CONGENITAL ADRENAL HYPERPLASIA Flashcards
Cortex produces 3 major classes of steroids
• Mineralocorticoids-aldosterone
*blood pressure,
*vascular volume, and
*electrolytes
•Glucocorticoids—cortisol
*modulating intermediary metabolism
*immune response
• Adrenal androgens-sex hormones
*secondary sexual characteristics
Congenital adrenal hyperplasia
•Autosomal recessive disorders,
•Caused by deficiency of 1 of the 5 enzymes involved in the synthesis of cortisol, aldosterone, or both.
•Most frequent is 21 OHlase def. (> 90%).
Other enzymes involved in CAH
Others are:
•3βOH steroid def,
•11βOHlase def,
•17αOHlase def,
•lipoid hyperplasia,
•aldosterone synthase def
CAH is Clinically divided into these phenotypes:
Classic:
–salt wasting
•A severe form with a concurrent defect in aldosterone biosynthesis
–simple virilizing
•apparently normal aldosterone biosynthesis
•Non-classic.
•a mild, non-classic form that may be asymptomatic or associated with signs of postnatal androgen excess
Pathogenesis
•↓ -ve feedback inhibition of cortisol → alteration in adrenal mineralocorticoid & androgen secretion
• → cortisol def → ↑ corticotrophin → adrenocortical hyperplasia → overproduction of intermediate metabolites →↑sex hormones → ± signs of androgen excess (AEG in NB girls) & rapid postnatal growth in both sexes
•Ass aldosterone def may → salt wasting
Epidemiology of CAH
most common form due to
–21-OH deficiency
•accounts for >90% of CAH
•found in all populations
•Classic: prevalence 1/ 16,000
•in selected populations (eg, the Yupik of Alaska), as high as 1/ 400
Non-classic form:
•0.2 % of general white population
•more frequent (1 – 2%) in certain populations, such as Jews of Eastern European origin
•11-beta-hydroxylase deficiency accounts for 5-8%
•more common in persons of Moroccan or Iranian-Jewish descent.
•Being autosomal recessive disorders, both sexes affected with equal frequency
Aetiopathogenesis
CYP21A has a pseudogene (CYP21P) 30 kb away from it
•98% homologous in structure but inactive because of minor differences in gene
•The proximity predisposes CYP21A gene to crossovers in meiosis btw CYP21A & CYP21P, resulting in loss of genetic function.
• Abnormalities of CYP21A, 95% thought to be due to recombination with CYP21P.
Owing to loss of enzyme function,
patients cannot synthesize cortisol efficiently,→ adrenal cortex is stimulated by corticotropin
•often cause hyperpigmentation especially in genitalia and areolae
•resulting in adrenal hyperplasia and overproduction of cortisol precursors.
•Concomitant aldosterone deficiency may → salt wasting with consequent failure to thrive, hypovolemia, and shock.
Some of these precursors are diverted to the biosynthesis of sex hormones, may → signs of androgen excess
•long-term promotes rapid somatic growth & advanced skeletal age,
• which leads to premature epiphyseal fusion (predominantly an effect of extragonadal aromatization of androgens to estrogens).
patients with classic CAH cannot adequately synthesize aldosterone which regulates sodium homeostasis.
• renal Na excretion in untreated patients is excessive and can result in hypovolemia and hyperreninemia.
•Such patients cannot excrete K efficiently & prone to hyperkalemia, especially in infancy
Clinical presentation
21-Hydroxylase Deficiency in females
*Mild forms identified later in childhood:
•Precocious pubic hair and/or
•Clitoromegaly,
•Accelerated growth &
•Skeletal maturation
due to excess postnatal exposure to adrenal androgens.
*Milder deficiencies in adolescence or adulthood with:
•oligomenorrhea,
•hirsutism, and/or
•infertility
Salt losers
75% also have concomitant aldosterone deficiency
•Symptoms begin soon after birth
•Neonates may present within the 1st week of life
•severe salt wasting, present 1-4 weeks with:
* failure to thrive,
* recurrent vomiting,
* dehydration,
* hypotension,
* hyponatremia,
* hyperkalemia, and
* shock (classic salt-wasting)
•Milder : childhood
* early development of pubic hair, and/or
* phallic enlargement,
* accelerated linear growth and
* advancement of skeletal maturation
In females
Female pseudohermaphroditism
•Evidence of masculinization at birth;
–clitoral hypertrophy (may be penile),
–variable labial fusion & rugation,
–common vagina & urethra opening (urogenital sinus) leading to
–sexual ambiguity since exposure by 7th wk of gestation
•Mistaken diagnosis of hypospadias & cryptorchidism as the urethra opens below
After birth masculinization continues: →
–Pubic & axillary hair,
–Acne,
–Masculine voice,
–Tall for age,
–Muscular build,
–Advanced bone age
–Normal female internal organs,
–Breast development but
–No menstruation except androgen excess is suppressed by adequate tx
In males
Normal at birth usually
•Signs of precosity by 6/12 of life:
–Sexual: penile, scrotal, prostatic enlargement,acne, pubic & axillary hair,
–Somatic: well developed muscles,
•Initially accelerated linear growth
–cos of premature androgen excess,
–advanced bone age(extragonadal aromatization of androgens to estrogens)
•but if untreated;
–→ premature closure of epiphyses
–→ stunted adult with diminished final height.
•levels of adrenal androgens suppress gonadotropins & thus testicular fxn.
–May therefore affect spermatogenesis in poorly controlled CAH (in classic cases)
Cryptic or ‘’late-onset’’ 21OHlase deficiency
•Present in childhood or early adulthood with premature pubarche.
Diagnosis & differentials diagnosis
Females:
–Diagnosis obvious becauses of virilization
•Males:
–Diagnosis delayed because of normal genitalia with significant neonatal mortality but
–symptoms of salt losing may alert.
•Consider in newborn with:
•genital ambiguity,
•salt wasting or hypotension
•Differentials:
•Intestinal Obstuction,
•Cowmilk intolerance,
•pyloric stenosis
Types of deficiency and comments
•17alpha-hydroxylase——Males ambiguous/female genitals inadeq T2 ; females fail to achieve puberty (inadeq E2). Salt-wasting not observed. hypertension…rare
•3beta-hydroxy steroid dehydrogenase——Males have ambiguous/female genitals ; female virilization mild. Salt-wasting may be seen. Ambiguity in both sexes…rare
•11 beta-Hydroxylase CYP11B1- Females virilized; hypertension (accum of DOC)..1in 100,000
•aldosterone synthase CYP11B2——Cortisol concentrations normal and virilization not seen. Salt-wasting occurs…rare
•StAR——global steroid deficiency state Male ambiguous/female genitalia (inadeq T2) females fail to achieve puberty. Salt-wasting occurs….rare
Investigations
↑ serum 17-hydroxyprogesterone (usually >1000 ng/dL) & urinary pregnanetriol ( its metabolite
•↑ 24-hour urinary 17-ketosteroids, metabolites of adrenal androgens.
Salt-wasting forms :
–low serum aldosterone,
–hyponatremia,
–hyperkalemia,
–↑ plasma renin activity (PRA),
(indicating hypovolemia)
Q
Non-classic forms:
–Synthetic corticotropin (Cortrosyn) stimulation test
•to demonstrate the abnormal accumulation of precursor steroids
–CT scanning of adrenal gland:
•To exclude bilateral adrenal hemorrhage in patients with signs of acute adrenal failure
•X-ray of Left wrist and hand (usually > 2yrs)——in those presenting with precocious puberty
•Pelvic ultrasonography
•karyotype
•Genetic testing:
Treatment: Salt Wasting form
IV bolus of isotonic sodium chloride solution (20 mL/kg or 450 mL/m2) over the first hour,
•then a continuous IV infusion of 3200 mL/m2/d or as needed, to restore their intravascular volume and blood pressure.
•Dextrose must be administered if the patient is hypoglycemic & to prevent it
Supplementation with NaCl (2-4 g/d) added to formula.
•Salty diet in older children
•Caloric intake may need to be monitored and restricted if excess weight gain occurs because glucocorticoids stimulate appetite.
Treatment of CAH
Objectives differ with age
•Overall goal- long-term glucocorticoid replacement to inhibit excessive secretn of CRH & corticotropin from hypothalamus & pituitary & mineralocorticoid to prevent further salt wasting crises
•Suppress adrenal androgen secretion so normal growth & skeletal maturation can proceed
•Inadequate replacement results initially in accelerated linear growth but ultimately short stature due to premature epiphyseal closure
•Response is best monitored thro’ growth velocity & bone age, 17OHP, DHEAS, testosterone
Starting dose of hydrocortisone
–10-20mg/m2/d in 2-3 divided doses.
–↑ Up to 100 mg/m2/d in crisis & life threatening situations.
•Monitor treatment by
–assay of 17OHP (3- 30nmol/L)
–androstenedione, &
–testosterone (prepubertal C & women)
(at values app for age & sex,)
•linear growth,
•Bone age annually
•Goal of treatment:
–lowest dose that suppresses adrenal androgen &
–gives normal growth & weight gain
Hydrocortisone:
–short half life,
–better than prednisolone & dexamethasone in terms of SE.
•May give to older adolescents
–Prednisolone 5-7.5mg dly or
–Dexamethasone 0.25- 0.5 mg in 2 div doses.
•Monitor for signs of iatrogenic Cushing’s (HT, rapid wt gain striae)
•Treatment not indicated in asymptomatic non-classic 21OHlase def.
Mineralocorticoids
–required in salt- wasting
–Fludrocortisone 0.1- 0.2 mg dly.
•NaCl 2-17g (17-34mmol) daily
•Monitor adequacy with
–Serum K,
–BP,
–plasma renin
Infants with ambiguous genitalia require surgical evaluation
• if needed, plans for corrective surgery.
•clitoral recession early in life followed by vaginoplasty after puberty
Long-term medical therapy
Goals (4)
supplying enough glucocorticoid to reduce hyperplasia and overproduction of androgens or mineralocorticoids (normal conditions and during stress)
•providing replacement mineralocorticoid and extra salt if the person is deficient
•providing replacement testosterone or estrogen at puberty if the person is deficient
•additional treatments to optimize growth by delaying puberty or delaying bone maturati
Follow up
As puberty progresses, monitor for adrenal rests within the gonads.
• If ACTH is inadequately suppressed, these maybe mistaken for gonadal tumors and may cause gonadal pain.
•Adrenal rests more commonly found in testes than ovaries
• vaginal adequacy assessed because many females suffer from dyspareunia due to vaginal stenosis
Screening
Newborn screening programs:
–for 21-OH & 11-OH deficiency
–by measuring 17-hydroxyprogesterone and 11-deoxycortisol, respectively,
–from heel blood samples collected on filter paper
Benefits of Screening
•has prevented salt-wasting crises in males whose condition is unrecognized at birth
• resulted in identification of both completely virilized females who may be mistaken for males with cryptorchidism
• patients of both sexes with simple virilizing CAH , enabling early treatment before undue advancement in skeletal maturation.
Prevention
In parents contemplating a subsequent pregnancy, genetic counseling for prenatal diagnosis and treatment is important
•preimplantation genetic diagnosis
•Prenatal testing using chorionic villus sampling 8-12 weeks or amniocentesis 18-20 weeks
•Prenatal treatment to prevent the virilization due to 21-OH deficiency in a female fetus
mother is treated with 20 mcg/kg/d of dexamethasone divided into 3 doses as soon as the pregnancy is recognized
•to suppress fetal ACTH secretion and
• to prevent the fetal adrenal gland from overproducing adrenal androgens
Complications
Too little gc →adrenal insufficiency and further virilization in the virilizing forms.
•excessive administration include growth failure, obesity, striae, hypertension, hyperglycemia, and cataracts.
•excess mc → hypertension and hypokalemia
• Short stature is a frequent complication of virilizing forms
decreased fertility rate in females from
•abnormal genital anatomy,
•vaginal stenosis,
•poor control of adrenal androgen production that results in diminished ovulation.
When pregnancy does occur, baby born by means of caesarian delivery because of vaginal stenosis or an android pelvis
Psychological issues
Males with uncontrolled CAH may develop masses in testes (adrenal rests/ adrenal tissue)
•may cause discomfort & be mistaken for testicular tumors → unnecessary surgery.
•may cause oligospermia or azoospermia and infertility
Differential Diagnoses
•Adrenocortical tumour
–may be palpable or seen on pyelography, ultrasound or CT scan
•True precocious puberty
–testes are small in CAH for degree of virilization but
–enlarged in TPP
•Leydig cell tumors
Prenatal diagnosis & Treatment of CAH
Prenatal genetic counselling:
•Prenatal treatment
•17OH can be assayed in amniotic fluid
•21OHlase deficiency
•Maternal dexamethasone by 6th wk of pregnancy
–Dose- 20micgm/kg (pregnancy weight) in 3 div doses
•Determine sex thro’ villus biopsy in 1st trimester,
•Prompt & accurate genetic diagnosis
•Continue treatment if an affected female
•Stop dexamethasone if male or normal female
•Birth- Confirm diagnosis
•Give cortisol to newborm
•Side Effect of prenatal treatment
–Ethical issues
–Unproven safety:
•may impair memory fxns-
–short term sig diff in developing brain (sample size- small),
–long-term deleterious effects on fetus,
•maternal cushingoid effect.
•Long-term safety of prenatal tx is uncertain
Variable incidence of maternal complications (abt 1% of all txed)
•Hypertension,
•Excessive wt gain,
•Cushing’s syndrome.
