Transcript ENDO HOUR

Marianne Joy B. Advincula, MD
 E.S.
 9/F
 Bataan
 Follow up consult
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.
 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
Review of systems
 (-) cough
(-) colds
(-) fever
 (-) diarrhea
(-) vomiting (-) headache
 (-) seizures
(-) BOV
(-) LOC
 (-) changes in sensorium
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
Family Medical History
 (+) ambiguous genitalia- sibling, died at 5 months of
age
 (+) HTN- grandmother
 (-) DM
 (-) Cardiac disease
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.
Nutritional history
 Initially breastfed at birth then shifted to Neosure.
Complementary feeding started at 6 months of age.
Presently eats regular table food.
Immunization History
 (+) BCG
 (+) DPT3
 (+) OPV
 (+) Hepa B
 (+) 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
Personal Social History
 Px is the only living child of a 37 y/o mother and a 35
y/o father, tricycle driver
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
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
Diagnosis
 CAH, salt losing
 S/P Genitoplasty (2005)
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
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.
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.
21-Hydroxylase deficiency
It is characterized by reduced
production of cortisol and aldosterone
and increased production of
progesterone;
17OH-progesterone, and sex steroids.
The urinary steroid metabolites
(17-ketosteroids and pregnanetriol)
are elevated above normal levels.
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.
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 nonclassic type remains asymptomatic till
late childhood when they may show
signs of sexual precocity.
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.
11-b-Hydroxylase
Accounts for 5-10% of casesDeficiency
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 11deoxycorticosterone.
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.
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.
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.
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
Enzyme pathway

Result of a 21-Hydroxylase Deficiency
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.
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. 17OH-Progest. or 11-Deoxycortisol.
ESSENTIALS OF DIAGNOSIS
Diagnosis is confirmed by
measurement of ACTH, Cortisol,
Aldosterone,
17-OHprogesterone, Testosterone &
urinary 17-ketosteroids.
Needs alertness for the possibility in
all babies with Diarrhea & Vomiting,
hypoglycemia or  BP.
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.
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.
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.
BOYS
WITHatCAH
Are unrecognized
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 mineralocorticoid
desoxycorticosterone
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 17hydroxyprogesterone).
Laboratory Findings
11-b-hydroxylase deficiency is
characterized by high serum 11deoxycorticosterone and 11deoxycortisol concentrations with
elevation of its urinary metabolites
(tetrahydrocompound-S).
Both are accompanied by elevated 24hour urinary 17-ketosteroids, the
urinary metabolites of adrenal
androgens.
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.
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.
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.
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.
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
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.
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.
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)
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.
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.
Prenatal diagnosis
Done by chorionic villus sampling
at 8-12 wk & amniocentesis at 1820 wk.
HLA typing in combination with
measurement of 17-OHprogesterone & androstenedion in
amniotic fluid is used for antenatal
diagnosis.
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.
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.
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.