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 conditionsThe symptoms of CAH vary depending upon the form of CAH andthe 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 beinitially 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-hydroxyla

se

Common medical term

% enzyme locus Substrate Products Mineralocorticoids

Androgens

21OH-ase def.

90-95%

P450c21

6p21.3

17OHprogesterone→progesterone→

11deoxycortisolDOC ↓ ↑

11βOH-ase def.

5% P450c 11β

8q21-22

11deoxycortisol→ DOC→

cortisol, corticosteron ↑ ↑

3βHSD def.

Very rare

3βHSDII 1p13 pregnenolone →17OH-pregnenolone →DHEA →

progesterone 17OH-progesterone androstenedion

↓ ↓

17αOH-ase def.

Very rare

P450c17

10q24.3

pregnenolone → progesterone→17OHpregnenolone →

17OHpregnenolone17OHprogesteroneDHEA

↑ ↓

20,22-desmolase def.

Very rare

StarP450scc

8p11.215q23-q24

transport of cholesterol cholesterol →

into mitochondrialpregnenolone

↓ ↓

21-hydroxylase deficiency

• The defective enzyme is P450c21 (cytochrome P450 oxidase ), commonly referred to as 21-hydroxylase (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 fashionCYP21 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

• the mildest form of CAH interferes with ovulation and fertility in adults

Type of 21OHD Sex steroid effects Other effects

Severe

salt-wasting CAH

The most common

cause of ambigous

genitalia due to

prenatal virilization of

genetically female

(XX) infants.

Salt-wasting crisis - life-

threatening vomiting and

dehydration occurring

within the first few weeks

of life.

17OHP ↑ ↑ (30 ng/ml

<)

Aldosterone ↓ Cortisol ↓

Moderate

simple virilizing

CAH

Causing virilization of

prepubertal children.

Cortisol ↓

Aldosterone normal

Milder form

non-classical CAH

(„late onset”)

Causing androgen

effects and infertility

in adolescent and

adult women.

Aldosterone normal

Cortisol normal

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 salt-wasting CAH due to 21-OH deficiency, which can leads to death in the first month of life if not recognized.

• 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 3.

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

• Name: • Date of Birth: • Address: • Parental phone number:• Doctor’s phone number: • Dg.:Congenital adrenal hyperplasia (21OHD)

Salt-wasting form/Simple virilising formHospital responsible for the care of patientCAH 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/intramuscularly3-6 mg/kg or 50-100 mg/m2 as a first aid before transporting the patient to a hospital.* Inj. Hydro-Adreson FAquosum, 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 one-

two 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.

CAH PassportEmergency Medical Information Card

„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 protein-coupled 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.

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 CHTRH,TSH ,TSHR def.,TSH resistance, iodine trapping and transport def., thyroglobulin def., deiodinase, peroxydase def., G-protein def.

• 2% transcription factor gene mutationTTF1, 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.

If the TSH is high (or the fT4 low), the screening labor must calls infant's doctor (or GP), parents andregional 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).

DIAGNOSTIC EVALUATION - Newborn screening 2.

• 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

Newborn screening 3.

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 hypothyroidismwere 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 - monthly3-12 months of age – 2-3 monthly1-2 years of age – 4 monthly2-3 years of age – 6 monthlyFrom 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 acapabel method to screen and check not onlyCH 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.

rhGH

Hypothyreosis

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