Introduction to Cretinism in Children

Cretinism, also known as congenital hypothyroidism, is a severe thyroid hormone deficiency present from birth. It is a significant endocrine disorder that, if left untreated, can lead to profound physical and mental developmental delays.

Historical Context

• The term "cretinism" is derived from the French word "chrétien," meaning "Christian" or "human being"
• Historically observed in iodine-deficient regions, leading to the term "endemic cretinism"
• In modern medical practice, the term "congenital hypothyroidism" is preferred due to the potentially pejorative nature of "cretinism"

Types of Cretinism

• Endemic Cretinism: Associated with severe iodine deficiency in a population
• Sporadic Cretinism: Occurs in individuals due to genetic or developmental thyroid gland abnormalities

Importance of Early Detection and Treatment

With the advent of newborn screening programs in many countries, severe cretinism has become rare in developed nations. Early detection and treatment are crucial to prevent the devastating consequences of untreated congenital hypothyroidism.

Etiology of Cretinism in Children

Endemic Cretinism

• Severe iodine deficiency in the mother during pregnancy
• Insufficient iodine for fetal thyroid hormone production
• Often associated with goiter in the affected population

Sporadic Cretinism

1. Thyroid Dysgenesis (85% of cases)
   • Thyroid agenesis (complete absence of the gland)
   • Thyroid hypoplasia
   • Ectopic thyroid gland
2. Dyshormonogenesis (10-15% of cases)
   • Genetic defects in thyroid hormone synthesis
   • Mutations in genes such as TPO, TG, DUOX2, SLC5A5
3. Central Hypothyroidism (rare)
   • Defects in the hypothalamic-pituitary axis
   • Associated with other pituitary hormone deficiencies
4. Transient Congenital Hypothyroidism
   • Maternal antithyroid medications
   • Maternal thyroid-blocking antibodies
   • Iodine excess or deficiency

Genetic Factors

• Most cases of thyroid dysgenesis are sporadic
• Dyshormonogenesis is often autosomal recessive
• Some forms associated with specific syndromes (e.g., Pendred syndrome, Bamforth-Lazarus syndrome)

Pathophysiology of Cretinism in Children

Role of Thyroid Hormones in Fetal Development

• Critical for normal brain development and maturation
• Essential for skeletal growth and maturation
• Important for the development of multiple organ systems

Consequences of Thyroid Hormone Deficiency

1. Neurological Development
   • Impaired neuronal migration and differentiation
   • Reduced myelination
   • Altered neurotransmitter function
2. Skeletal System
   • Delayed bone age
   • Impaired linear growth
   • Epiphyseal dysgenesis
3. Metabolic Effects
   • Reduced basal metabolic rate
   • Impaired thermogenesis
   • Altered lipid metabolism

Timing of Thyroid Hormone Deficiency

• First trimester: Critical for neuronal proliferation and migration
• Second trimester: Important for neuronal differentiation and synaptogenesis
• Third trimester and early postnatal period: Crucial for myelination and gliogenesis

Differences in Endemic vs. Sporadic Cretinism

• Endemic cretinism: Combined effects of iodine deficiency and hypothyroidism
• Sporadic cretinism: Effects primarily due to thyroid hormone deficiency

Clinical Presentation of Cretinism in Children

Early Signs and Symptoms (Neonatal Period)

• Prolonged jaundice
• Poor feeding and constipation
• Lethargy and somnolence
• Hypothermia
• Large anterior and posterior fontanelles
• Macroglossia
• Umbilical hernia
• Hypotonia

Physical Features (If Untreated)

• Coarse facial features
• Puffy face and periorbital edema
• Broad, flat nose
• Thick lips
• Large protruding tongue
• Dry, rough skin
• Sparse, brittle hair
• Short stature with disproportionately short limbs

Developmental Issues

• Delayed developmental milestones
• Intellectual disability (ranging from mild to severe)
• Speech and language delays
• Poor motor coordination

Other Systemic Manifestations

• Cardiovascular: Bradycardia, poor cardiac contractility
• Gastrointestinal: Constipation, poor appetite
• Respiratory: Respiratory distress, obstructive sleep apnea
• Reproductive (in older children): Delayed puberty

Endemic Cretinism-Specific Features

• Neurological cretinism: Predominant neurological deficits, deaf-mutism
• Myxedematous cretinism: More severe hypothyroidism, dwarfism

Note on Modern Presentation

Due to newborn screening programs in many countries, the classic severe presentation of cretinism is now rare. Most cases are detected and treated early, leading to milder or absent clinical features.

Diagnosis of Cretinism in Children

Newborn Screening

• Primary method of early detection in many countries
• Typically performed 24-48 hours after birth
• Measures TSH and/or T4 levels in dried blood spots

Confirmatory Tests

• Serum TSH: Elevated in primary hypothyroidism
• Free T4: Low in both primary and central hypothyroidism
• Total T3: Often low, but less reliable in neonates

Imaging Studies

• Thyroid ultrasound: To assess gland size and position
• Thyroid scintigraphy (123I or 99mTc pertechnetate): To evaluate thyroid location and function
• X-rays: To assess bone age and epiphyseal development

Additional Investigations

• Thyroid antibodies: To rule out autoimmune thyroiditis
• Thyroglobulin levels: May be elevated in dyshormonogenesis
• Urinary iodine: To assess iodine status in endemic areas
• Genetic testing: For suspected dyshormonogenesis or syndromic forms

Differential Diagnosis

• Down syndrome
• Other causes of neonatal hypotonia
• Inborn errors of metabolism
• Pituitary disorders

Prenatal Diagnosis

• Possible in families with known genetic defects
• Fetal ultrasound may detect goiter or growth retardation
• Measurement of fetal thyroid hormones in amniotic fluid or cord blood (rarely performed)

Treatment of Cretinism in Children

Primary Treatment: Thyroid Hormone Replacement

• Levothyroxine (L-T4) is the treatment of choice
• Initiation:
  • Start as soon as the diagnosis is confirmed
  • Initial dose: 10-15 µg/kg/day
  • Given orally, once daily
• Administration:
  • Crushed and mixed with a small amount of breast milk or formula
  • Avoid mixing with soy formula, iron, or calcium supplements

Monitoring and Dose Adjustment

• Frequent monitoring in the first year of life:
  • TSH and free T4 at 2 and 4 weeks after initiation
  • Every 1-2 months in the first 6 months
  • Every 2-3 months between 6 months to 3 years
• Target levels:
  • TSH: 0.5-2 mU/L
  • Free T4: Upper half of the normal range
• Dose adjustments based on growth, development, and laboratory results

Supportive Care

• Early intervention programs for developmental support
• Speech and language therapy
• Physical therapy for motor development
• Occupational therapy for daily living skills
• Special education services as needed

Management of Complications

• Regular monitoring of growth and skeletal maturation
• Hearing assessment and management of hearing loss
• Cardiovascular evaluation if indicated
• Psychological support for the child and family

Prevention (Endemic Cretinism)

• Iodine supplementation programs in endemic areas
• Iodization of salt
• Maternal iodine supplementation during pregnancy and lactation

Long-term Follow-up

• Lifelong thyroid hormone replacement
• Regular endocrine follow-up
• Transition to adult care in adolescence
• Genetic counseling for familial cases

Prognosis of Cretinism in Children

Factors Influencing Prognosis

• Timing of diagnosis and treatment initiation
• Severity of hypothyroidism at diagnosis
• Adequacy of treatment and compliance
• Etiology of hypothyroidism
• Presence of associated anomalies or syndromes

Outcomes with Early Treatment

• Normal or near-normal cognitive development
• Improved physical growth and maturation
• Better school performance and social adaptation
• Reduced risk of long-term complications

Potential Long-term Issues

• Subtle neurocognitive deficits (even with early treatment)
• Mild delays in motor development
• Hearing impairment (especially in endemic cretinism)
• Attention deficits and behavioral problems
• Fine motor skill deficits
• Persistent short stature in some cases
• Increased risk of obesity and metabolic syndrome

Prognosis in Untreated or Late-treated Cases

• Severe intellectual disability
• Persistent growth retardation
• Speech and language disorders
• Motor deficits and coordination problems
• Irreversible neurological damage
• Increased morbidity and reduced life expectancy

Quality of Life Considerations

• Need for lifelong medical care and hormone replacement
• Potential for normal education and employment with early treatment
• Importance of psychosocial support and family education
• Possible challenges in social integration and relationships

Monitoring and Follow-up

• Regular assessment of growth and development
• Periodic neuropsychological evaluations
• Ongoing thyroid function monitoring
• Screening for associated conditions (e.g., celiac disease, autoimmune disorders)

Future Perspectives

• Continued improvement in newborn screening techniques
• Potential for prenatal diagnosis and treatment
• Research into optimizing treatment protocols
• Exploration of novel therapeutic approaches (e.g., gene therapy for specific genetic forms)