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ENDO HOUR. Marianne Joy B. Advincula , MD. E.S. 9/F Bataan Follow up consult. History of Present Illness.

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ENDO HOUR

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  1. ENDO HOUR Marianne Joy B. Advincula, MD

  2. E.S. • 9/F • Bataan • Follow up consult

  3. History of Present Illness • Diagnosed case of CAH, initially presenting as ambiguous genitalia at birth ( phallus 1.8 cm, (+) opening ventral to phallic structure, (+) blind opening at phallic end, (+) hyperpigmentedlabioscrotal fold) • At 1 week of life, px had several episodes of vomiting, poor suck and poor activity. NBS was not done.

  4. Initially seen in PGH at 1 month old. • Initial 17 OHP: 320 nmol/L • Bone aging at 6 months: delayed skeletal maturity (less than 3 months) • Karyotyping: normal female karyotype • Previously maintained on Prednisone (23 mg/BSA) • Presently on hydrocortisone 15 mg/BSA

  5. Review of systems • (-) cough (-) colds (-) fever • (-) diarrhea (-) vomiting (-) headache • (-) seizures (-) BOV (-) LOC • (-) changes in sensorium

  6. Past Medical History • (+) previous hospitalizations- due to vomiting, diarrhea, UTI5 • (+) S/P genitoplasty (2005) • (+) PTB- completed treatment • (+) speech delay- diagnosed in 2003, underwent speech therapy • (-) BA

  7. Family Medical History • (+) ambiguous genitalia- sibling, died at 5 months of age • (+) HTN- grandmother • (-) DM • (-) Cardiac disease

  8. Birth Maternal History • Born FT to a then 30 y/o G3P1 (1-0-1-0) mother via SVD at Bataan Provincial Hospital. Mother had 7 PNCUc/o LHC. No feto-maternal complications were noted. At birth, px was already noted to have ambiguous genitalia. Px stayed in the hospital for 1 week and was treated for UTI.

  9. Nutritional history • Initially breastfed at birth then shifted to Neosure. Complementary feeding started at 6 months of age. Presently eats regular table food.

  10. Immunization History • (+) BCG • (+) DPT3 • (+) OPV • (+) Hepa B

  11. (+) social smile at 2 months • (+) grasps objects at 8 months • (+) sits with support at 8 months • Able to say mama and papa at 9 mos

  12. Personal Social History • Px is the only living child of a 37 y/o mother and a 35 y/o father, tricycle driver

  13. Physical examination • Awake, ambulatory, not in cardiorespiratory distress • BP- 100/70 CR- 100 RR- 20 afebrile • Wt- 55 kg (Z score >+2)Ht- 143.5 cm (Z score +1) • BSA- 1.3 m² BMI- 26 • Anictericsclerae, pink conjunctivae, (+) acne on face, (+) hyperpigmentation on face and lips • SCE, broad anterior chest, no retractions, CBS, • AP, NRRR, no murmurs • Abd flat, soft, NABS • No edema, no cyanosis

  14. Diagnosis • CAH, salt losing • S/P Genitoplasty (2005)

  15. CAH • It is a familial disorder of adrenal steroid biosynthesis with autosomal recessive mode of inheritance. • 5 major Enzymes deficiency are clinically important • 21-Hydroxylase • 11-b-Hydroxylase • 17-a-Hydroxylase • 3β-Hydroxysteroid dehydrogenase deficiency, classical • 17 a Hydroxylase/17,20 lyase 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 • 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 • 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 • 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 • 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.

  22. 11-b-Hydroxylase Deficiency • Accounts for 5-10% of cases of CAH. • Gene is located on the long arm of chromosome 8. • It is characterized by low plasma renin activity & elevation of serum 11-Deoxycortisol and 11-deoxycorticosterone. • Because of the strong mineralocorticoid activity of deoxycorticosterone, the condition is characterized by salt retention, hypertension & hypokalemic alkalosis. • The elevated plasma androgens may cause virilization of the female fetus.

  23. 17-a-Hydroxylase deficiency • Genetic defect is on chromosome 10. • Presents with similar features of those of 11-Hydroxylase deficiency except that Androgens are low, so no virilization in girls & genitalia is ambiguous in boys.

  24. 3-b-hydroxysteroid dehydrogenase deficiency • This is a very rare disorder that results in accumulation of DHEA, which is converted to testosterone in peripheral tissues. • It can cause virilization of female fetus and leads to ambiguous genitalia in the newborn.

  25. 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

  26. Enzyme pathway

  27. Result of a 21-Hydroxylase Deficiency

  28. ESSENTAILS OF DIAGNOSIS • Increased linear growth with advanced bone age and eventual short stature • Pseudohermaphroditismin girls due to androgen virilizing effect • Isosexual precocity in boys with small infantile testes.

  29. ESSENTIALS OF DIAGNOSIS • 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.

  30. ESSENTIALS OF DIAGNOSIS • 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.

  31. 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.

  32. CLINICAL COURSE • 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.

  33. 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.

  34. 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-b-hydroxylase deficiency and 17-a-hydroxylase deficiency due to the accumulation of the mineralocorticoiddesoxycorticosterone

  35. 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).

  36. Laboratory Findings • 11-b-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.

  37. Laboratory Findings • 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-b-hydroxylase deficiency and 17-a-hydroxylase deficiency) are associated with suppressed plasma renin activity and hypokalemia.

  38. 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.

  39. 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.

  40. TREATMENT • 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.

  41. 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

  42. Long Term Therapy • Glucocorticoids Replacement Hydrocortisone 10-15 mg/m2/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 • MineralocorticoidsTreatment 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. 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.

  48. 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 m/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.

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