What are the clinical manifestations, supporting examinations, and genetic examinations for hypotonia in children caused by thyroxine (T4) deficiency, particularly in those with congenital hypothyroidism?

Hypotonia in Children Caused by Thyroxine Deficiency

Clinical Manifestations

Hypothyroidism causes hypotonia through decreased metabolic activity affecting muscle function and central nervous system development, presenting with characteristic clinical features that distinguish it from other causes of hypotonia. 1

Core Clinical Features

• Hypotonia with preserved or increased deep tendon reflexes, distinguishing it from peripheral neuromuscular causes 2
• Prolonged neonatal jaundice (often extending beyond 2 weeks of life) 1, 3
• Feeding difficulties with poor suck and decreased activity 1, 4
• Macroglossia (enlarged tongue) - a highly characteristic finding 1, 3, 4
• Myxedematous facies with coarse facial features 1
• Constipation due to decreased gastrointestinal motility 1, 3
• Umbilical hernia and distended abdomen 1, 3
• Large fontanelles (both anterior and posterior) with delayed closure 1, 4
• Skin mottling and cool, dry skin 3
• Lethargy and increased sleep with decreased spontaneous movement 1, 4
• Hypothermia in severe cases 4

Developmental Impact

• Global developmental delays when central hypothyroidism is present 2
• Poor growth velocity and failure to thrive if untreated 5, 6
• Risk of permanent intellectual disability if treatment is delayed beyond 30 days of age 1

Key Distinguishing Features from Other Causes of Hypotonia

• Preserved or increased reflexes (unlike spinal muscular atrophy or peripheral neuropathies which show diminished reflexes) 2, 7
• Absence of fasciculations (unlike anterior horn cell disease) 7
• Normal creatine kinase levels (unlike muscular dystrophies) 2, 7

Supporting Examinations

First-Line Laboratory Tests

The American Academy of Neurology recommends thyroid function tests as first-line laboratory evaluation for all hypotonic infants. 2

• Serum TSH (thyroid-stimulating hormone): Elevated in primary hypothyroidism 1, 3, 6
• Free T4 or total T4: Low levels confirm hypothyroidism 1, 3, 6
• Creatine kinase: Normal in hypothyroidism, helping exclude muscular dystrophy 2, 7

Diagnostic Confirmation

• Primary hypothyroidism: Elevated TSH with low free T4 or total T4 1, 3
• Central hypothyroidism: Low or inappropriately normal TSH with low free T4 5, 6
• Serum thyroglobulin: May help identify thyroid dysgenesis (low in athyreosis, elevated in dyshormonogenesis) 1

Additional Imaging Studies

• Thyroid ultrasound: Identifies thyroid gland presence, size, and location (ectopic tissue) 1, 6
• Thyroid radionuclide uptake and scan: Distinguishes between thyroid dysgenesis and dyshormonogenesis 1
• Bone age radiograph: Shows delayed skeletal maturation in severe cases 1, 3
• Brain MRI: Should be performed in all cases of hypotonia as it is abnormal in 56% and diagnostic in 33% of cases 2

Newborn Screening

• Newborn screening programs detect most cases of congenital hypothyroidism before clinical symptoms develop 1, 4
• However, clinical symptoms should prompt immediate testing regardless of normal newborn screening results 4

Genetic Examination

Indications for Genetic Testing

For newborns presenting with hypotonia, congenital hypothyroidism, and additional features, specific genetic testing is recommended based on the clinical phenotype. 5

NKX2.1 (TTF-1) Gene Testing

For newborns who present with chILD syndrome, congenital hypothyroidism, and hypotonia, genetic testing for NKX2.1 (thyroid transcription factor) mutations or deletions is strongly recommended. 5

• Clinical triad: Hypothyroidism + hypotonia + neurologic abnormalities (choreoathetosis) 5
• Testing method: Sequence analysis and deletion/duplication analysis of NKX2.1 gene 5
• Inheritance pattern: Autosomal dominant with variable expressivity 5
• Additional features: May include respiratory problems (interstitial lung disease) forming "brain-lung-thyroid syndrome" 5

When to Consider NKX2.1 Testing

• Infants beyond the neonatal period with hypothyroidism and neurologic abnormalities (hypotonia or choreoathetosis) 5
• Severe disease with family history of adult ILD or childhood interstitial lung disease 5
• Negative testing for other surfactant dysfunction mutations (ABCA3, SFTPC) in cases with respiratory involvement 5

Other Genetic Considerations

• Chromosome microarray: Recommended as first-line genetic testing for children with dysmorphic features, growth abnormalities, or visceral anomalies accompanying hypotonia 2
• Trisomy 21 screening: Hypothyroidism is relatively common in children with Down syndrome 5

Genetic Counseling

Genetic counseling should be made available to family members of patients with genetic causes of hypothyroidism, particularly if asymptomatic family members may be carriers of a dominant gene mutation such as NKX2.1. 5

Treatment Priorities

Immediate Management

Treatment with levothyroxine should be started as soon as possible, preferably within the first 2 weeks of life, to optimize neurocognitive outcomes. 6, 4

• Starting dose: 10-15 mcg/kg/day of levothyroxine 8, 1, 6, 4
• Goal: Rapidly raise serum T4 above 130 nmol/L (10 mcg/dL) and normalize TSH 1
• Target range: Maintain free T4 in the upper half of age-specific reference range with TSH <5 mIU/L 6

Monitoring Schedule

• First 6 months: Measure TSH and free T4 every 1-2 months 1
• After 6 months: Every 3-4 months throughout childhood 1
• After dosage changes: Recheck levels 6-8 weeks after any adjustment 8

Critical Pitfall to Avoid

Do not miss hypothyroidism as a treatable cause of hypotonia—it is completely reversible with early treatment, but delays beyond 30 days of age may result in permanent neurocognitive impairment. 9, 1