Download Adrenal Disorders in Infants and Children ARS Question #1 Adrenal

Adrenal Disorders in Infants
and Children
Anzar Haider, M.D.
Staff Pediatric Endocrinologist
CCF Pediatric Board Review Symposium
August 2012
ARS Question #1
The adrenal glands are located:
A. Next to the pancreas
B. Near the thyroid gland
C. Adjacent to the pituitary gland
D. On top of the kidneys
E. Near the ovaries
Adrenal Gland Location
Embryology
• Cortex derived from mesoderm
• Medulla derived from neuroectoderm
• Gonadal differentiation: 6 weeks
• Adrenal function : 9-12 weeks
Fetal Adrenal
• Large fetal zone functions similar to
Reticularis; regresses afterbirth
• Transient zone functions similar to
Fasciculata
• Outer zone (Definite zone) evolve to
Glomerulosa
ARS Question #2
The principal hormones of the adrenal cortex
include all of the following EXCEPT:
A. Renin
B. Aldosterone
C. DHEA
D. Androstendione
E. Cortisol
Adrenal Physiology
15 %
Zona glomerulosa
Mineralocorticoids
75%
Zona fasiculata
Glucocorticoids
Zona reticularis
Androgens
Medulla
Catecholamines
10 %
Steroidogenesis
• Begins with cholesterol; mostly dietary
• Adrenal can synthesize cholesterol from acetate
• Adrenal and gonadal have similar enzymes
• 2 important enzyme groups in steroidogenesis
– Cytochrome P-450
– Hydroxysteroid dehydrogenesis
Adrenal Physiology
Control of Adrenal Cortex
Na, K, BP
Stress
CRH
Renin-Angiotensin
ACTH
Aldosterone
Cortisol
Androgens
ARS Question #3
Causes of primary adrenal failure include all of
the following EXCEPT:
A. Infection (TB, HIV)
B. Genetic defect
C. Autoimmune
D. Hemorrhage
E. Hypopituitarism
Primary Adrenal Insufficiency
Congenital
• Congenital Adrenal Hypoplasia
• Congenital Adrenal Hyperplasia
• Familial Glucocorticoid Deficiency (ACTH Res)
• Metabolic Disease : ALD; Wolmans, SLO
Congenital Adrenal Hypoplasia:Etiologies
• DAX-1: Dosage-sensitive sex reversalAdrenal hypoplasia congenital gene on the
X-chromosome, gene 1
• SF-1: defect may cause adrenal failure and or
XY sex reversal
• Autosomal Recessive defect
• IMAGe: Intrauterine growth retardation,
metaphyseal dysplasia, adrenal
insufficiency,genital abnormalities
Congenital Adrenal Hypoplasia
• May develop hyperpigmentation from ACTH.
• Signs of dehydration are often present.
• Hypotension and neuroglycopenia may be
present.
• Testes often undescended and micropenis is
rare. Other urologic anomalies have
occasionally been reported.
• X linked and autosomal recessive forms
DAXDAX-1 Gene
• Important in hypothalamic, gonads, adrenal dev
• Presents with adrenal crises in neonatal
sometimes may present late with growth failure,
primary adrenal insufficiency, hypogonadotropic
hypogonadism
• Impaired spermatogenesis
• May be part of Contiguous gene deletion
(Duchenne Muscular dystrophy, Glycerol kinase
deficiency
SFSF-1 gene defects
• Crtical for dev & function of adrenal
glands, gonads, gonadotropes
• May cause adrenal failure, XY sex
reversal,
• Isolated adrenal failure in females
Other Genetics form of Adrenal
insufficiency
• Adrenoleuokodystrophy: (Lorenzo’s oil)
– X Linked ABCD1 gene defect causing
peroxisomal disorder
– Characterized by accumulation of VLCFA in
the adrenal cortex , myelin of the CNS,
Leydig cells of the testes
– Treatment: gluco and mineralocorticoid; BMT
• Wolman disease: lipid storage disease with
adrenal calcification.
–
Acquired Adrenal Disorders
• In developed countries most common
cause is autoimmune destruction
– Isolated disorder or part of polyglandular
syndrome
– Type 1 polyglandular syndrome in first
decade
– Type 2 polyglandular syndrome in second
decade
Type 1 Polyglandular syndrome
• Hypoparathyroidism
• Adrenal insufficiency
• Mucocutaneous candidiasis
– Other features include hypothyroidism,
gonadal failure, Diabetes mellitus type 1,
vitiligo, alopecia, chronic active hepatitis,
and pernicious anemia
• Mutations in AIRE gene
Type 2 Polyglandular Syndrome
• Adrenal insufficiency
• Hypothyroidism (Schmidt syndrome)
• Type 1 diabetes mellitus (Carpenter )
– Other features include pernicious anemia,
vitiligo, gonadal failure, celiac, Sjogrens,
Graves disease, Myasthenia gravis
• Associated with HLAs DR3 &DR4
Acquired Adrenal Insufficiency
• Adrenal hemorrhage ( newborn with
prolong labor, traumatic birth,
Waterhouse Fredrichsen syndrome)
• Infections (e.g., TB, HIV, fungal, CMV,
Histoplasmosis, )
• Neoplastic destruction
• Medications: Ketoconazole, Megace
ARS Question #4
Patients with secondary adrenal insufficiency
may have all EXCEPT:
A. Weakness and fatigue
B. Hypoglycemia
C. Hyponatremia
D. Hyperkalemia
E. Hypotension
Adrenal Insufficiency :
Clinical Features
Symptoms
Signs
Fatigue
Orthostatic
Labs
cortisol
Dizziness
Hypotension
PRA
Anorexia
Tender abdomen
Glucose
Abdominal pain
Dehydration
sodium
Weight loss
Shock
calcium
Primary Adrenal Insufficiency:
Salt craving
Hyperpigmentation ACTH
Potassium
Aldosterone
Secondary Adrenal Insufficiency
• Loss of adrenal glucocorticoids and
androgens
• Normal mineralocorticoid production
• May have hyponatremia but normal
serum potassium levels
• Due to deficiency of ACTH or CRH, or
resistance of adrenal gland to ACTH
Secondary Adrenal Insufficiency
• CNS processes that affect
hypothalamus or pituitary
• Defects in ACTH receptor (MCR2)
• Allgrove syndrome (4-A Syndrome)
– AR loss of AAAS gene
– Adrenal insufficiency, Achalasia, Alacrima
– Autonomic abnormalities
– May be variable expressivity
ARS Question #5
21 hydroxylase deficiency CAH is associated
with all of the following EXCEPT:
A. Genital ambiguity
B. Growth failure
C. Infertility
D. Irregular menses
E. Acne
Pathophysiology of Various Forms Of
Congenital Adrenal Hyperplasia
• Specific deficiency of one of the enzymes
needed for cortisol biosynthesis
• Resulting in:
– Decreased cortisol production
– Increased ACTH
– Adrenal hyperplasia
– Increased precursors to cortisol
Common Enzyme Defects that
Cause CAH
• 21-OHase deficiency accounts for 95%
– Salt wasting (60-75%)
– Simple virilizing
– Non-classical (late onset)
• 11-OHase deficiency
– Hypertension
• 3-HSD (type II)
– Ambiguous genitalia
– Salt wasting
21 hydroxylase defect
Cholesterol
SCC CYP11A1
Pregnenolone17OHlase17-OH-Pregnenelone
CYP17
3HSD 3HSDII
3HSD 3HSDII
17,20lyase
DHEA
CYP17
3HSD 3HSDII
17,20lyase
17OHlase
17-OH-Progesterone
Androstenedione
CYP17
17 ketoreductase HSD3
21OHlase CYP21A2
21OHlase CYP21A2
DOC
11-deoxycortisol
11OHlase CPY11B1
11OHlase CPY11B1
Corticosterone
Cortisol
Testosterone
5 reductase SRD5A2
DHT
18OHlase CYP11B2
18-OH-Corticosterone
Aldo Synth CYP11B2
Aldosterone
11 hydroxylase defect
Cholesterol
SCC CYP11A1
Pregnenolone17OHlase17-OH-Pregnenelone
CYP17
3HSD 3HSDII
3HSD 3HSDII
17,20lyase
DHEA
CYP17
3HSD 3HSDII
17,20lyase
Progesterone 17OHlase 17-OH-Progesterone
CYP17
21OHlase CYP21A2
DOC
21OHlase CYP21A2
11-deoxycortisol
11OHlase CPY11B1
11OHlase CPY11B1
Corticosterone
Cortisol
18OHlase CYP11B2
18-OH-Corticosterone
Aldo Synth CYP11B2
Aldosterone
Androstenedione
17 ketoreductase HSD3
Testosterone
5 reductase SRD5A2
DHT
3 β HSD defect
Cholesterol
SCC CYP11A1
Pregnenolone17OHlase17-OH-Pregnenelone
CYP17
3HSD 3HSDII
3HSD 3HSDII
17,20lyase
DHEA
CYP17
3HSD 3HSDII
17,20lyase
Progesterone 17OHlase 17-OH-Progesterone
CYP17
21OHlase CYP21A2
DOC
21OHlase CYP21A2
Androstenedione
17 ketoreductase HSD3
11-deoxycortisol
11OHlase CPY11B1
11OHlase CPY11B1
Corticosterone
Cortisol
Testosterone
5 reductase SRD5A2
DHT
18OHlase CYP11B2
18-OH-Corticosterone
Aldo Synth CYP11B2
Aldosterone
Various Forms of 2121-hydroxylase
Deficiency With Different Phenotypes
• Classic or early onset
– Simple virilizing form (<10% enzyme activity)
– Salt-wasting form (<1% enzyme activity)
• Non-classic or late onset
– (30-50% enzyme activity)
– Premature pubarche or adrenarche
– Severe acne or hirsutism
– Menstrual abnormalities
– Female pattern baldness
CAH DUE TO 2121-OHase DEFICIENCY
• Occurs frequently in sibs
• Salt wasters become hyperkalemic
before hyponatremic
• Sex ratio is about 1:1
• Parents are not affected
• Genetic disorder transmitted as an
autosomal recessive trait
Mutations 2121-hydroxylase
(CYP21) Gene
C4a
CYP21P
C4b CYP21
• Two CYP21 genes in tandem with two C4 genes
on 6p21 within HLA locus
• Genetic instability of unit
– Misalignment and unequal crossover in meiosis
– Gene conversion during mitosis
• Gene conversions account for most mutations
Why Screen for CAH?
• Early screening detects the 70% of boys and
25% of girls with CAH missed on clinical
examination.
• Early treatment prevents adrenal crisis and
infant death
• Makes earlier gender assignment possible (3
days versus 23 days)
• Prenatal diagnosis permits dexamethasone
treatment (before 7 weeks) to reduce risk of
virilization of affected female fetus
Timing Of Blood Collection For
CAH Screening
• Adrenal crisis occurs at 2-3 weeks of age
– Median age of diagnosis in boys is 21 days
without screening and 9 days with screening1
• Many European programs test after 48 h
• Most U.S. programs test
– Within first 48 h and then repeat at 2 wk
– If before 24 h, then repeat at 48 h
– NICU on admission, then repeat
1Thilen
et al., Pediatrics 1998;101.
Congenital Adrenal Hyperplasia
• Laboratory evaluation
– 17OHP best screen and diagnostic test
• 17OHP > 10,000 ng/dL in classic type
• 17OHP > 1,000 ng/dL non classic type
– Newborn screening programs use cutoff
values based on gestational age
ARS Question #6
•
The clinical features of Cushing syndrome
include all of the following EXCEPT:
A. Hypertension
B. Obesity and striae
C. Alopecia
D. Growth failure
E. Precocious body hair distribution
Growth in Cushing Syndrome
• Obesity and Cushing
syndrome share many
common features
• Weight increases in
both obesity and
Cushing syndrome
• Growth velocity
increases in obesity
• Growth velocity
decreases in Cushing
syndrome
Clinical Features of Cushing
Syndrome
• Appearance can differ from adults with gross
obesity rather than central obesity
• Thin skin, bruising, and violaceous striae
• Pubic hair, acne, virilization, fuzzy hair
• Hypertension
• Muscle weakness and osteoporosis
• Glucose intolerance
• Psychosis
Cushing Syndrome
• Excess secretion of cortisol with loss of
diurnal variation
• Cushing syndrome refers to excessive
exposure to endogenous or exogenous
steroids
• Cushing disease refers to pituitarydependent ACTH production
– Pituitary adenoma or hypothalamic defect
Cushing Syndrome in Children
• Most common cause is iatrogenic
• Endogenous disease is rare
• Young children more likely to have
adrenal adenoma
• Older children more likely to have
pituitary dependent disease
• Nodular adrenal hyperplasia can cause
cyclical Cushing syndrome
Evaluation
• Select patients carefully – this is rare!
• Avoid random serum cortisol levels
• Midnight salivary cortisol is ideal
• 24 hour urinary free cortisol collection
• Overnight dexamethasone suppression
• Androgens (T and DHEA) also high
• Image CNS/adrenals AFTER lab confirmation!
Adrenal Tumors
• Adrenal cortical tumors are rare
• Often malignant in children
• May secrete several hormones
– Glucocorticoids
– Mineralocorticoids
– Androgens
– Estrogens
High Morbidity and Mortality
• Perforated viscera and opportunistic
fungal infections.
• Suppression of the HPA axis, with full
recovery taking up to 1 year
• After resolution patients are at risk for
developing an adrenal crisis.
• A primary pituitary tumor may cause
panhypopituitarism and visual loss.
Adrenal Medullary Disorders
• Pheochromocytoma
– Very rare (1:100,000 persons)
– 90% are benign and unilateral
– 90% are sporadic
– May be part of a familial syndrome
• Secrete excess catecholamines
– Sporadic tumors & non adrenal source secrete
norepinephrine
– Familial tumors & adrenal secrete epinephrine
ARS Question #7
Pheochromocytoma is associated with all of the
following disorders EXCEPT:
A. Neurofibromatosis
B. Von Hippel Landau syndrome
C. MEN 1
D. MEN 2A
E. MEN 2B
VON HIPPELHIPPEL- Landau Syndrome
•
•
•
•
•
•
•
•
•
V isual defect
O cular defect (retinal angioma)
N ephron (renal Ca)
H emangioblastoma of Cerebellum
I ncreased intra cranial pressure
P heochromocytoma
P ancreatic Cyst
E ctopic erythropoetin
L iver cyst
Pheochromocytoma Evaluation
• Headache, palpitations, diaphoresis and nausea
• 90% of patients have hypertension
• May have hyperglycemia or hypercalcemia
• 24 hr urine total catecholamines, vanillylmandelic
acid (VMA), and metanephrines
• Plasma metanephrine and normetanephrine
• Localize tumor with MRI, use 131I-MIBG only if
MRI is negative
Pheochromocytoma Evaluation
Once pheochromocytoma is diagnosed rule out
a familial syndrome:
• MEN 2A and MEN2B
– Serum levels of PTH and calcitonin
– RET gene analysis is commercially available
• Von Hippel Landau
– MRI of brain for cerebellar hemangioblastomas
– VHL gene testing is available
• Neurofibromatosis
Summary
• CAH is most important adrenal disorder
– 21 hydroxyase deficiency
– 17OHP screening test
• Childhood Cushing syndrome
– Delayed bone age and short stature
• Pheochromocytoma
– Part of several familial syndromes