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Marianne Joy B. Advincula, MD Slide 2 E.S. 9/F Bataan Follow up consult Slide 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, (+) hyperpigmented labioscrotal fold) At 1 week of life, px had several episodes of vomiting, poor suck and poor activity. NBS was not done. Slide 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 Slide 5 Review of systems (-) cough (-) colds (-) fever (-) diarrhea (-) vomiting (-) headache (-) seizures (-) BOV (-) LOC (-) changes in sensorium Slide 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 Slide 7 Family Medical History (+) ambiguous genitalia- sibling, died at 5 months of age (+) HTN- grandmother (-) DM (-) Cardiac disease Slide 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. Slide 9 Nutritional history Initially breastfed at birth then shifted to Neosure. Complementary feeding started at 6 months of age. Presently eats regular table food. Slide 10 Immunization History (+) BCG (+) DPT3 (+) OPV (+) Hepa B Slide 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 Slide 12 Personal Social History Px is the only living child of a 37 y/o mother and a 35 y/o father, tricycle driver Slide 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 m BMI- 26 Anicteric sclerae, 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 Slide 14 Diagnosis CAH, salt losing S/P Genitoplasty (2005) Slide 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 3-Hydroxysteroid dehydrogenase deficiency, classical 17 a Hydroxylase/17,20 lyase deficiency Slide 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. Slide 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. Slide 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. Slide 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. Slide 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. Slide 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. Slide 22 11- -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. Slide 23 17- -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. Slide 24 3- -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. Slide 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 Slide 26 Enzyme pathway Slide 27 Result of a 21-Hydroxylase Deficiency Slide 28 ESSENTAILS OF DIAGNOSIS Increased linear growth with advanced bone age and eventual short stature Pseudohermaphroditism in girls due to androgen virilizing effect Isosexual precocity in boys with small infantile testes. Slide 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. Slide 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. Slide 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. Slide 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. Slide 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. Slide 34 Slide 35 Slide 36 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 Slide 37 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). Slide 38 Laboratory Findings 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. Slide 39 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- -hydroxylase deficiency and 17- -hydroxylase deficiency) are associated with suppressed plasma renin activity and hypokalemia. Slide 40 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. Slide 41 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. Slide 42 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. Slide 43 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 Slide 44 Long Term Therapy Glucocorticoids 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. Slide 45 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. Slide 46 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) Slide 47 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. Slide 48 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. Slide 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. Slide 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. Slide 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. Slide 52 PROGNOSIS 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.