1. Presenting manifestations Watery Stools Vomiting Drowsy Generalized tonic-clonic seizures Vital Signs T: afebrile CR: 180 RR: 50-60 LAB results Na 120 K 6.0 Hgt low

2. Symptom, sign or laboratory finding pathognomonic of a disease Symptom, sign or laboratory finding pointing to an organ or part of an organ system Symptom, sign or laboratory finding pointing to a group of diseases Symptom, sign or laboratory finding whose mechanism is well understood Symptom, sign, or laboratory finding found in the least number of diseases 2 Approach to Diagnosis

4. Severe salt wasting: -vomiting, -Watery stools -electrolyte changes - cardiac arrhythmia

5. Acute adrenal crisis An acute form of adrenal insufficiency characterized by salt loss, circulatory collapse and hypoglycemia due to inadequate secretion of glucocorticoids and or mineralocorticoids Handbook of Medical and Surgical Emergencies, 6 th ed

6. Physiology The two adrenal glands are located on top of the kidneys. They consist of the outer portion, called the cortex, and the inner portion, called the medulla. The cortex produces three types of hormones, all of which are called corticosteroids. Cortisol is a glucocorticoid -- a corticosteroid that: – Helps regulate blood sugar (glucose) – Holds back the immune response – Is released as part of the body's response to stress Cortisol production is regulated by a small gland just below the brain called the pituitary gland. Cortisol is essential for life. www.umm.com

7. Adrenal crisis occurs when Primary adrenal insufficiency – Congenital adrenal hypoplasia or aplasia – Congenital adrenal hyperpalsia due to enzymatic defect (21-hydroxylase-most common; cholesterol 20, 22 desmolase, 17-hydroxylase, 11-B hydroxylase deficiency) – Adrenal hemorrhage (Waterhouse Friderichsen syndrome) – ACTH unresponsiveness – Acute illness – Adrenoleukodystrophy Handbook of Medical and Surgical Emergencies, 6 th ed

8. Secondary adrenal insufficiency – Anencephaly – Hypopituitarism – Isolated ACTH deficiency – Iatrogenic Prolonged steroid therapy Handbook of Medical and Surgical Emergencies, 6 th ed Adrenal crisis occurs when

9. Etiologies Primary Adrenal Insufficiency – Congental Adrenal Hypoplasia Hypoadrenalism usually presents acutely in the neonatal period but may be delayed until later childhood or even adulthood with a more insidious onset – Adrenal Hemorrhage (waterhouse Friedrichsen Syndrome) Neionatal Period (Difficult labor, causing trauma) An abdominal mass, anemia, unexplained jaundice, or scrotal hematoma may be the presenting sign. Often, the hemorrhage is asymptomatic initially and is identified later by calcification of the adrenal gland. Infection – Tuberculosis was a common cause of adrenal destruction in the past but is much less prevalent now – Adrenoleukodystrophy associated with demyelination in the central nervous system appearing in childhood or adolescence and progressing to severe dementia and deterioration of vision, hearing, speech, and gait, with death occurring within a few years

10. Risk factors for adrenal crisis include: Dehydration Infection and other physical stress Injury to the adrenal or pituitary gland Stopping treatment with steroids such as prednisone or hydrocortisone too early Surgery Trauma www.umm.com

11. Clinical manifestations Newborn and infant – Vomiting – Diarrhea – Weight loss higher than approved fluid loss – Cardiorespiratory distress – Hypotension – Seizure Handbook of Medical and Surgical Emergencies, 6 th ed

12. Children over 1 year – Vomiting – Diarrhea – Dehydration and fever – Hypotension – Vascular collapse – Coma Clinical manifestations

13. Laboratory Low cortisol level Hypoglycemia Hyperkalemia Hyponatremia Metabolic acidosis

14. Hypoglycemia : often accompanied by ketosis as the body attempts to utilize fatty acids as an alternative energy source. – Ketosis is aggravated by anorexia, nausea, and vomiting, all of which occur frequently. Hypovolemia due to decreased resorption of sodium in the distal nephron. Hyponatremia, due to decrease plasma osmolality – Hypotension and decreased cardiac output decrease glomerular filtration and thus decrease the ability of the kidney to excrete free water. Vasopressin (AVP) is secreted by the posterior pituitary in response to hypotension and also as a direct consequence of lack of inhibition by cortisol. Hyperkalemia, decreasing potassium excretion in the distal nephron

15. What is CAH?  It is a familial disorder of adrenal steroid biosynthesis with autosomal recessive mode of inheritance.  The defect is expressed as adrenal enzyme deficiency.  5 major Enzymes deficiency are clinically important 21-Hydroxylase 11-b-Hydroxylase 17-a-Hydroxylase 3-b-Hsteroid hydrogenese 20,22 Desmolase deficiency

16. CAH  The enzyme deficiency causes reduction in end-products, accumulation of hormone precursors & increased ACTH production.  The clinical picture reflects the effects of inadequate production of cortisol & aldosterone and the increased production of androgens & steroid metabolites.

17. 21-Hydroxylase Deficiency  Most common type, accounts for >80% of cases.  Incidence is 1:5000 to 1:15000 live birth.  Gene is located on the short arm of chromosome 6 near the C4 locus in close association with HLA genes.  Heterozygous carriers can be detected by ACTH stimulation test.

18. 21-Hydroxylase deficiency/2  It is characterized by reduced production of cortisol and aldosterone and increased production of progesterone; 17-OH-progesterone, and sex steroids.  The urinary steroid metabolites (17-ketosteroids and pregnanetriol) are elevated above normal levels.

19. 21-Hydroxylase deficiency/3  Decreased secretion of aldosterone results in salt loss with hyponatremia and hyperkalemia; plasma renin activity is therefore elevated.  In partial enzyme deficiencies, the aldosterone deficiency is not expressed, and patients remain normonatremic and normokalemic.  The excess androgens causes virilization of girls & ambiguous genitalia & dark scrotum in boys.

20. 21-Hydroxylase Deficiency/4  2 forms, classic early virilization type with or without salt-losing crisis and non- classic type with late-onset virilization.  Male babies with non salt-losing non- classic type remains asymptomatic till late childhood when they may show signs of sexual precocity.

21. 21-Hydroxylase Deficiency/5  Because members of the same family may have classic, non-classic & asymptomatic forms, the disorder may be due to allelic variations of the same enzyme.  Mass neonatal screening using filter paper blood sample for 17-OH-Progesterone is used in the USA.

22. Pathophysiology  Anatomically, the adrenal gland can be divided into 3 zones:  Zona glomerulosa, which produces predominately mineralocorticoid  Zona fasciculata, which produces predominately glucocorticoid  Zona reticularis, which produces predominately androgens

23. Enzyme pathway

24. Result of a 21-Hydroxylase Deficiency

25. ESSENTIALS OF DIAGNOSIS  Increased linear growth with advanced bone age and eventual short stature  Pseudohermaphorditism in girls due to androgen virilizing effect  Isosexual precocity in boys with small infantile testes.

26. ESSENTIALS OF DIAGNOSIS/2  Adrenal crisis with salt-loss & metabolic acidosis or Hypertension & hypokalemic alkalosis.  Low cortisol with high androgens, ACTH and steroid precursors e.g. 17- OH-Progest. or 11-Deoxycortisol.

27. ESSENTIALS OF DIAGNOSIS/3  Diagnosis is confirmed by measurement of ACTH, Cortisol, Aldosterone, 17- OH-progesterone, Testosterone & urinary 17-ketosteroids.  Needs alertness for the possibility in all babies with Diarrhea & Vomiting, hypoglycemia or  BP.

28. CLINICAL COURSE  The clinical phenotype depends upon the nature and severity of the enzyme deficiency.  Approximately 50% of patients with classic congenital adrenal hyperplasia due to 21-hydroxylase (CYP21) deficiency have salt wasting due to inadequate aldosterone synthesis.  Girls are usually recognized at birth because of ambiguous genitalia.

29. CLINICAL COURSE/2  Non salt losing CAH present late in childhood with precocious pubic hair and/or clitoromegaly, often accompanied by accelerated growth and advanced bone age.  Those individuals with mild deficiencies of the enzyme present in adolescence or adulthood with varying virilizing symptoms ranging from oligomenorrhea to hirsutism and infertility.

30. GIRLS WITH CAH Have ambiguous genitalia at birth:  complete fusion of the labioscrotal folds and a phallic urethra. clitoromegaly and partial fusion of the labioscrotal folds  In less severe forms, genitalia is normal at birth. Precocious pubic hair & clitoromegaly and excess facial or body hair appear later in childhood, often accompanied by tall stature.

33. BOYS WITH CAH  Are unrecognized at birth because their genitalia are normal.  They are not diagnosed until later, often with a salt wasting crisis resulting in dehydration, hypotension, hyponatremia and hyperkalemia or later in childhood with early pubic hair & phallic enlargement accompanied by accelerated linear growth and advancement of skeletal maturation.  High blood pressure & hypokalemia may occur in those with 11-  - hydroxylase deficiency and 17-  - hydroxylase deficiency due to the accumulation of the mineralocorticoid desoxycorticosterone

34. Laboratory Findings  Demonstration of inadequate production of cortisol and/or aldosterone in the presence of accumulation of excess concentrations of precursor hormones is diagnostic.  In 21-hydroxylase deficiency, very high serum 17-hydroxyprogesterone is characteristic together with very high urinary pregnanetriol (metabolite of 17-hydroxyprogesterone).

35. Laboratory Findings/2  11-  -hydroxylase deficiency is characterized by high serum 11-deoxycorticosterone and 11- deoxycortisol concentrations with elevation of its urinary metabolites (tetrahydrocompound-S).  Both are accompanied by elevated 24-hour urinary 17-ketosteroids, the urinary metabolites of adrenal androgens.

36. Laboratory Findings/3  Salt wasting forms of adrenal hyperplasia are accompanied by low serum aldosterone, hyponatremia, hyperkalemia and elevated plasma renin activity indicating hypovolemia.  In contrast hypertensive forms of adrenal hyperplasia (11-  -hydroxylase deficiency and 17-  -hydroxylase deficiency) are associated with suppressed plasma renin activity and hypokalemia.

37. Other Tests  A karyotype is essential in the evaluation of the infant with ambiguous genitalia in order to establish the chromosomal sex.  Prenatal diagnosis of adrenal hyperplasia is possible through biochemical and genetic tests.

38. Imaging studies A pelvic ultrasound: in the infant with ambiguous genitalia to demonstrate the presence or absence of a uterus or associated renal anomalies A urogenitogram is often helpful to define the anatomy of the internal genitalia. A CT scan of the adrenal gland to R/O bilateral adrenal hemorrhage in the patient with signs of acute adrenal failure A bone age study is useful in the evaluation of the child who develops precocious pubic hair, clitoromegaly, or accelerated linear growth.

39. TREATMENT PRINCIPLES  Treatment is life-long  Treatment goals are:  to maintain growth velocity & skeletal maturation.  to normalize electrolytes & hormone levels using the smallest dose of glucocorticoids that will suppress the  ACTH to normal. Mineralocorticoid replacement may be needed to sustain normal electrolyte homeostasis.

40. MODES OF TREATMENT  Steroid replacement  Supportive therapy when needed  Treatment is life-long  Plastic surgery for ambiguous genitalia at early age  Genetic counseling  Psychological support

41. Acute Medical Management  Fluid therapy in babies with salt losing crisis 0.9% sodium chloride 20 ml/kg as IV bolus, followed by a continuous IV infusion of 0.9% or 0.45% saline 3200 ml/m 2 /day.  If the patient is hypoglycemic, 2-4 ml of 10% dextrose will correct the hypoglycemia.  Patients with 11-  -hydroxylase and 17-alpha- hydroxylase deficiency, may be hypokalemic and require potassium.

42. Long Term Therapy  Glucocorticoid Replacement  Hydrocortisone 10-15 mg/m 2 /day divided in 3 oral doses. Dose should doubled during crisis & stressful conditions. The goals of therapy are: To replace the body's requirement under normal conditions and during stress. To suppress ACTH secretion, which drives the adrenal gland to overproduce adrenal androgens in virilizing forms of congenital adrenal hyperplasia.

43. Long Term Therapy/2 Mineralocorticoids Treatment – Fludrocortisone acetate 0.05-0.2 mg once daily orally is indicated for patients who have salt-wasting forms of CAH to replace the aldosterone that is insufficiently produced by the adrenal cortex. It will restore the sodium- potassium balance.

44. New Trends of treatment  A New approach therapy is the combined use of 4 drugs: glucocorticoid (to suppress ACTH and adrenal androgen production), mineralocorticoid (to reduce angiotensin II concentrations), aromatase inhibitor (to slow skeletal maturation), flutamide (an androgen blocker to reduce virilization)

45. Surgical Management  Infants with CAH may require surgical evaluation and, if needed, corrective surgery.  Traditional approach is clitroplasty early in life, followed by vaginoplasty after puberty.  Some female infants with adrenal hyperplasia are only mildly virilized and may not require corrective surgery if they receive adequate medical therapy to prevent further virilization.

46. Further Outpatient Care  Monitor patients adequacy of dosing of glucocorticoid and/or mineralocorticoid.  Too little glucocorticoid results in symptoms of adrenal insufficiency (e.g., anorexia, nausea, vomiting, abdominal pain, asthenia) and will result in progressive virilization and advancement of skeletal maturation in virilizing forms of CAH.  Too much glucocorticoid results in excess weight gain, cushingoid features, hypertension, hyperglycemia, cataracts, and growth failure.

47. Patient Education  Educate the caretakers and patients about the nature of the disease.  Patients & parents must understand the need for additional glucocorticoids in times of illness and stress in order to avoid an adrenal crisis which may be life- threatening.

48. Neonatal Screening  Is done by measuring 17- hydroxyprogesterone from heel blood samples collected on filter paper.  Mass neonatal screening program is adopted in the USA.  This approach has permitted early identification of newborns with CAH and prevented salt wasting crisis in boys who are unrecognized at birth.  It also identifies the completely virilized girls with ambiguous genitalia who may be mistaken for boys with cryptorchidism

49. Prenatal diagnosis  Done by chorionic villus sampling at 8-12 wk & amniocentesis at 18- 20 wk.  HLA typing in combination with measurement of 17-OH- progesterone & androstenedion in amniotic fluid is used for antenatal diagnosis.

50. Prenatal Treatment  Prenatal treatment of 21-hydroxylase deficiency prevents intrauterine virilization of female fetuses.  According to the protocol proposed by Carlson et al, the mother is treated with dexamethasone (20  /kg/d in 3 divided doses) as soon as the pregnancy is recognized to suppress fetal ACTH secretion & prevent the fetal adrenal gland from overproducing adrenal androgens.

51. PROGNOSIS  Is good and complications like short stature, sexual precocity & metabolic effects are not seen with early adequate therapy.  However, children with CAH are at  risk of developing mesodermal tumours e.g. osteogenic sarcoma, pulmonary liposarcoma, uterine leiomyomata and brain tumours.

52. PROGNOSIS /2 Late diagnosis & inadequate therapy may cause:  Death of newborns with salt-losing types & if patients are not provided with stress doses of glucocorticoid in times of illness, trauma, or surgery.  Psychological problems in girls with ambiguous genitalia.  Short stature and infertility.