Transcript CAH

Congenital Adrenal Hyperplasia (CAH) and
Congenital Hypothyroidism (CH)
the importance of newborn screening
Balázs Gellén MD. Ph.D.
Dept. of Pediatrics
University of Szeged
Congenital adrenal hyperplasia (CAH)
Refers to autosomal recessive
diseases resulting from mutations of
genes for enzymes mediating the
steroidogenesis from cholesterol by
the adrenal glands
Associated conditions
The symptoms of CAH vary depending upon the form of CAH and
the gender of the patient.
Symptoms can include:
• Due to inadequate mineralocorticoids:
- vomiting due to salt-vasting leading to dehydration and death
• Due to excess mineralocorticoids:
- hypertension (11 β-OH deficiency)
• Due to excess androgens:
- ambiguous genitalia in some females, such that it can be
initially difficult to determine sex
- early pubic hair and rapid growth in childhood
- precocious puberty or absent or delayed puberty
- virilization (enlarged clitoris and shallow vagina), and/or
menstrual irregularity in adolescence
- infertility due to anovulation
Classification
• Cortisol production begins in the second month of
fetal life. Inefficient cortisol production results
in rising levels of ACTH, which in turn induces
overgrowth (hyperplasia) and overactivity of the
androgen-producing cells of the adrenal cortex.
• Synthesis of cortisol shares steps with synthesis
of mineralocorticoids, androgens, and estrogens.
• The resulting excessive or deficient production of
these three classes of hormones produce the most
important problems for people with CAH.
11β-hydroxylase
Common
medical
term
enzyme
locus
Substrate
Products
Minera Andro
locorti gens
coids
21OH90ase def. 95%
P450c21
6p21.3
17OHprogesterone
→
progesterone→
11deoxycortisol
DOC
↓
↑
11βOH- 5%
ase def.
P450c
11β
8q2122
11deoxycortisol→
DOC→
cortisol,
corticosteron
↑
↑
1p13
pregnenolone →
17OHpregnenolone →
DHEA →
progesterone
17OHprogesterone
androstenedion
↓
↓
17αOH- Very P450c17
ase def. rare
10q24.
3
pregnenolone →
progesterone→
17OHpregnenolone
→
17OHpregnenolone
17OHprogesterone
DHEA
↑
↓
20,22- Very StarP45
desmola rare 0scc
se def.
8p11.2
15q23q24
transport of
cholesterol
cholesterol →
into mitochondrial
pregnenolone
↓
↓
3βHSD
def.
%
Very 3βHSDI
rare I
21-hydroxylase deficiency
• The defective enzyme is P450c21 (cytochrome
P450 oxidase ), commonly referred to as 21hydroxylase (21-OH), encoded by the CYP21 gene.
• CAH due to 21-OH deficiency accounts for about
95% of diagnosed cases of CAH.
• The terms "salt-wasting CAH", and "simple
virilizing CAH" usually refer to subtypes of this
condition.
• The incidence of salt wasting CAH is 1 in
15,000 children !!!
21-hydroxylase CAH is inherited in an autosomal recessive fashion
CYP21 is paired with a nonfunctional pseudogene CYP21P
Penetrance
Variability and recombination of abnormal
alleles of CYP21 and homologous region of
CYP21P gene is introduced by the degree of
enzyme inefficiency.
• severe degrees produce changes in the fetus
and problems in prenatal or perinatal life
• milder degrees are usually associated with
excessive or deficient sex hormone effects in
childhood or adolescence
Type of 21OHD
Sex steroid effects
Other effects
Severe
The most common cause Salt-wasting crisis - life-
salt-wasting CAH
of ambigous genitalia
threatening vomiting and
due to prenatal
dehydration occurring
virilization of
within the first few weeks
genetically female (XX)
of life.
infants.
17OHP ↑ ↑ (30 ng/ml <)
Aldosterone ↓ Cortisol ↓
Moderate
Causing virilization of
Cortisol ↓
simple virilizing CAH prepubertal children.
Aldosterone normal
Milder form
Causing androgen
Aldosterone normal
non-classical CAH
effects and infertility
Cortisol normal
(„late onset”)
in adolescent and adult
women.
Newborn screening 1.
Conditions justifying newborn
screening for any disorder include
(1) a simple test with an acceptable
sensitivity and specificity,
(2) a dire and severe consequence if
not diagnosed early,
(3) an effective treatment if
diagnosed,
(4) a frequency in the population high
enough to justify the expense.
Newborn screening 2.
In the last decade more countries are
adopting newborn screening for saltwasting CAH due to 21-OH deficiency,
which can leads to death in the first
month of life if not recognized.
Newborn screening 3.
• Currently, in over 40 countries, every
child born is screened for CAH at birth.
This test will detect elevated levels of
17-hydroxy-progesterone (17-OHP).
• Detecting high levels of 17-OHP enables
early detection of CAH.
• Newborns detected early enough can be
placed on medication and live a relatively
normal life.
Newborn screening 4.
• The salt-wasting form of CAH is potentially
fatal within a month if untreated.
• Steroid replacement is a simple, effective
treatment.
• However, while the 17OHP level is easy to
measure and sensitive (rarely missing real
cases!!), the test has a poorer specificity.
• It’s a higher rate of false positives than
the screening tests for many other
congenital metabolic diseases.
Newborn screening 5.
• When a positive result is detected, the
infant must be referred to a pediatric
endocrinologist to confirm or disprove
the diagnosis.
• Since most infants with salt-wasting
CAH become critically ill by 2 weeks of
age, the evaluation must be done rapidly
despite the high false positive rate.
The main future directions and discussions in
development of CAH treatment:
• debate over the value of genital reconstructive
surgery and changing standards
• debate over sex assignment of severely virilized
XX infants
• new treatments to improve height outcomes
• newborn screening programs to detect CAH at
birth
• increasing attempts to treat CAH before birth
Basic guidelines of treatment of 21OHD:
• supplying glucocorticoid to reduce
hyperplasia and overproduction of androgens
• providing replacement mineralocorticoid and
extra salt if the person is deficient
• additional treatments to optimize growth by
delaying puberty or delaying bone maturation
• genital reconstructive surgery if necessary
• psychotherapy
CAH Passport
Emergency Medical Information Card
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Name:
Date of Birth:
Address:
Parental phone number:
Doctor’s phone number:
Dg.:Congenital adrenal hyperplasia (21OHD)
Salt-wasting form/Simple virilising form
Hospital responsible for the care of patient
CAH is a special form of adrenal insufficiency.
The patient needs continuous STEROID
replacement therapy.
Maintenance dose:
Increase to two to three times regular dosage during
periods of intercurrent illness or other periods of stress.
IN EMERGENCY:
(severe stress or trauma, adrenal crisis)
GIVE Hydrocortisone* intravenously/intramuscularly
3-6 mg/kg or 50-100 mg/m2 as a first aid before
transporting the patient to a hospital.
* Inj. Hydro-Adreson F
Aquosum, Inj. Solu-Cortef, Solu -Medrol
For the emergency room physician:
In the situation of adrenal crisis the patient will need
1.) Immediate IV normal saline with 5 % glucose
20 ml/kg in one hour followed by continuous and
appropriate IV fluid replacement in children,
a liter of normal saline with 5 % glucose in onetwo hours in adults followed by continuous and
appropriate IV fluid replacement and
2.) Solu-Cortef, or Hydro-Adreson F Aquosum
IV bolus injection:
younger than 3 years: 25 mg,
3-10 years: 50 mg,
in adolescents and adults: 100 mg.
Thereafter during the time of acute crisis, administer
for infants Solu-Cortef 25-30 mg/day by IV drip or 4
divided doseses IM or IV, for young children 50-60
mg/day by continuous IV drip or 4 divided doseses IM
or IV, and for adolescents and adults 100 mg/day by
continuous IV drip or 4 divided doseses IM or IV.
„thyreos = shield”
(Thomas Wharton
1656 London)
• thyroid hormons: thyroxin ,trijodthyronin
- iodine content dipeptid hormons
• Key factor in:
- growing
- metabolism
- development of cardiovascular system
- development of central nervous system
Thyroid stimulating hormone (TSH)
• TSH is a noncovalently linked glycoprotein
heterodimer and is part of a family of
pituitary hormones containing a common
alpha subunit and a unique beta subunit
that confers specificity.
TSHR
• The thyroid-stimulating hormone receptor
is a receptor (and associated protein) that
responds to thyroid-stimulating hormone,
and stimulates the production of thyroxine
(T4) and triiodothyronine (T3). The TSH
receptor is a member of the G proteincoupled receptor superfamily.
• It is primarily found on the surface of the
thyroid epithelial cells.
Paired box gene 8 - PAX8 - a member of
the paired box (PAX) family
• This gene encoded a transcription factor
protein. This nuclear protein is involved in
thyroid follicular cell development and
expression of thyroid-specific genes.
• Mutations in this gene have been associated
with thyroid dysgenesis, thyroid follicular
carcinomas and atypical follicular thyroid
adenomas.
Congenital hypothyroidism (CH) is a condition of
thyroid hormone deficiency present at birth.
• Approximately 1 in 3000 newborn infants has a severe
deficiency of thyroid function, while even more have
mild or partial degrees.
• If untreated for several months after birth, severe
CH can lead to growth failure and permanent mental
retardation.
• Treatment consists of a daily dose of thyroid
hormone (thyroxine) by mouth.
• Because the treatment is simple, effective, and
inexpensive, nearly all of the developed world practices
newborn screening to detect and treat CH in the first
7-14 days of life.
ETIOLOGY of CH (1.)
In the past the most common cause WAS iodine
deficiency, but in most of the developed world areas of
adequate environmental iodine and iodine supply reduce
this problem.
• Defect of development of the thyroid gland itself,
resulting in an absent (agenesia) or underdeveloped
(hypoplastic) gland. A hypoplastic gland may develop
higher in the neck or even in the back of the tongue or
other region (ectopic).
- result from genetic defects, and some are "sporadic,"
with no identifiable cause.
• CH detected by screening may be transient
- most common cause of this is the presence of maternal
antibodies which temporarily impair or inhibits thyroid
function for some week.
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ETIOLOGY of CH (2.)
85% thyreoid gland dysgenesis organification def.
agenesia, hypoplasia, ectopia
10% dyshormongenesis - defects of thyroxine or
triiodothyronine synthesis within a structurally
normal gland - nongoitrous CH
TRH,TSH ,TSHR def.,TSH resistance, iodine
trapping and transport def., thyroglobulin def.,
deiodinase, peroxydase def., G-protein def.
2% transcription factor gene mutation
TTF1, TTF2, PAX8
3% others – maternal radio-iodine therapy during
pregnancy etc.
DIAGNOSTIC EVALUATION - Newborn screening 1.
Nearly all cases of congenital hypothyroidism
can be detected by the newborn screening
program.
- These are based on measurement of TSH
(and/or in some countries free thyroxine - fT4)
on the second or third day of life.
DIAGNOSTIC EVALUATION - Newborn screening 2.
If the TSH is high (or the fT4 low), the screening
labor must calls infant's doctor (or GP), parents and
regional pediatric endocrinologist and the baby must be
referred to a pediatric endocrine center to confirm the
diagnosis and initiate treatment.
Often a technetium (Tc-99m pertechnetate) thyroid
scan is performed at diagnosis to detect a structurally
abnormal gland (because it has no therapeutic
consequences, usually we recommend it later age in
Hungary).
Newborn screening 3.
• In Hungary:
- Incidency of CH: 1:3000
- Screening program from 1984: Guthrie-test
(+ PKU, galactosaemia, biotinidase def. - MTS)
- measurement of TSH must be on the 2nd or 3rd day
of life – DRIED BLOOD SPOT
If TSH > 30 μU/ml
the infant must be transported to the regional pediatric
endocrinology and screening center to confirm the
diagnosis and initiate treatment.
If TSH = 20-29 μU/ml – test must be repeated
immidiately
Symptoms 1.
• Infants born with CH may show no effects,
or may display mild effects that often go
unrecognized as a problem (!)
• If fetal deficiency was severe because of
complete absence of the gland, physical
features may include more characteristic
signs
Classic signs: excessive sleeping, reduced
interest in nursing, bad appetite, poor muscle
tone, low or hoarse cry, infrequent bowel
movements, constipation, exaggerated jaundice,
low bodytemperature, dry skin, larger anterior
fontanel, persistence of a posterior fontanel,
umbilical hernia, large tongue (macroglossia),
lethargia, wide nasal sella, oedema, bradycardia
and sometimes - goiter .
Symptoms 2.
• In the era before newborn screening, less
than half of cases of severe hypothyroidism
were recognized in the first month of life (!)
These infants would grow poorly and be
delayed in their development.
• By several years of age, they would display
the recognizable facial and body
features of cretinism with
severe mental and physical
retardation, with an IQ below
80 in the majority.
Treatment 1.
• The goal of newborn screening programs is to
detect and start treatment within the first 1–2
weeks of life.
• Treatment consists of a daily dose of thyroxine,
available as a small tablet. The generic name is
levothyroxine, and several brands are available.
• The tablet is crushed and given to the infant with
a small amount of water or milk.
Treatmnet 2.
• The most commonly recommended dose about
12-15 μg/kg daily, typically 50 (or 37,5) μg.
• Within a few weeks, the freeT4 and TSH levels
are rechecked to confirm that they are being
normalized by treatment.
• As the child grows up, these levels are checked
regularly to maintain the right dose.
Treatment guideline:
Dosage: 12-15 μg/kg/day LT4
≈ 50μg = 1tbl/day LT4
(Letrox, Euthyrox, L-Thyroxin)
to maintain the right dose of LT4
based on clinical signs and regular
checked lab results of serumTSH,
freeT4 (and dried blood spotTSH)
Timepoint of regular checking:
1-3 months of age - monthly
3-12 months of age – 2-3 monthly
1-2 years of age – 4 monthly
2-3 years of age – 6 monthly
From 3 years of age - 6-12 monthly
Prognosis
• Most children born with CH and correctly treated
with thyroxine grow and develop normally in all
respects, develop with normal intelligence.
• In some cases, the CH patients as a population
academic performance tends to be below that of
siblings and may occur mild learning problems (due to
bad compliance?, due to intrauterin hypothyreoid
condition?)
Congenital hypothyroidism is the most common
preventable cause of mental retardation.
Few treatments in the practice of medicine
provide as large a benefit for as small an effort.
Other benefits of TSH-screening
The dried blood spot test forTSH is a
capabel method to screen and check not only
CH but all hypothyreoid patients.
The GP, parents, welfare nurse can take easily
the sample, and send it by post to the Endocrine
Center (between two outpatient clinic visits)
• to follow the efficacy of treatment,
• to maintain the right dose of LT4,
• to check and improve compliance.
Hypothyreosis
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