1. Congenital Adrenal Hyperplasia
Hala H Mosli
PGY-5
January 13, 2010

2. Objectives: Anatomy and Physiology of the adrenal glands
Definition of CAH
Pathophysiology of CAH
Clinical Features
Diagnosis
Management

3. Adrenal Facts….
The two adrenal (suprarenal) glands sit on top of the kidneys, one on each side.
They lie in the retroperitoneum at the level of T12
The adrenals are derived embryologically from the mesoderm and the neural crest.

4. Adrenal gland development and defects Kempna
Adrenal gland development and defects Kempna . Flu ̈ck, Best Practice & Research Clinical Endocrinology & Metabolism Vol. 22, No. 1, pp. 77–93, 2008

5. http://academic. kellogg. edu/herbrandsonc/bio201_mckinley

6. Adrenal Cortex: Mineralocorticoids:
Aldosterone: Secreted by the ZonaGlomerulosa of the adrenal cortex through stimulation by renin.
Renin, in turn, is regulated by multiple factors.
Main role is maintenance of fluid and electrolyte balance, thus playing a role in blood pressure control.

7. Epithelial Sodium Channel Mendelian Versus Essential Hypertension, Rossier and Schild, Hypertension. 2008;52:

8. Glucocorticoids:
Cortisol: secreted by the zonafasciculata of the adrenal cortex.
Overall actions are directed at enhancing the production of glucose and reducing all other metabolic activity not directly involved in this process:
Glucose metabolism:
Protein metabolism:
Lipid metabolism:
Glucose: Inhibits insulin secretion, promotes insulin resistance and
Hepatic gluconeogenesis…hyperglycemia
Protein: mainly catabolic effect…hyperaminoacidemia also promotes gluconeogenesis by stimulating glucagon secretion
Lipids: regulates fatty acid mobilization by enhancing activation of lipases

9. Anti-inflammatory activity
Causes a leukocytosis that reflects release from the bone marrow of mature cells as well as inhibition of their exit through the capillary wall.
Produces a redistribution of eosinophils and lymphoid tissue (esp T-cells) from the circulation into other compartments, which depletes their numbers and impairs cell-mediated immunity.

11. Cortisol has major effects on body water
Cortisol has major effects on body water. It helps regulate the ECFV by inhibiting the migration of water into cells and by promoting renal water excretion, the consequence is to prevent water intoxication by increasing solute-free water clearance.
Glucocorticoids also have weak mineralocorticoid-like properties, and high doses promote renal tubular sodium reabsorption and increased urine potassium excretion.
Can also influence behavior; emotional disorders may occur with either an excess or a deficit of cortisol.
Cortisol suppresses the secretion of pituitary POMC and its derivative peptides (ACTH,β-endorphin, and β-LPT) and the secretion of hypothalamic CRH and vasopressin.
the latter effect mediated by suppression of vasopressin secretion, by an increase in the rate of glomerular filtration, and by a direct action on the renal tubule.

13. Adrenal androgens:
The major androgen secreted by the adrenal is dehydroepiandrosterone (DHEA) and its sulfuric acid ester (DHEAS).
Smaller amounts of androstenedione, 11-hydroxyandrostenedione, and testosterone are secreted.
DHEA and androstenedione are weak androgens and exert their effects via conversion to the potent androgen testosterone in extraglandular tissues.

14. Adrenal androgens have a minimal effect in males whose sexual characteristics are predominately determined by gonadal androgens (testosterone).
In females, adrenal androgens mediate androgen-like effects eg sexual hair.
DHEA also has poorly understood effects on the immune and cardiovascular systems.
Adrenal androgen formation is regulated by ACTH, not by gonadotropins and are suppressed by exogenous glucocorticoid administration

15. Adrenal Medulla:
The adrenal medulla is the location of the majority of the organism’s chromaffin cells, derived embryologically from neuroectoderm
Ganglion cells and sustentacular cells are also found in the medulla.
Chromaffincells store catecholamines in secretory vesicles also known as chromaffingranules and are found in clusters (or nests) and in trabeculae,
Ganglion cells are found singly or in clusters interspersed among the chromaffin cells or in association with nerve fibres.
The sustentacular cells, or support cells, are located at the periphery of clusters of chromaffin cells.

16. The major secretory products of the adrenal medulla are the catecholamines epinephrine, and to a lesser extent norepinephrine.
Their release is stimulated predominantly by cholinergic innervation through the splanchnic nerve. The synthesis of epinephrine from norepinephrine is catalyzed by the enzyme phenylethanolamine N- methyltransferase (PNMT)
Also produce, store, and secrete a whole series of neuropeptides.
A minority of these cells also migrate to form paraganglia on both sides of the aorta, referred to as the organ of Zuckerkandl.

18. Congenital Adrenal Hyperplasia

19. Definition
Congenital adrenal hyperplasia is a group of autosomal recessive disorders resulting from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex.
Owing to this loss of enzyme function, patients with 21-hydroxylase deficiency cannot synthesize cortisol efficiently, and as a result, the adrenal cortex is stimulated by corticotropin and overproduces cortisol precursors

20. Congenital Adrenal Hyperplasia ,Speiser& White, N Engl J Med 2003;349:776-88.

21. The most frequent type is steroid 21-hydroxylase deficiency, accounting for more than 90% of cases.
Three other enzyme deficiencies in the steroid biosynthesis pathway, along with one cholesterol transport protein defect, account for the remaining cases.

22. The inheritance is autosomal recessive.
The overall incidence of CAH due to 21OHD is approximately 1 in 16,000, with variations seen in different ethnic and racial groups.
The inheritance is autosomal recessive.
The activity of 21-hydroxylase is mediated by cytochrome p450c21, found in the endoplasmic reticulum.
The 21-hydroxylase genes (CYP21) lie within the class III region of the human major histocompatibility complex on chromosome 6.
Molecular genetic testing of the CYP21 gene is available commercially and has the ability to detect common mutations and deletions in the different forms in up to 95% of affected individuals.

23. Congenital Adrenal Hyperplasia ,Speiser& White, N Engl J Med 2003;349:776-88.

24. 21OHD Deficiency
Classic
Salt-wasting
Simple virilizing
Non-classic
75%
Depending on the severity of the enzyme deficiency, 21OHD is defined as classic (severe form) or nonclassic (mild form).
Approximately 75% of patients who have the classic form also have salt wasting due to inadequate aldosterone production, further subdividing the classification into classic simple virilizing and classic salt-wasting forms.

26. Clinical Manifestations
Classic, salt-wasting CAH:
Classic, simple virilizing CAH:
Non-Classic CAH
progesterone and 17-hydroxyprogesterone

27. A. Classic, salt-wasting CAH:
In the classic, salt-wasting type
Due to inadequate synthesis of aldosterone
Elevated levels of 21-OHase precursors may act as mineralocorticoid antagonists, exacerbating the effects of aldosterone deficiency.

28. Excessive renal sodium-wasting leads to intravascular depletion and hypovolemia as well as hypereninemia
Abnormal renal handling of potassium leads to hyperkalemia, especially in infancy
Also have catecholamine deficiency, potentially further exacerbating shock
Patients with the salt-wasting form are identified through the measurement of serum electrolytes, aldosterone, and plasma renin and the finding of expected abnormalities — hyperkalemia, low levels of aldosterone, and hyperreninemia.
Age-specific reference values for renin should be used, since plasma renin activity is normally higher in neonates than in older children

29. Cortisol deficiency:
contributes to poor cardiac function, poor vascular response to catecholamines, a decreased GFR, and increased secretion of ADH.
The combination of cortisol and aldosterone deficiency leads to significant hypovolemia and shock.
Patients with salt-wasting form frequently present with acute adrenal crisis, often within the first few weeks after birth.

30. Typical Signs and Symptoms of Acute Adrenal Crisis
Decreased activity/fatigue
Altered sensorium/unresponsiveness
Poor feeding/weak suck
Dry mucous membranes
Hyperpigmentation
Abdominal pain
Vomiting
Hyponatremia
Hyperkalemia
Hypoglycemia
Metabolic acidosis
Hypothermia
Hypotension
Dehydration
Lack of weight gain

31. Hyperpigmentation of skin creases and genitalia may be early signs of adrenal insufficiency.
Affected infants initially demand frequent feedings, possibly due to dehydration or salt craving.
Poor feeding is a late sign of CAH and severe adrenal crisis

32. Androgen excess: Males are usually not affected by this.
Females mainly affected.
Girls with classic 21-hydroxylase deficiency are exposed to high systemic levels of adrenal androgens from approximately the seventh week of gestation

33. Consequences of exposure to high levels of androgens:
Ambiguous genitalia:
In the severe classic form
21OHD has been recognized as the most common cause of ambiguous genitalia in a genetically female fetus.
The phenotypic virilization varies from simple clitoromegaly, with or without partial fusion of the labioscrotal folds, to the appearance of a penile urethra.

34. A sex-determining region on the Y chromosome is required for differentiation of testes from the early bipotential gonads between 6 and 8 weeks of gestation.
Whether male or female internal genitalia develop depends on the presence of two hormones produced by the fetal testis: testosterone, secreted by the Leydig cells, and anti-Mu ̈llerian hormone (AMH), secreted by the Sertoli cells.
By 8 weeks of gestation, a normal male fetus is able to secrete these two hormones.
Fetal internal and external genitalia initially are bipotential, with the presence of both Wolffian and Mu ̈llerian ducts presenting the potential for developing male or female internal genitalia, respectively.

35. http://www. ncbi. nlm. nih. gov/bookshelf/br. fcgi

36. the important differentiating points are the absence of testes and pres- ence of normal uterus and ovaries.

38. In males: subtle penile enlargement and slight hyperpigmentation.

39. Postnatal virilization:
In patients who either are not treated or are inadequately treated, long-term exposure to high levels of sex hormones promotes rapid somatic growth (predominantly an androgen effect) and advanced skeletal age, which leads to premature epiphyseal fusion (predominantly an effect of extragonadal aromatization of androgens to estrogens).
Pubic and axillary hair may develop early.
Clitoral growth may continue in girls

40. In boys:
May have penile growth despite having small testes, since the androgens are adrenal in origin.
Long-term exposure to androgens may activate the hypothalamic–pituitary–gonadal axis, causing centrally mediated precocious puberty.

41. Linear growth:
Linear growth is affected by congenital adrenal hy- perplasia, even with close therapeutic monitoring.
A meta-analysis of data from 18 centers showed that adult heights in patients with classic congenital adrenal hyperplasia averaged 1.4 SD below the population mean.
Both undertreatment and overtreatment put patients at risk for short stature.

42. Reproductive function:
Females:
Oligomenorrhea or amenorrhea may develop in ado-lescence.
Prenatal exposure to androgens may influence subsequent sex-role behavior.
Most affected females have been reported to exhibit increased behavior more typical of boys during childhood in terms of toy preferences, rough play, and aggressiveness.
However, most women are heterosexual, and their sexual identity is almost invariably female.
Women with classic salt-wasting or simple virilizing disease who were born and treated in the 1940s and 1950s had a tendency to shun heterosexual relationships, especially if the introitus was inadequate or androgen levels were chronically elevated

43. The issue of fertility is inextricably related to psychosocial adjustment
With improved therapy, more women with 21- hydroxylase deficiency have successfully completed pregnancies and given birth, most by cesarean section.
About 80% of women with simple virilizing disease and approximately 60% of those with the severe salt-wasting form are fertile.

44. In males:
Affected men have fewer problems with reproductive function, specifically gonadal function.
Most have normal sperm counts and are able to father children.
One relatively common form of gonadal abnormality in affected males is the development of testicular adrenal rests, detectable by sonographic imaging before they become palpable.
Such tumors have been detected even in childhood.

45. In males with salt wasting, testicular rest tissue may be accompanied by deficient spermatogenesis despite treatment.
These tumors, although almost invariably benign, have prompted biopsies and even partial orchiectomy.
Proper medical treatment consists of pituitary suppression with dexamethasone, since the tumors are usually responsive to corticotropin.
Infertility can be circumvented by intracytoplasmic sperm injection

46. B. Classic, simple virilizing CAH:
Patients with simple virilizing 21-hydroxylase deficiency do not synthesize cortisol efficiently, but adequate aldosterone secretion remains and thus sodium balance is maintained.
Usually diagnosed in female patients shortly after birth owing to genital ambiguity,

47. In males, the diagnosis is often delayed for several years.
Without newborn screening, affected boys are usually identified when signs of androgen excess develop.
Later diagnosis is associated with greater difficulty in achieving hormonal control, abnormal tempo of puberty, and short stature.

48. Non-Classic CAH:
Nonclassic 21OHD may be the most common autosomal recessive disorder in humans.
Its prevalence rate is approximately 3.7% (1 in 27) in Ashkenazi Jews and 0.1% (1 in 1,000) in white populations
These patients produce normal amounts of cortisol and aldosterone at the expense of mild-to-moderate overproduction of sex hormone precursors.
Family studies indicate that overt androgen excess never develops in many patients with non-classic disease.

49. A few non-classic cases are detected by newborn-screening programs, but most are missed because of the relatively low baseline levels of 17-hydroxyprogesterone.
It is not known what proportion of cases diagnosed by neonatal screening eventually become symptomatic.
Some children grow rapidly or have advanced bone age, and pubic or axillary hair prematurely develops in some.

50. Hirsutism is the single most common symptom at presentation in approximately 60% of symptomatic women, followed by oligomenorrhea (54%) and acne (33 percent), as well male-pattern baldness.
Can also have PCOS.
Short-stature, insulin resistance and severe cystic acne can occur in both males and females with non-classic CAH

51. Decreased fertility is an indication for glucocorticoid treatment in both men and women
The prevalence of non-classic 21-hydroxylase deficiency is not greater among patients in infertility clinics than in the general population
Infertility appears to be a presenting symptom in only 13% of women with non-classic 21-hydroxylase deficiency.

53. Diagnosis
Classic 21-hydroxylase deficiency is characterized by markedly elevated serum levels of 17-hydroxy- progesterone
Basal 17-hydroxyprogesterone values measured by radioimmunoassay usually exceed 10,000 ng/dL (300 nmol/L) in affected infants (levels in normal newborns are below 100 ng/dL (3 nmol/L))
10% have low 17-Ohprogesterone. False negative when patients discharged before they are 2-3 days old…no normative data.

54. The gold standard for differentiating 21-hydroxylase deficiency from other steroidogenic enzyme defects is the cosyntropin stimulation test, performed by injecting a mg or 0.25-mg bolus of cosyntropin and measuring baseline and stimulated levels of 17-hydroxyprogesterone.

55. should be obtained immediately prior to
To make the diagnosis and to help determine the deficient enzyme a full adrenal profile, including measurement of:
17-OHP,
cortisol,
deoxycorticosterone,
11-deoxycortisol,
17-hydroxypregnenolone,
dehydroepiandrosterone(DHEA),
androstenedione,
should be obtained immediately prior to
and 60 minutes after cosyntropin administration

57. Elevated plasma renin activity (PRA) values, particularly the ratio of PRA to aldosterone, are markers of impaired mineralocorticoid synthesis.
Additional tests for evaluation of ambiguous genitalia include a rapid karyotype and pelvic and abdominal ultrasonography.
Identification of internal structures such as a uterus or ovaries via US may be helpful in initial period, when both parents and clinicians are seeking rapid answers.
Additional testing may be required, depending on the outcome of initial tests

58. Characteristics of Different Forms of CAH

60. Treatment
Acutely: Management of acute adrenal crisis +/- initial diagnosis.
Pediatric stages
Adult stages

61. Multidisciplinary team:
Endocrinologists,
gynaecologistsspecializing in reconstructive surgery,
urologists,
fertility specialists,
Dietitians
Sex therapists
biochemists,
geneticists,
psychologists and
clinical nurse specialists

62. Acute Adrenal Crisis:
Fluid resuscitation with a 20-mL/kg bolus of 0.9% normal saline + boluses PRN + replacement of ongoing losses
Stress doses of hydrocortisone (100 mg/m2 per day) as early as possible
CV access
Vasopressors
Glucose
Management of hyperkalemia

63. Pediatrics: Glucocorticoid therapy: Replace adrenal function
Suppress ACTH and CRH
Suppress androgen formation

64. In children, the preferred cortisol replacement is oral hydrocortisone, in three divided doses of 10 to 20 mg/m2 per day.
Hydrocortisone is the treatment of choice due to its short half-life and minimal growth suppressive effect.
Treatment efficacy is assessed by monitoring ACTH, 17-OHP, DHEA, and androstenedione.
A target 17-OHP range of 500 to 1,000 ng/dL, although still higher than normal, helps to avoid the adverse effects of overtreatment.
Patients should be monitored carefully for signs of iatrogenic Cushing syndrome, including rapid weight gain, poor growth velocity, hypertension, pigmented striae, and osteopenia. Children also should have an annual bone age radiograph and careful monitoring of linear growth. Advanced bone age and increased growth velocity should alert pediatricians to undertreatment

65. In older children and adolescents, where growth is complete, once-daily dexamethasone offers a simpler dosing regimen and may be considered instead of hydrocortisone for improved compliance.
Require stress dosing orally or intravenously according to the degree of systemic stress.
Medical alert bracelet.
Medical information card

66. Mineralocorticoid replacement:
In infants with the salt-wasting form.
Require treatment with fludrocortisone and sodium chloride
The dose of fludrocortisone is usually 0.1 to 0.2 mg, but occasionally patients require up to 0.4 mg/day.
Supplementation with 1 to 2 g of sodium chloride often is required (each gram of sodium chloride contains 17 mEq of sodium)
Requirements decrease. Develop taste for salty foods.
Monitoring with PRA: Hypertension, tachycardia, and suppressed PRA production are clinical signs of overtreatment.

67. Genital surgery:
Affected female infants may require surgical reconstruction, with reduction clitoroplasty and construction of a vaginal opening.
Later revision may be required.
With appropriate management, a normal sex life and fertility may be expected.

68. Adults: Many areas to be addressed. steroid replacement:
No optimum regimen
Variable dosing
Main concern is overtreatment/steroid overexposure as well long term sequelae of treatment with steroids.
General strategy is minimum effective dose, monitoring clinical and biochemical markers.
 17OHP---short term ≈ Random blood sugar
Testosterone and androstenedione---longer term ≈ glycated hemoglobin. Indicate undertreatment.

69. The optimal dose of glucocorticoid is that which fails to fully suppress 17-hydroxyprogesterone and maintains androgens in the mid-normal range.
In transition from pediatric care, compliance can be very variable but often improves in the third decade of life, allowing reduction of ‘prescribed’ doses in early adult life

70. Mineralocorticoid replacement:
Requires precise monitoring in adulthood
An important aspect is the tendency towards HTN is adulthood.
Goal is to maintain normal blood pressure, normokalemia, and PRA in the upper range of normal.

71. Bone density:
The overall conclusion from several studies is that, despite lower serum concentrations of bone turnover markers, bone density is normal in most individuals with CAH.
Unless there is a clinical suspicion of previous overtreatment with glucocorticoids, routine bone density measurements are not necessary in the young adult with CAH.
If there is evidence of significant glucocorticoid overtreatment, one baseline BMD measurement is probably justified

72. Adult female issues Fertility in women with CAH:
Usually reduced, especially in the salt-wasting from.
Multifaceted – biological, psychological, social and sexual factors
Fertility reported spontaneously, with induced ovulation, and improves post-bilateral adrenalectomy.
Treatment of CAH in pregnancy:
Several new management issues arise.
Glucocorticoidreplacement should consist of either prednisolone or hydrocortisone, not dexamethasone.
Two main strategies:
Maintain glucocorticoid replacement at prepregnancy doses, increasing doses of hydrocortisone and mineralocorticoid as indicated by maternal symptoms alone.
Monitor testosterone and 17α-hydroxyprogesterone and aim to suppress these markers to the top of the normal pregnancy range.
dexamethasone is not inactivated by placental 11β-hydroxysteroid dehydrogenase and therefore can cause suppression of the fetal adrenals and low birthweight.
In cases of maternal CAH, however, fetal virilization is extremely rare. Cliteromegaly in the female newborn has been reported in a CAH mother who stopped glucocorticoid treatment prepregnancy.

73. Adult male issues:
Long-term control of CAH in men is required to preserve fertility.
There have been a series of anecdotal reports of testicular abnormalities in male patients with CAH, which have been correlated with fertility and glucocorticoidsuppression
Large palpable tumors were associated with low testosterone and normal LH levels
In patients with known CAH, adrenal rest tissue can be clinically differentiated from Leydig cell tumors as it is more often bilateral, occurs in men who show evidence of poor adrenal suppression and the tumor regresses with increased glucocorticoidsuppression
. If the mass is located near the mediastinum testis and does not show distortion of testicular contour then it is more likely to be an adrenal rest

74. LH suppression:
Uncontrolled adrenal androgen secretion in men with CAH can result in increased aromatization of androgen to estrogen.
Estrogen feeds back to the pituitary gland to cause gonadotrophinsuppression
Some men with CAH have hypogonadotrophichypogonadism and small testes and this picture reverses with increased glucocorticoid suppression as androgen and estrogen levels decrease and fertility is restored
Natural history of fertility in men with CAH is unclear; may be prudent to offer semen preservation to all patients.

75. Prenatal screening and diagnosis
Molecular genetic testing of the fetus is available
Prenatal genetic counseling is advised for all affected families.
Prenatal treatment is possible
Maternally administered dexamethasone ameliorates genital ambiguity in affected female fetuses
The recommended dose is 20 μg/kg body wt/d(based on prepregnancy weight), given in three divided doses.

77. Newborn Screening
Screening programs for CAH were developed primarily to identify cases in male infants of the salt-wasting type of classic 21OHD, where clinicians may not be alerted to the disorder given the lack of genital ambiguity.
Newborn screening also helps avoid incorrect sex assignment in newborn females born with severe virilization.
Most states in the United States include CAH in their newborn screening panels by measuring 17-OHP concentrations using filter paper blood collection cards, which also are used to screen for hypothyroidism, phenylketonuria, and other disorders

78. Screening performed in Ontario

79. THANK YOU

81. References
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Epithelial Sodium Channel Mendelian Versus Essential Hypertension, Rossier and Schild, Hypertension. 2008;52:

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