Congenital Hypothyroidism: Symptoms, Types, Causes and Treatment

Congenital hypothyroidism (CH) is one of the most common and preventable causes of intellectual disability worldwide. Thanks to advances in newborn screening and early treatment, the prognosis for affected infants has dramatically improved. This article provides a comprehensive overview of CH, focusing on its symptoms, types, causes, and treatment, synthesizing the latest evidence-based information.

Symptoms of Congenital Hypothyroidism

Early recognition of congenital hypothyroidism is crucial, as timely intervention can prevent severe neurodevelopmental impairment. However, the symptoms are often subtle or absent at birth, making routine newborn screening essential for early diagnosis.

Symptom	Description	Age of Onset	Source
Prolonged Jaundice	Yellowing of skin and eyes	Newborn period	2 3
Constipation	Infrequent or difficult stools	Early infancy	2 3
Hypotonia	Decreased muscle tone ("floppy baby")	Newborn period	1 3 4
Poor Feeding	Difficulty feeding or slow feeding	Newborn period	2 3
Large Fontanels	Enlarged soft spots on skull	Newborn period	2 3
Umbilical Hernia	Bulge at belly button area	Infancy	3 4
Macroglossia	Enlarged tongue	Infancy	3
Hoarse Cry	Unusual, rough-sounding cry	Newborn/Infancy	3
Myxedematous Facies	Puffy face with coarse features	Infancy	3
Delayed Stooling	Lag in first bowel movement	Newborn period	2
Respiratory Distress	Breathing difficulties	Newborn period	2 3
Hypothermia	Low body temperature	Newborn period	2
Edema	Swelling, especially in limbs	Newborn period	2
Developmental Delay	Slow to reach milestones	Untreated Infancy	1 3

Table 1: Key Symptoms

Overview of Clinical Presentation

Most infants with CH appear normal at birth, largely due to some maternal thyroid hormone crossing the placenta and residual thyroid function in the newborn. However, as these hormone stores are depleted, classic symptoms may develop. The constellation of symptoms is variable and can be subtle, especially in cases with milder forms of CH or those detected early by screening 2 3.

Early Signs in the Newborn Period

• Prolonged jaundice and constipation are among the earliest signs, often noticed by caregivers.
• Hypotonia, or decreased muscle tone, leads to the classic "floppy baby" presentation.
• Poor feeding and lethargy are common, with affected infants sleeping more than usual and demonstrating little interest in feeding.
• Respiratory distress, hypothermia, and peripheral cyanosis may also occur, especially in severe cases 2.

Physical Findings

• Large posterior fontanel and macroglossia are commonly observed on examination.
• Myxedematous facies refers to the puffy facial appearance with coarse features.
• Abdominal distension with umbilical hernia is frequent, as is a lag in stooling 3 4.
• In some rare genetic forms, additional symptoms like choreoathetosis (involuntary movements) and pulmonary issues may be present due to syndromic causes 1.

Progression and Consequences

• If untreated, neurodevelopmental delay becomes evident as the child fails to meet milestones.
• The longer the delay in diagnosis and treatment, the greater the risk of irreversible intellectual disability and growth failure 1 3.

Types of Congenital Hypothyroidism

CH is a heterogeneous disorder with multiple forms, categorized by duration, origin, and underlying mechanisms.

Type	Description	Key Feature or Example	Source
Permanent	Lifelong deficiency, requires ongoing therapy	Primary or Central CH	3 6 12
Transient	Temporary, resolves over time	Often in preterm/iodine def.	3 6 12
Primary	Thyroid gland dysfunction	Thyroid dysgenesis	3 6 12
Secondary	Pituitary TSH deficiency	Central CH	3 6 12
Peripheral	Resistance to thyroid hormone	Transporter defects	3 5 6
Syndromic	Associated with other organ involvement	NKX2-1 mutations	1 5

Table 2: Types of Congenital Hypothyroidism

Permanent vs. Transient Congenital Hypothyroidism

• Permanent CH: Most cases are lifelong and require continuous levothyroxine therapy. Permanent CH is typically due to defects in thyroid gland development (dysgenesis) or hormone synthesis (dyshormonogenesis) 3 6 12.
• Transient CH: Some infants, particularly those born preterm or in areas of endemic iodine deficiency, may have temporary hypothyroidism. Factors like maternal antibodies or iodine exposure can cause transient cases, which may resolve spontaneously 3 6 12.

Primary, Secondary (Central), and Peripheral CH

• Primary CH: The most common form, resulting from pathology intrinsic to the thyroid gland itself. Subdivided into:
  • Thyroid dysgenesis (absent, ectopic, or hypoplastic gland)
  • Dyshormonogenesis (defects in hormone biosynthesis)
• Secondary (Central) CH: Caused by pituitary or hypothalamic dysfunction leading to insufficient TSH stimulation. This form is rarer and may be associated with other pituitary hormone deficiencies 3 6 12.
• Peripheral CH: Results from defects in thyroid hormone transport or action, such as mutations in hormone transporters or receptors. These are rare, but important to recognize 3 5 6.

Syndromic and Atypical Forms

• Some forms of CH are “syndromic,” meaning they occur with other organ system abnormalities. For example, mutations in NKX2-1 can cause CH along with neurological and pulmonary symptoms 1 5.
• There is increasing recognition of variable and overlapping forms, especially as genetic testing becomes more widespread 5 9 10.

Causes of Congenital Hypothyroidism

Understanding the causes of CH helps inform prognosis, guide genetic counseling, and direct management approaches.

Cause	Mechanism/Example	Prevalence	Source
Thyroid Dysgenesis	Agenesis, ectopy, hypoplasia	~85% of permanent	3 5 6 7
Dyshormonogenesis	Enzyme or transporter defects	10–15%	3 5 6 7 8 9
Genetic Mutations	TSHR, TG, TPO, PAX8, NKX2-1, etc.	Variable	5 7 8 9 10
Maternal Factors	Antibodies, iodine deficiency/excess	Transient cases	3 6 8 12
Central (Pituitary)	TSH deficiency, hypopituitarism	Rare	3 6 12
Environmental	Iodine exposure, antithyroid drugs	Transient/variable	3 6 8 12

Table 3: Causes of Congenital Hypothyroidism

Thyroid Dysgenesis

• Agenesis: Complete absence of thyroid tissue.
• Ectopy: Thyroid tissue located outside the normal position (e.g., lingual thyroid).
• Hypoplasia: Underdeveloped thyroid gland.
• Dysgenesis accounts for the majority (~85%) of permanent, primary CH cases, but only a small fraction are familial 3 5 6 7.

Dyshormonogenesis

• Caused by inherited defects in the enzymes or transporters responsible for thyroid hormone synthesis (e.g., TPO, TG, NIS, DUOX2).
• Accounts for 10–15% of cases; typically autosomal recessive inheritance, more common in consanguineous families 3 5 8 9 10.
• Genetic diagnosis can help differentiate between transient and permanent forms and inform family counseling 8 9.

Genetic Mutations

• Multiple genes have been implicated, including transcription factors (PAX8, NKX2-1, FOXE1), hormone synthesis genes (TG, TPO, DUOX2, NIS), and TSH receptor (TSHR) 5 7 8 9 10.
• Syndromic CH may result from mutations affecting not only the thyroid but also other organs (e.g., NKX2-1 mutations) 1 5 9.

Maternal and Environmental Factors

• Maternal TSH receptor blocking antibodies can transiently suppress fetal thyroid function 3 6.
• Iodine deficiency or excess (including exposure to iodine-containing antiseptics) can cause transient CH, especially in certain world regions 3 6 8.
• Antithyroid drugs taken during pregnancy can also lead to transient hypothyroidism in the infant 3 6.

Central (Secondary) and Peripheral Causes

• Central (Secondary) CH: Due to pituitary or hypothalamic disorders. May be isolated or part of multiple pituitary hormone deficiencies 3 6 12.
• Peripheral CH: Rare defects in thyroid hormone transport or metabolism, sometimes associated with severe neurological impairment 5 8.

Treatment of Congenital Hypothyroidism

Effective management of CH is centered on prompt initiation of thyroid hormone replacement, regular monitoring, and long-term follow-up to ensure normal growth and neurodevelopment.

Treatment	Key Aspects/Goals	Monitoring Frequency	Source
Levothyroxine	10–15 μg/kg/day starting dose	Every 1–2 months (infancy)	3 4 6 11 12 13 14
Early Initiation	Begin ASAP after diagnosis	Within first 2 weeks	3 6 11 12 14
Monitoring	Adjust dose to keep T4 in upper normal	Every 1–2 months (1st yr), 2–3 months thereafter	3 6 11 12 13
Long-term Follow-Up	Assess neurodevelopment, growth	Ongoing	3 4 12 13 14
Genetic Counseling	For familial/genetic CH	As needed	5 8 9 12

Table 4: Treatment Strategies

Initiation and Dosage

• Levothyroxine is the treatment of choice. The recommended initial dose is 10–15 μg/kg per day 3 4 6 11 12 13 14.
• Treatment should begin as soon as CH is confirmed—ideally within the first 2 weeks of life—to maximize cognitive outcomes 3 6 11 12 14.
• The immediate goal is to normalize serum T4 (or free T4) and TSH concentrations rapidly 3 6 11 12.

Monitoring and Dose Adjustment

• Regular monitoring of serum TSH and free T4 is critical, especially during the first three years of life when brain development is most sensitive to thyroid hormone levels 3 6 11 12 13.
• Frequency:
  • Every 1–2 months during the first 6–12 months.
  • Every 2–3 months during the second and third years.
  • Adjust dosage with growth and laboratory results 3 6 12 13.
• The aim is to keep T4/free T4 in the upper half of the reference range and TSH within normal range 3 6 11 12.

Special Considerations

• Infants with severe CH (athryeosis) may require closer monitoring and higher doses, while those with milder or dyshormonogenetic forms may stabilize more quickly 13.
• Transient CH may not require lifelong therapy; reassessment can be considered after age 3 to determine if thyroid function has normalized 12.
• Central CH requires clinical vigilance, as TSH may not be elevated, and other pituitary hormone deficiencies may coexist 3 11 12.

Long-Term and Multidisciplinary Care

• Ongoing assessment of growth, neurodevelopment, and hearing is essential, with support from multidisciplinary teams as needed 3 4 12.
• Transition planning from pediatric to adult care ensures continuity and optimal lifelong health 12.
• Genetic counseling is recommended for families with hereditary or syndromic forms of CH 5 8 9 12.

Conclusion

Congenital hypothyroidism is a complex disorder with a broad spectrum of clinical presentations, causes, and outcomes. Early detection and treatment have transformed the prognosis for affected children. Ongoing research continues to refine our understanding of its genetics and optimal management.

Key Points:

• CH often presents subtly but can lead to severe developmental impairment if untreated.
• Newborn screening is essential for early detection, as symptoms may be absent at birth.
• CH is classified by permanence (permanent/transient), origin (primary/secondary/peripheral), and sometimes as syndromic.
• Most cases are due to thyroid gland dysgenesis or dyshormonogenesis, with multiple genetic and environmental causes identified.
• Prompt initiation of levothyroxine therapy and regular monitoring are critical for normal neurodevelopment.
• Lifelong follow-up and individualized care, including genetic counseling where appropriate, optimize outcomes for children with CH.

By understanding the nuances of CH, healthcare providers and families can work together to ensure every child reaches their full developmental potential.