What is the differential diagnosis and management of hypotonia in neonates?

Differential Diagnosis of Neonatal Hypotonia

The differential diagnosis of neonatal hypotonia must first distinguish between central (upper motor neuron) and peripheral (lower motor neuron/motor unit) causes through careful clinical examination, with central hypotonia accounting for approximately 50% of cases, peripheral 18%, and mixed 32%. 1

Initial Clinical Localization

Central Hypotonia Features

• Preserved or increased deep tendon reflexes with abnormal plantar responses distinguish central from peripheral causes 2, 3
• Associated findings include seizures, microcephaly/macrocephaly, dysmorphic features, and abnormal primitive reflexes 3
• Normal or only mildly elevated creatine kinase (CK) levels 2

Peripheral Hypotonia Features

• Diminished or absent deep tendon reflexes are the hallmark of peripheral involvement 2, 3
• Tongue fasciculations strongly suggest spinal muscular atrophy and require urgent referral 4
• Significantly elevated CK (>3× normal) indicates muscular dystrophy and mandates immediate neurology referral 4
• Preserved feeding and bulbar function suggest congenital myopathy over more severe neuromuscular disorders 2

Major Diagnostic Categories

Central Causes (50% of cases) 1

Systemic/Metabolic:

• Sepsis, hypoxic-ischemic encephalopathy, heart failure, and electrolyte abnormalities remain common reversible causes 5
• Hypothyroidism is treatable and must not be missed 4

Genetic/Chromosomal:

• Prader-Willi syndrome should be considered in any infant with significant hypotonia, poor feeding, reduced spontaneous arousal, and hypogonadism (undescended testes, small phallus, or small clitoris) 6
• Chromosomal disorders account for a significant proportion of central hypotonia 7
• For newborns with hypotonia, congenital hypothyroidism, and hypotonia, genetic testing for NKX2.1 (thyroid transcription factor) mutations or deletions is recommended 6

Structural CNS:

• Intracranial hemorrhage, CNS malformations, and brain imaging abnormalities 7
• MRI is abnormal in 56% of cases and contributes to diagnosis in 33% 1

Drug Exposure:

• Diazepam exposure causes hypotonia, poor suck, hypothermia, and apnea with onset from hours to weeks 6
• Ethchlorvynol causes lethargy, hypotonia, and poor suck 6
• Hydroxyzine produces hypotonia with tremors, irritability, and feeding problems 6

Peripheral Causes (18% of cases) 1

Anterior Horn Cell:

• Spinal muscular atrophy presents with fasciculations (especially tongue), absent reflexes, and risk of rapid deterioration requiring urgent referral 4

Muscle Disorders:

• Congenital myopathies present with hypotonia, preserved or reduced reflexes, normal or minimally elevated CK, and relatively preserved bulbar function 2
• Normal CK essentially excludes congenital muscular dystrophy, which shows significantly elevated levels 2
• Pompe disease improves with early enzyme replacement therapy and must not be missed 4

Neuromuscular Junction:

• Congenital myasthenic syndromes present with fluctuating weakness and feeding difficulties 8

Diagnostic Workup Algorithm

First-Line Investigations

• Creatine kinase level: Elevated >3× normal indicates muscular dystrophy 4
• Thyroid function tests: Hypothyroidism is treatable 4
• Basic metabolic panel and lactate: Screen for metabolic disorders 7
• Maternal drug history: Identify drug withdrawal syndromes 6

Neuroimaging

• MRI brain/spine should be performed in all cases, as it is abnormal in 56% and diagnostic in 33% 1
• Use lowest radiation dose CT only when MRI unavailable 6

Genetic Testing Strategy

• Molecular genetic testing is the recommended next step after careful phenotyping 1
• Whole exome sequencing has the highest diagnostic yield: 72% positive results with 59% diagnostic 1
• Gene panels show 58% abnormal results with 30% diagnostic 1
• Microarray studies yield 27% abnormal with only 9% diagnostic 1

Specific Genetic Testing Indications:

• For newborns with severe/rapidly progressive disease or family history of ILD, test for SFTPB, SFTPC, and ABCA3 mutations 6
• For hypotonia with hypothyroidism and neurologic abnormalities, test for NKX2.1 mutations/deletions 6

Electrophysiology and Biopsy

• EMG confirms myopathy but can be misleading in infants under 2 years 2
• Muscle biopsy remains the gold standard for definitive diagnosis of congenital myopathies 2

Management Priorities

Immediate Interventions (Regardless of Diagnosis)

• Refer immediately to early intervention programs for needs assessment, even without definitive diagnosis 4
• Initiate physical therapy focusing on antigravity muscle power and gross motor skills 4
• Begin occupational therapy for sensory integration and fine motor skills 4
• Perform speech/language evaluation including oral-motor functioning assessment 4

Urgent Referrals Based on Red Flags

• CK >3× normal: Immediate pediatric neurology referral for suspected muscular dystrophy 4
• Fasciculations: Urgent referral for suspected spinal muscular atrophy due to rapid deterioration risk 4
• Respiratory insufficiency with weakness: Consider inpatient evaluation for neuromuscular disorders with respiratory failure risk 4
• Loss of motor milestones: Urgent neurology referral for suspected neurodegenerative process 4

Monitoring and Supportive Care

• Monitor respiratory function closely, as respiratory failure can occur during acute illness in neuromuscular disorders 4
• Regular growth measurements using CDC/WHO curves to detect microcephaly, macrocephaly, or growth impairments 4
• Cardiac evaluation for certain congenital myopathies that develop cardiomyopathy 2

Critical Pitfalls to Avoid

• Do not delay early intervention services while awaiting definitive diagnosis—therapy must begin immediately 4
• Do not diagnose hypotonic cerebral palsy without excluding other causes, especially with uneventful perinatal history and normal brain imaging 4
• Do not miss treatable conditions: Pompe disease (enzyme therapy), hypothyroidism (hormone replacement), and spinal muscular atrophy (emerging therapies) 4, 8
• Do not overlook respiratory monitoring in neuromuscular disorders 4
• For mild abnormalities without red flags, close observation with time-definite follow-up is acceptable 4

Prognosis

Mortality in neonatal hypotonia is approximately 30%, with nearly 90% of deaths occurring before one year of age 7. Developmental disorders occur in 47% of survivors, while only 22% achieve normal development 7. Early diagnosis and intervention significantly improve outcomes, particularly for treatable conditions 8.