1. BYBY

2. History  Female patient 6 yrs old with a history of progressive weight gain and increasing hair growth of 3 months duration.  History of polyphagia, abdominal distension, generalized bony pains.  No history of abdominal pain, no change in bowel habits.  No history of drug intake.  Mother mentioned that her child photos (face) changed a lot recently.

3. The main complaint for this child is rapidly progressive weight gain of 3 months duration. Anthropometric measurements of this child revealed:  Her height was 123.5 (on 97th centile = +2 SDS).  Weight was 29.5 kg (above 97th centile = +3 SDS).  BMI 19.3 (97th centile = +2 SDS).  From the above measurements her weight and BMI were above and on the 97 th percentile (respectively) which means that she is obese.

4. Examination  She looks depressed.  She had rounded, plethoric face.  Increased pigmentation affecting the groin and the back of the neck.  Lipomastia (no breast disc could be felt).  Buffalo hump, fine red purple striae on the anterior abdominal wall.  Hirsutism (affecting the face, back, abdominal wall, the upper limbs, and lower limbs, pubic hairs (P4), acne, mild cliteromegaly.  BP: 140/95 (hypertensive) on 3 different occasions.

7. Abdominal Examination Large mass in the right hypochondrium (circular outline (20 cm in diameter, rounded border, irregular surface, firm in consistency, not attached to the overlying skin, doesn't move with respiration).

9. From the above examination the patient has clinical signs suggestive of Cushing’s syndrome.

10. Then what is the etiology of this obesity Is it exogenous or endogenous obesity???????  From her complaint (weight gain and hirsutism) as well as the examination which showed clinical signs of Cushing’s syndrome therefore endogenous cause.  But patients with Cushing’s syndrome are usually short. Our patient is tall her height SDS is + 2 SDS??????? Almost all endogenous causes are associated with short stature.

11. Most Specific Nonspecific Spontaneous Bruising Proximal Myopathy Abdominal striae Central obesity w/ extremity wasting Dorsocervical fat pads (“Buffalo Hump” Round facies (“Moon Facies”) DM HTN Obesity Oligomenorrhea Osteoporosis Depression Insomnia Psychosis Impaired Cognition Hirsutism Fungal Skin Infections Nephrolithiasis Polyuria

12. Cushing’s Syndrome  Cushing’s syndrome (hypercortisolism) is a hormonal disorder caused by prolonged exposure high levels of glucocorticoids (which may be exogenous or endogenous steroids).  Exogenous Cushing’s syndrome: caused by taking excessive amounts of steroids.  Endogenous Cushing’s syndrome: excess cortisol produced by the adrenal glands (rare)  Endogenous Cushing’s syndrome may be ACTH dependent or not an ACTH dependent.

14. When to suspect Cushing’s syndrome in an obese child???? Patients with clinical features suggestive of Cushing’s syndrome. Patients with unusual features for age (osteoporosis, hypertension). Children with growth retardation and increased weight Obese short children.

15. Therefore from the history and examination The child suffers from manifestations of endogenous hypercortisolism and also she is virilized. The diagnosis of CS is made in two steps: 1.Establish the presence of CS (hypercortisolism) 2.Determine the source of excessive cortisol secretion.

16. Investigations  Free urinary cortisol: 287 ug/24hr (N 20-80)  DHEA-S: 456 u/dl (N 5-55u/dl).  Testosterone: 7.2 ng/dl (N <0.5ng/dl).  Na, K & PRA are normal. Serum cortisol (ug/dl) ACTH (pg /ml)Free urinary cortisol (ug/ml) 8 (am)50 (N 6-16)3.7 (N <82)280 (N 20-80) 8 (pm)37 (N 3-11)2 (N<82)

17. Interpretation of Labs The above investigation revealed increased cortisol (both urinary and serum cortisol at 8 am and 8pm). ACTH is not elevated therefore this hypercortisolism is not ACTH dependent (it is not Cushing’s disease). Cushing’s syndrome here is ACTH independent (adrenal adenoma or adrenal carcinoma). Since the size of the mass clinically > 4 cm in diameter and the patient had symptoms of virilization (acne, hirsutism, cliteromegaly), in addition to increased androgen levels including testosterone and DHEA-S therefore it is most probably adrenal carcinoma and not an adenoma (small sized < 4cm, secreting only cortisol in excess).

18. To confirm whether it : Is this hypercortisolism ACTH dependent or not ACTH dependent????

19. Dexamethasone suppression test Serum cortisol (ug/dl)ACTH (pg /ml)Free urinary cortisol (ug/ml) Low dose DS363 High dose DS372.2180 ACTH levels are not elevated which means that hypercortisolism is ACTH independent. Cortisol is not suppressible by dexamethasone either in the low dose or the high dose dexamethasone suppression test which indicates adrenal origin of the hypercortisolism as adrenal tumors are autonomously secreting hormones and unresponsive to manipulation of the hypothalamic pituitary adrenal axis with pharmacological agents. Normal response: Plasma cortisol should be less than 1.8 mcg/dL (sensitivity > 95%, specificity = 80%).The old cut off value of 5 mcg/dL following single dose overnight DST is not currently used.

20. Algorithm for testing Cushing’s syndrome suspected Exclude exogenous steroid use Perform two of these  Late night salivary cortisol  Overnight dexamethasone suppression test  24 hour urinary free cortisol Perform two of these  Late night salivary cortisol  Overnight dexamethasone suppression test  24 hour urinary free cortisol Positive negative Cushing’s syndrome unlikely Cushing’s syndrome ACTH dependent or ACTH independent LDDST HDDST

21. Abdominal U/S and CT scan Confirmed the presence of a large retroperitoneal mostly right adrenal mass. What to do next??? Check for complications of Cushing’s????

22. Complications  Diabetes or impaired glucose tolerance.  Enlargement of any tumours that are the underlying cause (pressure effect on nearby organs)  Fractures due to osteoporosis  High blood pressure  Serious infections

23. Two issues to be explained: This patient is tall (height SDS +2) this can be explained by: rapid progression of symptoms (as for excessive steroids to affect growth it has to be long term condition). Tall stature may also be a consequence of excess androgens (anabolic hormone causing advancement of bone growth and bone age) Another issue: the patient has some hyperpigmentation in the neck and the groin although ACTH is not elevated and the Cushing’s syndrome is not ACTH dependent; this can be explained also by that these areas described are characteristic areas for insulin resistance, to support this the patient random blood glucose was 228mg/dl (diabetic level, secondary diabetes).

24. PREOPERATIVELY The patient received propranolol to control her blood pressure. She had done an MRI abdomen, chest and bone scan to exclude metastasis. All were normal, apart from adrenal mass.

26. TREATMENT Unilateral right adrenalectomy Grossly and microscopically (adrenal carcinoma) followed by chemotherapy.

27. POSTOPERATIVELY She received steroid immediately after the operation, then withdrawn successfully. She received mitotane followed by radiotherapy with no recurrence. She is now 15 years old and she is performing a yearly follow up of an MRI abdomen and chest, and serum DHEA-s, testosterone, cortisol (24-hour UFC or single dose DST) which are so far normal.

28. TAKE HOME MESSAGE Cushing’s syndrome is a disorder caused by prolonged exposure of the body’s tissues to high levels of cortisol. Cushing’s syndrome is caused by exposure to glucocorticoids, either exogenous or endogenous. Typical signs and symptoms of Cushing’s syndrome include truncal obesity, a rounded face, skin that bruises easily and heals poorly, weakened bones, hirsuitism and menstrual irregularities in female patient. Several tests are usually needed to diagnosis Cushing’s syndrome, including urine, blood, and saliva tests. Other tests help find the cause of the syndrome. Treatment depends on the specific reason including surgery, radiation, chemotherapy, or the use of cortisol- inhibiting drugs.

29. My thanks and grateful appreciation to Prof Dr. Isis Ghali, Prof Dr. Mona Hafez, Prof Dr. Mona Mammdouh who shared me their valuable remarks and advice and offered great help and guidance to prepare such work.