8
Congenital Hypothyroidism All forms of congenital hypothyroidism occur in 1 in 4,000 live births worldwide. The dysgenetic form affects twice as many females as males. It is the most prevalent congenital endocrine disease. The incidence is approximately 1 in 32,000 in Blacks and 1 in 2,000 in Hispanics. Synonyms and Related Disorders Ectopic thyroid gland; Thyroid agenesis; Thyroid dys- genesis; Thyroid hypoplasia; Thyrotropin resistance Genetics/Basic Defects 1. Inheritance (Ambrugger et al. 2001) a. Thyroid dysgenesis i. The most frequent cause of congenital hypo- thyroidism (85% of cases) ii. Morphological classification a) Ectopic thyroid gland: the most frequent malformation, observed most frequently at the base of the tongue b) Athyreosis (absence of any detectable thyroid tissue) c) Hypoplasia (partially absent thyroid) iii. Sporadic in most cases iv. Genetic factors contributing to the develop- ment of thyroid dysgenesis in 2% of cases with a positive familial history v. Molecular defects clarified only in few cases of thyroid dysgenesis (Gruters et al. 2002) a) TSH-receptor gene (thyroid hypoplasia, “apparent athyrosis”) b) Transcription factors: Thyroid-specific transcription factor-1 (TTF-1) (hypothy- roidism, chorea, choreoathetosis, respira- tory distress), TTF-2 (thyroid hypoplasia, cleft palate, choanal atresia, curly hair, developmental delay), PAX-8 (thyroid hypoplasia, ectopy) c) NKX2A (athyrosis, hypoplasia, normally developed gland, choreoathetosis, pul- monary problems, mental retardation, pituitary abnormalities) b. Autosomal recessive defects of thyroid hor- mone biosynthesis with identification of the following candidate genes for congenital hypothyroidism i. Thyroid peroxidase (TPO) gene a) A hemoprotein responsible for tyrosine iodination and coupling b) Intriguing role of TPO mutations in the development of thyroid tumor ii. Sodium-iodide symporter (NIS) gene iii. Thyroglobulin (TG) gene iv. Pendrin (PDS) gene (Pendred syndrome) v. Thyroid oxidase 2 (THOX2) gene (Pfarr et al. 2006) c. Autosomal dominant transmission of congenital hypoplasia due to loss-of-function mutation of PAX-8 (Vilain et al. 2001) 2. Etiology of thyroidal congenital hypothyroidism (De Vijlder 2003) a. Disorders in development of the thyroid gland (85% of cases with congenital hypothyroidism) i. Absent thyroid ii. Under-development with migration failure iii. Under-development with normal migration H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_54, # Springer Science+Business Media, LLC 2012 471

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Page 1: Atlas of Genetic Diagnosis and Counseling || Congenital Hypothyroidism

Congenital Hypothyroidism

All forms of congenital hypothyroidism occur in 1 in

4,000 live births worldwide. The dysgenetic form

affects twice as many females as males. It is the most

prevalent congenital endocrine disease. The incidence

is approximately 1 in 32,000 in Blacks and 1 in 2,000

in Hispanics.

Synonyms and Related Disorders

Ectopic thyroid gland; Thyroid agenesis; Thyroid dys-

genesis; Thyroid hypoplasia; Thyrotropin resistance

Genetics/Basic Defects

1. Inheritance (Ambrugger et al. 2001)

a. Thyroid dysgenesis

i. The most frequent cause of congenital hypo-

thyroidism (85% of cases)

ii. Morphological classification

a) Ectopic thyroid gland: the most frequent

malformation, observed most frequently

at the base of the tongue

b) Athyreosis (absence of any detectable

thyroid tissue)

c) Hypoplasia (partially absent thyroid)

iii. Sporadic in most cases

iv. Genetic factors contributing to the develop-

ment of thyroid dysgenesis in 2% of cases

with a positive familial history

v. Molecular defects clarified only in few cases

of thyroid dysgenesis (Gr€uters et al. 2002)

a) TSH-receptor gene (thyroid hypoplasia,

“apparent athyrosis”)

b) Transcription factors: Thyroid-specific

transcription factor-1 (TTF-1) (hypothy-

roidism, chorea, choreoathetosis, respira-

tory distress), TTF-2 (thyroid hypoplasia,

cleft palate, choanal atresia, curly hair,

developmental delay), PAX-8 (thyroid

hypoplasia, ectopy)

c) NKX2A (athyrosis, hypoplasia, normally

developed gland, choreoathetosis, pul-

monary problems, mental retardation,

pituitary abnormalities)

b. Autosomal recessive defects of thyroid hor-

mone biosynthesis with identification of the

following candidate genes for congenital

hypothyroidism

i. Thyroid peroxidase (TPO) genea) A hemoprotein responsible for tyrosine

iodination and coupling

b) Intriguing role of TPO mutations in the

development of thyroid tumor

ii. Sodium-iodide symporter (NIS) gene

iii. Thyroglobulin (TG) geneiv. Pendrin (PDS) gene (Pendred syndrome)

v. Thyroid oxidase 2 (THOX2) gene (Pfarr et al.

2006)

c. Autosomal dominant transmission of congenital

hypoplasia due to loss-of-function mutation of

PAX-8 (Vilain et al. 2001)

2. Etiology of thyroidal congenital hypothyroidism

(De Vijlder 2003)

a. Disorders in development of the thyroid gland

(85% of cases with congenital hypothyroidism)

i. Absent thyroid

ii. Under-development with migration failure

iii. Under-development with normal migration

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_54,# Springer Science+Business Media, LLC 2012

471

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b. Disorders in thyroid hormone synthesis

(10–20%)

i. TSH hypo-responsiveness (TSH-receptor

abnormalities)

ii. Defects in iodide transport from circulation

into the thyroid cells

iii. Defects in iodide transport from the thyroid

cell to the follicular lumen, often combined

with inner ear deafness (Pendred syndrome,

sensorineural hearing loss, and goiter)

iv. Defects in the synthesis of hydrogen

peroxide

v. Defects in the oxidation of iodide, iodin-

ation, and iodothyronine synthesis

vi. Defects in processes involved in the

synthesis or degradation of thyroglobulin

vii. Defects in iodine recycling

3. Etiology of central (hypothalamic or pituitary) con-

genital hypothyroidism

a. Disorders in development and/or function of the

hypothalamus

b. Disorders in development and/or function of

the pituitary glands

c. Disorders in development and/or function of

the hypothalamus and pituitary glands

4. Transient form of primary congenital hypothyroid-

ism (Moreno et al. 2002)

a. Occurs in 5–10% of infants detected by newborn

screening

b. Represents about 5% of cases with congenital

hypothyroidism

c. Etiology

i. Mothers with chronic autoimmune thyroi-

ditis: transplacental passage of maternal

TSH-receptor blocking antibodies leading

to inhibition of TSH action on the infant’s

thyroid gland until the maternal antibodies

disappear

ii. Antithyroid drugs taken by pregnant women

with thyroid autoimmune disease

iii. Maternal dietary iodide deficiency

iv. Maternal dietary goitrogen ingestion

v. Exposure to excess iodine in the perinatal

period

a) Use of iodinated disinfectants

b) Use of contrast agents

5. Down syndrome: Congenital hypothyroidism

occurs approximately 28 times more common

among infants with Down syndrome than in the

general population with an incidence of 1%

detected by newborn screening

6. Pathogenesis of mental retardation in congenital

hypothyroidism: due to the central role of

thyroid hormones in brain development, which

takes place during fetal life and early postnatal life

up to the second or third year of age (DeLange

1997)

Clinical Features

1. Most newborn are asymptomatic (Beltroy et al. 2003)

2. Severe dysgenetic and athyrotic hypothyroidism

a. Early symptoms

i. Feeding problems

ii. Constipation

iii. Growth failure

iv. Hoarse cry

b. Signs and symptoms in infants and toddlers

i. Delayed linear growth

ii. Hypotonia

iii. Decreased activity

iv. Lethargy

v. Prolonged jaundice

vi. Bradycardia

vii. Hypothermia

viii. Cold to touch

ix. Dry/puffy/thick skin

x. Sparse hair

xi. Characteristic craniofacial appearance

a) Coarse facial feature

b) Puffy eyes

c) Myxedematous facies

d) Large fontanelles

e) A broad, flat nose

f) Pseudohypertelorism

g) Large, protruding tongue

xii. Delayed tooth eruption

xiii. Occasional cardiomegaly

xiv. Protuberant abdomen with umbilical

hernia

xv. Constipation

xvi. Poor nail growth

xvii. Delayed return of the deep tendon reflexes

xviii. Irreversible growth failure and mental

retardation

472 Congenital Hypothyroidism

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Diagnostic Investigations

1. Newborn screening: Ideally universal screening at

3–4 days of age should be done for detecting CH.

Abnormal values on screening (T4 < 6.5 ug/dL,

TSH > 20mu/L) should be confirmed by a venous

sample (using age appropriate cutoffs) before initi-

ating treatment

a. Successful identification of infants with congen-

ital hypothyroidism

b. Enables early diagnosis and treatment of infants

and prevention of mental retardation

c. Newborn screening measures either TSH or T4

in neonatal blood placed on filter paper

d. Confirmation with a serum sample if the filter

paper result is abnormal

i. Primary congenital hypothyroidism

a) Low serum T4 levels

b) Elevated serum TSH

ii. Hypopituitary hypothyroidism

a) Low total T4 levels

b) Low or normal TSH

iii. Thyroxine-binding globulin (TBG) deficiency

a) Low total T4 but normal serum-free T4

levels

b) Normal TSH

e. Screening programs for congenital hypothyroid-

ism in premature newborns (Kugelman et al.

2009)

i. Sick premature infants may display transient

hypothyroxinemia secondary to immaturity

of the hypothalamic-pituitary axis.

ii. Therefore, early screening programs of such

infants may be misleading.

iii. Recommendations

a) Screening programs should report thy-

roid stimulating hormone (TSH) as well

as thyroxin (T4) levels in premature

infants, which will allow the treating

physicians to be aware of possible abnor-

mality that needs to be followed.

b) Sick premature infants and other

populations at risk should undergo a full

serum thyroid function evaluation

including free T4 and TSH beyond the

screening program at discharge or at

30 days of age, whichever comes first.

c) Physicians should use their clinical

judgment and experience even in the

face of normal newborn thyroid screen-

ing test and reevaluate for hypothyroid-

ism when there is a clinical suspicion.

f. Pendred syndrome (Banghova et al. 2008)

i. An autosomal recessive disorder character-

ized by sensorineural hearing loss and

thyroid dyshormonogenesis

ii. Caused by mutations in the PDS/SLC26A4

gene

iii. Present from birth

iv. Can be diagnosed by newborn screening

2. Laboratory diagnosis

a. Thyroid function tests

i. Elevated serum TSH

ii. Low serum T4 levels

b. Determine antithyroglobulin and antithyroid

peroxidase antibodies if indicated

c. Determine TBG levels for suspected TBG

deficiency

3. Radiography for bone age

4. Ultrasonography, considered as the best noninva-

sive method for the anatomical assessment of the

thyroid gland

5. Radionuclide scan (thyroid scintigraphy) using99mTc or 123I (DeLange 1997)

a. To demonstrate the presence of ectopic thyroid

tissue or thyroid aplasia

b. Iodide transport defect

i. Low or absent uptake of 123I

ii. Response to therapeutic doses of potassium

iodide

c. Defective organification of iodide

i. Rapid uptake of 123I

ii. Marked decrease in thyroid radioactivity

when perchlorate or thiocyanate is adminis-

tered 2 h after administering radioiodine

iii. Occasional sensorineural hearing loss

(Pendred syndrome)

d. Iodotyrosine-coupling defect

i. Rapid uptake of 123I

ii. No discharge by perchlorate

iii. Very high thyroid gland content of

monoiodotyrosine (MIT) and diiodotyrosine

(DIT)

iv. Virtually undetectable T4 and T3

v. Adequately iodinated thyroglobulin

Congenital Hypothyroidism 473

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e. Defects in thyroglobulin gene expression and

thyroglobulin secretion

i. Elevated uptake of 123I

ii. No discharge by perchlorate

iii. Abnormal serum iodoproteins

iv. Elevated protein-bound/T4 iodine ratio

v. Low or borderline serum thyroglobulin

f. Iodotyrosine deiodinase defect

i. Rapid uptake and turnover of 123I

ii. Elevated serum and urinary iodotyrosines

(MIT, DIT)

iii. Response to iodine supplementation

6. Intelligence quotient (IQ) measurement for testing

neuropsychological progress and outcome

7. Molecular genetic diagnosis by sequencing of

select exons to identify mutations

Genetic Counseling

1. Recurrence risk

a. Patient’s sib

i. Sporadic cases: low recurrence risk

ii. Autosomal recessive inheritance: 25%

iii. Autosomal dominant inheritance: low recur-

rence risk unless a parent is affected

b. Patient’s offspring

i. Sporadic cases: low recurrence risk

ii. Autosomal recessive inheritance: low recur-

rence risk unless the spouse carries the reces-

sive gene

iii. Autosomal dominant inheritance: 50%

2. Prenatal diagnosis

a. Ultrasonography and percutaneous fetal blood

sampling

i. Detection of fetal goiter

a) A rare yet potentially dangerous condition

b) A large goiter may cause hyperextension

of the neck of the fetus caused by a large

goiter, resulting in malpresentation and

complicating labor and delivery

c) Possibility of compressing the trachea and

asphyxiating the neonate after birth

ii. Fetal blood sample

a) Elevated TSH

b) Low T4

b. Amniocentesis

i. Determination of TSH concentration

(markedly elevated TSH level) in amniotic

fluid in the second trimester for the offspring

of a couple both known to have an

iodide (iodothyronine synthesis) enzymatic

organification defect

ii. Affected fetus with markedly increased TSH

level in the amniotic fluid sample for the

trimester

c. Molecular genetic diagnosis possible by

sequencing of select exons on fetal DNA for

previously identified mutations in a research

laboratory

3. Management

a. Sodium L-thyroxine

i. The treatment of choice

ii. Early therapy (within 14 days) with appro-

priate doses of thyroxine (about 10 mg/kg/day) will prevent any brain damage even in

case of evidence of fetal hypothyroidism,

since thyroxine of maternal origin will

reach and protect the fetus (DeLange 1997)

iii. Avoid over treatment to prevent the follow-

ing adverse effects (LaFranchi 1999):

a) Premature cranial suture fusion

b) Acceleration of growth and skeletal

maturation

c) Problemswith temperament and behavior

b. X-linked dominant thyroxine-binding globulin

deficiency (causing a low total T4 but normal

free T4): no need for thyroid hormone

replacement

c. Intrauterine treatment of fetus with a large goiter

(Davidson et al. 1991)

i. Indicated because of the morbidity associated

with compression of the trachea and mechan-

ical interferences during delivery

ii. Intra-amniotic administration of levothyroxine

presents the least invasive approach to fetal

treatment

a) Rapid decrease in the fetal goiter size

b) Normalization of fetal thyroid function

d. Intrauterine treatment of fetus affected with

iodide organification defect with synthroid

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476 Congenital Hypothyroidism

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a b c

Fig. 1 (a–c) A neonate with congenital hypothyroidism showing coarse facial features, hypotonia, macroglossia, and umbilical

hernia

Fig. 2 A twin affected with congenital hypothyroidism (left)shows coarse facial features. The normal co-twin is on the right

Congenital Hypothyroidism 477

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