Common Adrenal Disorders in Children

1. . Common Adrenal Disorders in Children Dr Sarar Mohamed FRCPCH (UK), MRCP (UK), CCST (Ire), CPT (Ire), DCH (Ire), MD Consultant Paediatric Endocrinologist & Metabolist Associate Professor of Pediatrics King Saud University

2. . Agenda • Physiology of adrenal • Causes of adrenal insufficiency • Addison Disease • Adrenal crisis • Congenital adrenal hyperplasia • Cushing Syndrome

5. Aldosterone • Mineralocorticoid • Regulates concentration of Na+ and K+. • Kidney conserves Na+. • Kidney excretes K+. • Therefore, decreased aldosterone will lead to hyperkalemia and hypornatremia. • Responds to changes in composition of plasma. • Regulated by renin-angiotensin system of kidney

6. ACTH Regulation of adrenal gland secretion Cortisol Cortisol

7. Aldosterone is regulated by the renin angiotensin system while cortisol is regulated by the hypothalamic pituitary axis. Random cortisol measurement is not useful, ACTH stimulating test to stimulate the adrenals must be done to measure it. If it’s still low after stimulation, then it suggests adrenal insuffeciency.

8. Pattern of cortisole level during the day

9. Adrenal Dysfunction . Decrease function Increase function Cushing syndrome High Cortisol Hyperaldosteronism High aldestrone Pheochromocytoma High catecholamine • Adrenal insufficiency • Low cortisol, aldestrone Eg Addison disease

10. . Causes of Adrenal insufficiency • Congenital adrenal hyperplasia • Addison disease most common cause and it’s acquired. • Infection (TB, sepsis) • Adrenoleukodystrophy very rare.

11. . Addison disease • Autoimmune • Isolated or associated with other autoimmune disease • Presents with tiredness, weight loss, skin pigmentation • Hypotension, hyponatremia, hyperkalemia • Aldestrone & cortisol low, high ACTH, high renin • Low sodium , high potasium • ACTH stimulation test: diagnostic test by giving synthetic ACTH (IV or IM) and measuring the serum cortisol at 30 and 60 minutes. In normal individuals the baseline cortisol should be doubled after the test whereas in adrenal insufficiency, the baseline (which is low) is only increased to 25% after the test. • Adrenal antibodies • Treatment : cortisol + aldosterone

13. Hyperpigmentation A Color Atlas of Endocrinology p97

14. Addisonian crisis • Life threatening complication • Severe vomiting and diarrhoeafollowed by dehydration • Low blood pressure and shock • Hypoglycemia • Loss of consciousness • Treatment: IV fluids + IV hydrocortisone

15. Adrenal insufficiency with echomosis is suggestive of meningeococcal septicemia.

16. Congenital Adrenal Hyperplasia • Family of inherited disorders of adrenal synthesis • Autosomal Recessive (M=F) • Each disorder results from a deficiency of one of the five enzymes necessary for steroid synthesis • 21-hydroxylase  is the commonest form (90–95% of CAH cases)

17. Steroid biosynthetic enzymes • Cholesterol side chain cleavage= desmolase) 2) 3-Hydoxysteroid dehydrogenase 3) 17  hydroxylase 4) 21-Hydroxylase 5) 11-Hydroxylase

18. Minerlocorticoid Glucocoticiod Sex Steroid Desmolase Cholesterol 17,20 lyase 17 a OH Pregnenlolone 17 OH Pregnenlolone DeHydroEpiAndrosterone 3 B HSD 3 B HSD 3 B HSD 17 a OH Progesterone 17 OH Progesterone Androstendione 21 OH 21 OH Desoxycorticosterone 11 Desoxycortisol 11 OH 11 OH Testosterone Estradiol Corticosterone Cortisol 18 OH 18 OH Corticosterone Aldosterone

19. Desmolase is the first step in the pathway and if deficient all three pathways will be stopped. Only female genitalia because no androgens at all. • 3BHSD deficiency: all 3 enzymes will be absent but will also present with ambiguous genitalia because of high levels of DHEA • 17aOH: cortisol and androgens are deficient and males will present with ambiguous genitalia. Aldosterone is present; therefore, they will not develop adrenal crisis and will have hypertension due to the excess aldosterone levels.

20. 21aOH: is the commonest cause of CAH, both cortisol and aldosterone will be missing, the pathway will be shifted to the production of androgens which will be manifested as ambiguous genitalia in females and hyper-pigmentation and virilization in males. • 11aOH: both cortisol and aldosterone will be deficient, but there will be accumulation of the Desoxycorticosterone which has an aldosterone like activity, therefore they will present hypertension, hypernatremia and hypokalemia), but it similar to 21OH in that they both present with ambiguous genitalia and low cortisol levels. • Hypertension is only present in 11 And 17 OH deficiency.

21. . Congenital Adrenal Hyperplasia

22. Congenital Adrenal Hyperplasia

23. 21-OH CAH: Clinical phenotypes • “Classic, severe” salt-wasting (SW) form: it is the life-threatening form. • “Classic, less severe” simple-virilizing (SV) • “Mild, non-classic” forms

24. 21-OHCAH: Treatment Hydrocortisone Fludrocortisone For life Desmolase Cholesterol Desmolase 17 a OH Pregnenlolone 17 OH Pregnenlolone DeHydroEpiAndrosterone 3 B HSD 3 B HSD 3 B HSD Androstendione 17 a OH Progesterone 17 OH Progesterone Testosterone Estradiol 21 OH 21 OH • 90 % of CAH • 50-70 % salt wasting • Female = • ambiguous, Hyperpig • Male = • Virlization and hyperpigmentation Desoxycorticosterone 11 Desoxycortisol 11 OH 11 OH Corticosterone Cortisol 18 OH 18 OH Corticosterone Aldosterone

25. Salt wasting form • Salt wasting form • Adrenal crisis in the 1st-4th weeks of life, peaking at 3rd • Poor feeding, vomiting, diarrhea, FTT • Dehydration • Shock • Electrolytes imbalance • Hyponatremia • Hyperkalaemia • Hypoglycemia • Hyperpigementations • If untreated  circulatory collapse  shock  death • Permanent brain injury due to shock and hypoglycemia  lower IQ

26. Simple virilizing form 21-OH CAH • Simple virilizing form • No adrenal-insufficiency symptoms unless subjected to severe stress but exhibit virilization • Girls present with ambiguous genitalia at birth • Males usually not diagnosed until later (virilization, precocious, growth acceleration) • Advanced skeletal age diagnosed late  short adult stature

27. Prader Classification of Virilization

28. Newborn Screening • Type 1: increase in the size of the clitoris. • Type 2: more increase in the size of the clitoris. • Type 3: one opening, the vagina and clitoris opens in the same opening. • Type 4: one opening and more increase in the size, starts looking as a penis. • Type 5: looks like male genitalia with no testis.

29. Prader 1 .

30. .Prader 2

31. Prader 3 • .

32. Prader4

33. Prader5

34. Nonclassical CAH • Residual enzyme activity. • Non-salt losing CAH • Presents late in childhood with precocious pubic hair and/or clitoromegaly and accelerated growth. • Present in adolescence or adulthood with varying virilizing symptoms ranging from oligomenorrhea to hirusutism and infertility.

35. . Non classicCAH

36. Diagnosis of CAH • Serum electrolytes & glucose • Low Na & high K • Fasting hypoglycemia • Elevated serum urea due to associated dehydration • Elevated plasma Renin & ACTH levels • Low Cortisol • High 17 – OHP • High androgens especially testosterone level • Low Aldosterone • Urinary steroid profile • Chromosomal study and US of external genitalia if they present with ambiguous genitalia. • Pelvic US

37. Management • Hydrocortisone • Fludrocortisone 0.05 - 0.2 mg/day • Triple dose of hydrocortisone and mineralcorticoids during stress or very sick. • During adrenal crisis intravenous hydrocortisone and IV fluid • Surgery for female external genitalia can be done in the 1st year of life. • Antenatal diagnosis and treatment

38. . Newborn screening for CAH • Neonatal screening by filter paper on 3rd day of life • 17 Hydroxyprogestrone blood level (17 OHP)

39. 11 Hydroxylase Deficiency: Desmolase Cholesterol Desmolase 17 a OH Pregnenlolone 17 OH Pregnenlolone DeHydroEpiAndrosterone • 5 % of CAH • HTN • Female = • ambiguous, Hyperpig • Male = • virlization 3 B HSD 3 B HSD 3 B HSD 17 a OH Progesterone 17 OH Progesterone Androstendione 21 OH 21 OH Desoxycorticosterone 11 Desoxycortisol 11 OH 11 OH Testosterone Estradiol Corticosterone Cortisol 18 OH 18 OH Corticosterone Aldosterone

40. . 17 Hydroxylase Deficiency: (adrenal crisis doesn’t occur) Desmolase Cholesterol Desmolase 17 a OH • HTN • Hypokalemic alkalosis • Female = • Normal • Male = • Ambiguous Pregnenlolone 17 OH Pregnenlolone DeHydroEpiAndrosterone 3 B HSD 3 B HSD 3 B HSD 17 a OH Progesterone 17 OH Progesterone Androstendione 21 OH 21 OH Desoxycorticosterone 11 Desoxycortisol 11 OH 11 OH Testosterone Estradiol Corticosterone Cortisol 18 OH 18 OH Corticosterone Aldosterone

41. 3 B Hydroxy steroid DH Deficiency: . Weak Androgen; therefore, ambiguous genitalia in females only. Desmolase Cholesterol Desmolase 17 a OH Pregnenlolone 17 OH Pregnenlolone DeHydroEpiAndrosterone 3 B HSD 3 B HSD 3 B HSD 17 a OH Progesterone Survival is rare due to more proximal enzyme bloke 17 OH Progesterone Androstendione 21 OH 21 OH Desoxycorticosterone 11 Desoxycortisol 11 OH 11 OH Testosterone Estradiol Corticosterone Cortisol 18 OH 18 OH Corticosterone Aldosterone

42. Inability to convert cholesterol to pregnenolone thus all 3 classes of steroids are absent (1st step is inhibited due to the absence of desmolase) Clinical Manifestations: Salt-losing crisis XX and XY have female genitalia Massive cholesterol accumulation in adrenal cortex Absent puberty in males Females may have puberty Congenital Lipoid Adrenal Hypoplasia

43. Harvey Williams Cushing (1869-1939)

44. Definitions • Cushing’s Syndrome • Excess cortisol in the blood • Cushing’s Disease most common • Excess cortisol in the blood due to an ACTH secreting pituitary tumour, due to pituitary adenoma.

45. HYPOTHALAMUS CRH PITUITARY ACTH CORTISOL ADRENAL CORTEX

46. Cushing’s syndrome • Cushing’s Syndrome • Results from increased adrenocortical secretion of cortisol • Causes include: • ACTH-secreting tumor of the pituitary (Cushing’s disease) • excess secretion of cortisol by a neoplasm within the adrenal cortex • ectopic secretion of ACTH by a malignant growth outside the adrenal gland • excessive or prolonged administration of steroids

48. Cushing’s syndrome • Cushing’s Syndrome • Characterized by: • truncal obesity • moon face • buffalo hump • acne, hirsutism • abdominal striae • hypertension • psychiatric disturbances • osteoporosis • Amenorrhea • Diabetes