A189114 1. BACKGROUND Cushing syndrome in children, also known as hypercortisolism, is a condition that happens when there is too much of a hormone called cortisol in the child’s body. Cortisol is synthesized from cholesterol. It is the primary stress hormone produced mainly by the zona fasciculata of the adrenal cortex in an adrenal gland. Cortisol plays an important role in regulating the child’s body stress response. For instance, cortisol is released after adrenaline in “fight or flight’ situations to stay alert. It increases the level of gluconeogenesis which inhibits the uptake of glucose in insulin-sensitive tissues and allows the body to repair tissues. Aside from that, cortisol helps to control the body pressure and reduce inflammation. However, when the child’s body produces too much cortisol, it can disrupt puberty and cause growth deceleration, weight gain, facial plethora, and other conditions. 2. EPIDEMIOLOGY Cushing syndrome (CS) is a rare endocrine disorder in the pediatric population, representing about five to ten percent of all cases of endogenous Cushing syndrome. The incidence of Cushing disease, a specific form of CS caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, is estimated to be one to two cases per million children each year. Most affected individuals are between the ages of five and fifteen, with a slight female predominance. The epidemiology of Cushing syndrome in children highlights the distinct characteristics of this disorder compared to adults. While Cushing syndrome is more prevalent in adults, particularly in the context of Cushing disease, pediatric cases often present differently. In children, the most frequent cause of endogenous Cushing syndrome is ACTH overproduction from pituitary adenomas, whereas adults may have larger pituitary adenomas or other causes such as adrenal tumors. From a molecular aspect, cortisol acts through the glucocorticoid receptor (GR), which is present throughout the body. When cortisol binds to the GR, the receptor translocates to the nucleus, where it regulates the expression of genes involved in metabolism, immune function, and stress response. The production of ACTH is  controlled by corticotropin-releasing hormone (CRH) released from the hypothalamus. In cases of Cushing disease, the excessive production of ACTH from pituitary adenomas leads to an overproduction of cortisol by the adrenal glands, which in turn causes the symptoms associated with Cushing syndrome. Additionally, genetic mutations may contribute to the development of Cushing syndrome, especially in cases linked to familial syndromes such as multiple endocrine neoplasia (MEN) and Carney complex, which can increase the likelihood of developing adrenal tumors or pituitary adenomas. 3. ETIOLOGY It is known that Cushing syndrome in pediatricians both males and females are uncommon and evenly distributed either influenced by: a) endogenous or b) exogenous type. Mostly exogenous or iatrogenic types are the common cause due to chronic administration of glucocorticoids or ACTH (Lodish et al. 2018). In treatment settings, glucocorticoids are mostly used as non-endocrine disease while ACTH is a seizure disorder. Although pediatric patients diagnosed from endogenous type are odd, they are still significant due to pituitary adenomas (Cushing disease), adrenal tumors, or ectopic ACTH production. This uncommon but significant occurrence can impact a patient's life because of slow onset making it more challenging for early diagnosis and treatment of Cushing syndrome. (a) Endogenous Cushing syndrome Endogenous Cushing syndrome can be classified into two subtypes: i) ACTH-dependent and ii) ACTH-independent. The common cause for endogenous disease mostly comes from ACTH-dependent types which refer to the Cushing disease. This is because pituitary overproduces ACTH in the system due to ACTH-secreting pituitary microadenoma. Cushing disease reportedly occurs in children ≥7 years old. While for infants, Cushing syndrome mostly persists due to ACTH-independent adrenal is the cause either from unilateral or bilateral adrenal factors. Ectopic Cushing syndrome (ECS) in adolescence also is rare due to pituitary adenoma overproducing ACTH thus this hallmark is much less common in this  age group. This overproduces ACTH mainly caused by the mechanism of neuroendocrine tumors, for example bronchial carcinoids or thymic tumors that are commonly seen in adults. Although, this clinical presentation is significant as a differential diagnosis for adolescents, typically when ruling out or excluding ECS sources that yield misleading results when CRH-induced ACTH oversecretion is included. (b) Exogenous Cushing syndrome Exogenous Cushing syndrome in adolescents is primarily caused by the prolonged use of synthetic glucocorticoid medication. These medications are commonly used to treat a variety of conditions, including asthma, autoimmune diseases, inflammatory bowel disease, certain cancers and after organ transplants. This prolonged medication can mimic the effects of cortisol and lead to suppression of the hypothalamic-pituitary adrenal (HPA) axis that decreases the body’s natural cortisol production. Increased levels of cortisol in the body cause characteristic symptoms of Cushing syndrome. 4. STRESS PATHOPHYSIOLOGY IN TERMS OF ENDOCRINOLOGY  Figure 4.1 Synthesis of glucocorticoids Cushing syndrome in children is mainly caused by dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which is central to the body's response to stress. Paraventricular nucleus (PVN) of the hypothalamus, which is a part of the HPA axis, regulates the release of corticotropin-releasing hormone (CRH). The CRH will stimulate the anterior pituitary gland to release adrenocorticotropic hormone (ACTH), which will then trigger the adrenal gland through ACTH receptors and melanocortin 2 receptor (MC2R) to release cortisol, a glucocorticoid hormone. The MC2R/ACTH receptors are facilitated by melanocortin receptor accessory protein 1 (MRAP1). When there is dysregulation of the HPA axis, the release of CRH will increase. Large amount of ACTH will be stimulated to release an increased number of cortisol. Figure 4.2 Mechanism of steroidogenesis Aside from that, pituitary adenoma has also significantly affected children with Cushing syndrome. A pituitary adenoma is a benign tumor on the pituitary gland. This specific tumor will affect the secretion of ACTH, where it makes excessive ACTH. This will stimulate the adrenal gland to produce and release too much cortisol.  In normal conditions, cortisol levels are controlled by negative feedback, where high levels of cortisol actually inhibit the release of CRH and ACTH. Nevertheless, in children with Cushing syndrome, there is a blunting of the normal feedback inhibition of the HPA axis. Thus, they often have an impaired response to additional stress. Elevated baseline cortisol levels may suppress the normal ACTH and cortisol response to stress and lead to inadequate stress adaptation. Moreover, high cortisol levels will further interfere with other endocrine systems, including growth hormone secretion, gonadotropin release, and thyroid function, thereby giving rise to a wider spectrum of symptoms beyond those expected from the direct effects due to excess cortisol. In addition, psychological stress does play a key role in the pathophysiology of Cushing syndrome, particularly in its psychiatric presentations. It is eventually possible that symptoms of anxiety and depression could develop with chronic hypercortisolism. Those parts of the brain that play a role in mood regulation, such as the hippocampus and prefrontal cortex, are highly sensitive to cortisol levels. Continuous exposure to high cortisol may cause changes at a structural and functional level in these regions of the brain, leading to enhanced stress responses and more psychiatric symptoms. 5. CLINICAL FEATURES The clinical features of Cushing syndrome in children can be subtle and variable, often leading to delayed diagnosis. Common clinical features include growth retardation, which occurs as children with Cushing syndrome may experience stunted growth due to the catabolic effects of excess cortisol on bone and muscle. The clinical features of Cushing syndrome in children frequently differ from those observed in adults. Children are more likely to experience significant growth retardation, increased body weight, and noticeable changes in physical appearance resulting from prolonged exposure to elevated cortisol levels. In adults, hypertension and metabolic syndrome are more commonly reported. The long-term effects of hypercortisolism in children can substantially hinder growth and development, potentially leading to reduced final height and various metabolic complications.  Obesity is another prominent feature, characterized by central obesity with increased fat deposition in the abdomen and face, often referred to as "moon facies." Skin changes are also common; patients may exhibit thinning of the skin, easy bruising, and striae, which are purple stretch marks, particularly on the abdomen and thighs. Psychological disturbances can significantly impact the quality of life for affected children. They may experience mood swings, anxiety, and depression, which can complicate their overall health and well-being. Additionally, Cushing syndrome can disrupt puberty in adolescents, leading to irregular menstrual cycles in females and delayed puberty in both genders. Facial plethora, headaches, hypertension, hirsutism, and skin conditions such as acne and fungal infections are also commonly reported. In some cases, pubertal children may present with signs of virilization. The morbidity associated with hypercortisolism in children is significant, making early investigation crucial in suspected cases. Confirming the presence of endogenous Cushing syndrome and determining the underlying cause, whether ACTH-dependent or ACTH-independent, are essential goals in the diagnostic process. Early detection and appropriate management can greatly improve outcomes and enhance the quality of life for children with this condition. 6. DIAGNOSIS An accurate classification of Cushing syndrome when diagnosing in children is important to determine suitable therapeutic treatment. At initial diagnosis, an evaluation and observation of patient’s physical development and medical history are crucial, and if Cushing syndrome is speculated, hypercortisolism profile should be documented through: (a) 24-hour urinary free cortisol (UFC), (b) midnight cortisol both serum or saliva, and (c) dexamethasone suppression (DST). (a) 24-hour UFC test is commonly done as the initial step to diagnose Cushing syndrome. This test is mostly done at least 2 but preferably 3 consecutive collections for better results based on the body surface area. However, to obtain urine samples is difficult thus this might interfere with results obtained which  either makes the UFC become falsely high due to stress, malnutrition or high water intake known as pseudo-Cushing syndrome or falsely low due to inadequate collection of urine samples. This urine sample is analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) because of its accuracy and ability to exclude interferences from medications. (b) Midnight serum or salivary cortisol tests are highly effective in diagnosing Cushing syndrome due to its ability to identify loss of normal diurnal variation in cortisol levels. This test is usually obtained through intravenous. For serum cortisol, blood will be taken at midnight where the level of cortisol is at the lowest while saliva, no blood included as saliva cortisol test is a non-invasive procedure. In terms of analysis, cortisol obtained from serum are usually measured using immunoassay such as chemiluminescent immunoassay (CLIA) or enzyme-linked immunosorbent assay (ELISA) as this method is highly specific and sensitive in cortisol detection level in blood samples. Whereas for cortisol from saliva samples, it is usually measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as it is highly accurate and can detect small changes of cortisol levels. If serum cortisol level ≥20 µg/dL, it indicates a patient diagnosed with cushing syndrome as the test has 99% sensitivity and 100% specificity. While for saliva cortisol, if the level >0.13 µg/dL, it is highly indicated for Cushing syndrome due to abnormalities. (c) Low-dose or 1 mg overnight dexamethasone suppression test (DST) is usually done similarly in adults. This test is characterized by failure of serum cortisol to decrease to 3, indicate pituitary ACTH secretion.. Initially the sensitivity of this test when done is lower compared to that used in adults but after the stimulation, the increased observation proves that it is efficiently worked as alternative methods to CRH test. 7. TREATMENT/PREVENTION The first line treatment for all types of Cushing syndrome is surgical interventions. Pediatricians that diagnose with Cushing disease, most preferable treatment is transsphenoidal resection of pituitary tumor (TSS) due to >90% success rate chances. However, surgery intervention can be unsuccessful and the disease may reoccur over years after the first surgery has been done. Compared to initial TSS surgery, the success rate becomes lower overtime, approximately 60%. This can cause problems after surgery such as infection, growth hormone deficiency and hypogonadism. However the occurrence of death within the population is low (