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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
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
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
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
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