Clinical Case: Congenital Hypothyroidism

A 3-week-old female infant is brought to the pediatric clinic by her parents for a routine check-up. The parents report the following observations:

• Prolonged jaundice since birth
• Difficulty feeding and poor weight gain
• Excessive sleepiness and reduced activity
• Constipation
• Hoarse cry

On physical examination, the pediatrician notes:

• Weight: 3.1 kg (below 3rd percentile)
• Length: 49 cm (10th percentile)
• Head circumference: 35 cm (25th percentile)
• Pale, dry skin with mottling
• Large fontanelles
• Macroglossia
• Umbilical hernia
• Hypotonia
• Delayed relaxation of deep tendon reflexes

The pediatrician orders thyroid function tests, which reveal:

• TSH: 150 mIU/L (normal range: 0.5-5 mIU/L)
• Free T4: 5 pmol/L (normal range: 10-25 pmol/L)

Based on these findings, a diagnosis of congenital hypothyroidism is made. The infant is immediately started on levothyroxine replacement therapy, and follow-up appointments are scheduled to monitor growth, development, and thyroid function.

Clinical Presentations of Congenital Hypothyroidism

1. Classic Presentation

   • Prolonged jaundice
   • Feeding difficulties
   • Constipation
   • Lethargy and somnolence
   • Large anterior and posterior fontanelles
   • Macroglossia
   • Umbilical hernia
   • Hypotonia
   • Cool, dry skin
   • Delayed reflexes

2. Mild or Subclinical Presentation

   • Subtle or absent clinical signs
   • Normal growth and development initially
   • Mild elevation of TSH with normal or slightly low T4
   • May be detected only through newborn screening

3. Severe Presentation (Untreated)

   • Profound intellectual disability
   • Severe growth retardation
   • Coarse facial features
   • Myxedematous skin changes
   • Persistent jaundice
   • Severe constipation
   • Hypothermia
   • Bradycardia

4. Transient Congenital Hypothyroidism

   • Temporary thyroid dysfunction
   • May present with mild symptoms
   • Often due to maternal factors (e.g., iodine deficiency or excess, anti-thyroid medications)
   • Thyroid function normalizes within weeks to months

5. Syndromic Presentation

   • Congenital hypothyroidism associated with other congenital anomalies
   • Examples: Pendred syndrome (hearing impairment), Bamforth-Lazarus syndrome (cleft palate)
   • May present with additional features specific to the syndrome

6. Late-Onset Presentation

   • Subtle signs appearing in infancy or early childhood
   • Mild developmental delay
   • Growth deceleration
   • Acquired goiter

7. Central Congenital Hypothyroidism

   • Due to pituitary or hypothalamic dysfunction
   • May present with additional pituitary hormone deficiencies
   • Normal or low TSH with low free T4
   • Often part of multiple pituitary hormone deficiency syndromes

Viva Questions and Answers on Congenital Hypothyroidism

1. Q: What is the definition of congenital hypothyroidism?

   A: Congenital hypothyroidism is a condition characterized by thyroid hormone deficiency present at birth, resulting from the complete or partial absence of the thyroid gland, its failure to migrate to the correct position during embryogenesis, or defects in thyroid hormone biosynthesis.

2. Q: What is the incidence of congenital hypothyroidism?

   A: The worldwide incidence of congenital hypothyroidism is approximately 1 in 2,000 to 1 in 4,000 newborns, with variations depending on geographical location and screening methods.

3. Q: What are the main causes of congenital hypothyroidism?

   A: The main causes include:

   • Thyroid dysgenesis (aplasia, hypoplasia, or ectopia) - 85% of cases
   • Dyshormonogenesis (defects in thyroid hormone synthesis) - 10-15% of cases
   • Central hypothyroidism (pituitary or hypothalamic dysfunction) - <5% of cases
   • Transient hypothyroidism (maternal factors, iodine deficiency or excess)

4. Q: What are the key clinical features of congenital hypothyroidism in a newborn?

   A: Key clinical features include prolonged jaundice, feeding difficulties, constipation, lethargy, large fontanelles, macroglossia, umbilical hernia, hypotonia, cool and dry skin, and delayed reflexes.

5. Q: How is congenital hypothyroidism diagnosed?

   A: Diagnosis is primarily made through newborn screening programs, which typically measure TSH levels in dried blood spots. Confirmatory testing includes serum TSH and free T4 levels. Additional tests may include thyroid ultrasound, thyroid scintigraphy, and genetic testing.

6. Q: What is the recommended timing for newborn screening for congenital hypothyroidism?

   A: Most screening programs recommend testing between 48-72 hours after birth. Some programs perform a second screening at 2-6 weeks of age to detect cases that may have been missed in the initial screen.

7. Q: What are the treatment options for congenital hypothyroidism?

   A: The primary treatment is thyroid hormone replacement therapy with levothyroxine (L-thyroxine). Treatment should be initiated as soon as possible, ideally within the first two weeks of life.

8. Q: What is the initial dose of levothyroxine for a newborn with congenital hypothyroidism?

   A: The recommended initial dose is 10-15 μg/kg/day, typically ranging from 37.5 to 50 μg daily for most term newborns. The dose is adjusted based on clinical response and thyroid function tests.

9. Q: How often should thyroid function be monitored in infants with congenital hypothyroidism?

   A: Thyroid function tests (TSH and free T4) should be checked:

   • 2-4 weeks after initiation of treatment
   • Every 1-2 months during the first 6 months of life
   • Every 3-4 months between 6 months and 3 years of age
   • Every 6-12 months thereafter until growth is complete

10. Q: What are the target levels for TSH and free T4 during treatment?

    A: The target levels are:

    • TSH: 0.5-2 mIU/L
    • Free T4: Upper half of the normal range for age

11. Q: What is the prognosis for children with congenital hypothyroidism who receive early treatment?

    A: With early diagnosis and adequate treatment, most children with congenital hypothyroidism can achieve normal growth and neurological development. However, subtle neurocognitive deficits may persist in some cases, particularly if treatment is delayed or inadequate.

12. Q: What are the potential complications of untreated congenital hypothyroidism?

    A: Untreated congenital hypothyroidism can lead to severe intellectual disability, growth retardation, delayed bone maturation, cardiovascular problems, and myxedema.

13. Q: How does central congenital hypothyroidism differ from primary congenital hypothyroidism?

    A: Central congenital hypothyroidism is caused by defects in the pituitary gland or hypothalamus, resulting in insufficient TSH production. Unlike primary hypothyroidism, TSH levels are low or inappropriately normal, while free T4 is low. It may be associated with other pituitary hormone deficiencies.

14. Q: What genetic mutations are associated with congenital hypothyroidism?

    A: Genetic mutations associated with congenital hypothyroidism include:

    • Thyroid dysgenesis: PAX8, NKX2-1, FOXE1, NKX2-5
    • Dyshormonogenesis: TG, TPO, DUOX2, SLC5A5, SLC26A4, IYD
    • Central hypothyroidism: TSHB, TRHR, IGSF1

15. Q: What is the role of thyroid scintigraphy in the evaluation of congenital hypothyroidism?

    A: Thyroid scintigraphy, typically using technetium-99m pertechnetate, helps determine the presence, size, and location of thyroid tissue. It can differentiate between thyroid agenesis, ectopic thyroid, and normally located gland, which aids in determining the etiology and guiding long-term management.

16. Q: How does maternal iodine status affect the risk of congenital hypothyroidism?

    A: Both iodine deficiency and excess can lead to congenital hypothyroidism. Severe iodine deficiency can cause endemic cretinism, while excessive iodine intake (e.g., from iodine-containing antiseptics or contrast agents) can result in transient hypothyroidism in the newborn due to the Wolff-Chaikoff effect.

17. Q: What is the significance of thyroid peroxidase (TPO) antibodies in newborns with congenital hypothyroidism?

    A: The presence of TPO antibodies in a newborn usually indicates transplacental transfer of maternal antibodies. This may signify transient congenital hypothyroidism in the infant or the need to screen for maternal autoimmune thyroid disease.

18. Q: How does congenital hypothyroidism affect bone maturation, and how is this assessed?

    A: Congenital hypothyroidism leads to delayed bone maturation. This is typically assessed using a bone age X-ray, usually of the left hand and wrist. In untreated cases, bone age is significantly delayed compared to chronological age.

19. Q: What is the approach to managing congenital hypothyroidism in preterm infants?

    A: Preterm infants require special consideration:

    • Lower screening cutoffs for TSH may be needed
    • Repeated screening at 2-4 weeks of age is recommended
    • Initial levothyroxine dosing may be lower (8-10 μg/kg/day)
    • More frequent monitoring of thyroid function is necessary

20. Q: What is the concept of "brain-thyroid hormone threshold" in congenital hypothyroidism?

    A: The "brain-thyroid hormone threshold" refers to the critical level of thyroid hormone required for normal brain development. It suggests that even mild thyroid hormone deficiency during critical periods of brain development can lead to neurodevelopmental impairments, emphasizing the importance of early and adequate treatment.

21. Q: How does congenital hypothyroidism affect cardiovascular function?

    A: Congenital hypothyroidism can lead to:

    • Bradycardia
    • Decreased cardiac output
    • Pericardial effusion
    • Increased peripheral vascular resistance
    • Impaired myocardial contractility
    These changes are generally reversible with appropriate thyroid hormone replacement.

22. Q: What is the approach to managing children with congenital hypothyroidism who reach 3 years of age?

    A: At 3 years of age, the approach includes:

    • Re-evaluation of the diagnosis if not done earlier
    • Consideration of a trial off therapy in cases of possible transient hypothyroidism
    • Gradual dose reduction of levothyroxine over 4-6 weeks
    • Reassessment of thyroid function 4 weeks after stopping therapy
    • If hypothyroidism is confirmed, treatment is restarted and continued indefinitely

23. Q: What are the potential neurodevelopmental outcomes in children with congenital hypothyroidism?

    A: Neurodevelopmental outcomes can vary:

    • With early and adequate treatment, most children achieve normal or near-normal cognitive development
    • Subtle deficits may persist in visual-spatial processing, attention, and memory
    • Severity at diagnosis, timing of treatment initiation, and adequacy of therapy influence outcomes
    • Children with severe congenital hypothyroidism or delayed treatment may have more significant cognitive impairments

24. Q: How does congenital hypothyroidism affect growth and puberty?

    A: Congenital hypothyroidism can significantly impact growth and puberty:

    • Untreated or inadequately treated cases show severe growth retardation
    • Bone age is typically delayed
    • With proper treatment, most children achieve normal adult height
    • Puberty may be delayed in untreated cases, but typically occurs normally with adequate therapy

25. Q: What is the significance of thyroglobulin (Tg) measurement in congenital hypothyroidism?

    A: Thyroglobulin measurement is useful in several ways:

    • Detectable Tg indicates the presence of thyroid tissue
    • Very low or undetectable Tg in a hypothyroid infant suggests thyroid agenesis
    • Elevated Tg may indicate dyshormonogenesis
    • Tg can be used to monitor for residual thyroid tissue after treatment for thyroid cancer in older children

26. Q: How does congenital hypothyroidism differ from acquired hypothyroidism in children?

    A: Key differences include:

    • Congenital hypothyroidism is present at birth, while acquired develops later in childhood
    • Congenital cases are mostly due to thyroid dysgenesis or dyshormonogenesis, while acquired cases are often autoimmune
    • Neurodevelopmental impact is more severe in untreated congenital cases
    • Screening programs typically catch congenital cases, while acquired cases are diagnosed based on symptoms

27. Q: What are the challenges in managing congenital hypothyroidism in developing countries?

    A: Challenges include:

    • Lack of universal newborn screening programs
    • Limited access to thyroid function tests and imaging
    • Inconsistent availability of levothyroxine
    • Inadequate follow-up and monitoring
    • Low awareness among healthcare providers and the public
    • Higher prevalence of iodine deficiency, complicating diagnosis and management

28. Q: What is the role of triiodothyronine (T3) in the treatment of congenital hypothyroidism?

    A: Triiodothyronine (T3) is generally not used in the routine treatment of congenital hypothyroidism:

    • Levothyroxine (T4) is the standard treatment
    • The body efficiently converts T4 to T3 as needed
    • T3 has a shorter half-life and can cause more fluctuations in thyroid hormone levels
    • In rare cases of T4 to T3 conversion defects, combined T4 and T3 therapy may be considered

29. Q: How does congenital hypothyroidism affect the auditory system, and what screening is recommended?

    A: Congenital hypothyroidism can impact auditory development:

    • Thyroid hormones are crucial for cochlear development and auditory processing
    • Untreated cases may have increased risk of hearing impairment
    • Routine newborn hearing screening is recommended for all infants
    • Additional audiological evaluations may be necessary during follow-up
    • Some genetic forms (e.g., Pendred syndrome) are associated with hearing loss