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Floppy Infant Syndrome, Pediatric

Basics

Description

- Pregnancy and delivery - Pregnancy - Maternal illness - Drug or teratogen exposure - Abnormalities on prenatal ultrasound - Polyhydramnios (poor prenatal swallow) - Reduced fetal movements (neuromuscular disorders)

- Delivery - Gestational age and presentation - Birth trauma, anoxia, or complications - Shortened umbilical cord - Low Apgar scores - Maternal perinatal infection

- Course of hypotonia - Age at onset - Improved or worsened

- Family history - Parental consanguinity - Three-generation pedigree specifically inquiring about history of neuromuscular disease, birth defects, intellectual disability, and recurrent infantile deaths

- General physical exam - Dysmorphic features (may lead to particular syndromic diagnosis) - Alertness: Infants with neuromuscular disease are typically alert. - Poor spontaneous movements - Abnormal head size and/or shape - High-arched palate (neuromuscular disorders) - Tongue fasciculations (anterior horn cell) - Large tongue (storage disorders) - Ophthalmologic exam: cataracts (peroxisomal disorders), pigmentary retinopathy (peroxisomal disorders), cherry red spot (storage disorders), lens dislocation (sulfite oxidase/molybdenum cofactor deficiency) - Abnormal fat pads, inverted nipples (congenital disorders of glycosylation) - Cardiac enlargement and signs of cardiac failure (Pompe disease) - Visceral enlargement (storage disorders) - Arthrogryposis (central, neuromuscular, or connective tissue disorders) - Hip dislocation (intrauterine hypotonia) - Joint laxity (connective tissue disorders)

- Muscle tone - Abnormal resting posture (abducted, externally rotated legs, flaccid arms) and prominent head lag with pull-to-sit - Fisting indicates spasticity. - Abnormal posture and tone in supine position, ventral and horizontal suspension, and traction - Elbow may easily extend beyond midsternum (scarf sign). - Generalized hypotonia with increased tone in thumb adductors, wrist pronators, and hip adductors: early cerebral palsy - Fatigability: cardinal feature of myasthenic syndromes but may occur in other neuromuscular diseases

- Examination of the mother - Signs of myotonia (myotonic dystrophy) - Handgrip myotonia (inability to release handgrip quickly) - Percussion myotonia (inability to release muscle tapped with reflex hammer), including tongue myotonia, a more reproducible feature than handgrip myotonia - Action myotonia (delayed muscle relaxation after voluntary contraction)

- Toxoplasmosis, other viruses, rubella, cytomegalovirus, or herpes (TORCH) screen; blood, urine, and CSF cultures (infection) - Screen for inborn error of metabolism: - Ammonia (high in urea cycle defects, organic acidemias, fatty acid oxidation disorders) - Lactate in blood, urine, CSF (high in carbohydrate metabolism and mitochondrial disorders) - Quantitative amino acid analysis in blood and urine (aminoacidopathies) - Plasma acylcarnitine profiles and urine organic acid analysis (organic acidemias, fatty acid oxidation defects) - Plasma very-long-chain fatty acids (peroxisomal disorders) - Uric acid (low in molybdenum cofactor deficiency) - Transferrin isoelectric focusing (abnormal pattern seen in congenital disorders of glycosylation) - 7-dehydrocholesterol (high in Smith-Lemli-Opitz syndrome) - WBC lysosomal enzyme assays - Urine GAA/GMT(creatine deficiency disorders) - Urine purine/pyrimidine (purine/pyrimidine metabolism disorders) - CSF neurotransmitters - Stools for Clostridium toxin when botulism suspected (endemic in Pennsylvania, some Northwestern states)

- Molecular studies - Karyotype (Down syndrome) - Microarray/SNP array (microdeletion/microduplication syndromes) - DNA methylation/MS-MLPA (Prader-Willi/Angelman syndrome) - DNA-based molecular testing - Exome sequencing

- Acute systemic disorders - Sepsis - Trauma - Malnutrition - GI obstruction or bleed - Toxic (hyperbilirubinemia, maternal sedative, analgesic, and/or anesthetic exposure)

- Central hypotonia - Disorders involving cerebral cortex, cerebellum, and brainstem - Structural brain abnormalities (lissencephaly, holoprosencephaly) - Hypoxic-ischemic encephalopathy - Intracranial hemorrhage - Infections (meningitis, encephalitis)

- Peripheral hypotonia - Disorders of anterior horn cell including the following: - Spinal muscular atrophy (SMA) - SMA with respiratory distress (SMARD) - Arthrogryposis multiplex congenita - Pompe disease (glycogen storage type II) - Neonatal poliomyelitis

- Disorders of peripheral nerve - Dejerine-Sottas disease - Guillain-Barr © syndrome - Charcot-Marie-Tooth disease - Familial dysautonomia

- Combined hypotonia - Dystroglycanopathies - Leukodystrophies (Canavan disease, Pelizaeus-Merzbacher disease) - Marinesco-Sj ¶gren syndrome - Mitochondrial encephalomyopathies

  • "Floppy infant" refers to the newborn/infant presenting at birth or early in life with hypotonia, a symptom of diminished tone of skeletal muscles associated with decreased resistance of muscles to passive stretching.
  • Hypotonia can be caused by abnormalities of the CNS (central hypotonia), peripheral neuromuscular system (peripheral hypotonia), or combined abnormality involving both (combined hypotonia).
  • Nonspecific transient hypotonia occurs in nonneurologic conditions and may suggest gastrointestinal (GI), cardiac, pulmonary, infectious, renal, or endocrine disease.

Epidemiology

No comprehensive prevalence known owing to presence of hypotonia as a feature of many distinct disorders; overall, central hypotonia is more common than peripheral hypotonia.

Risk Factors

Genetics

Substantial proportion (>50%) of infantile hypotonia cases accounted for by genetic-metabolic disorders.

Etiology

Causes may be divided into two major categories:

  • Central: hypotonia with decreased alertness, developmental delay, and lack of or minimal weakness; caused by upper motor neuron defect
  • Peripheral: hypotonia with profound weakness, paucity of antigravity movements, decreased or absent deep tendon reflexes (DTRs), and visual alertness; caused by lower motor neuron defect (i.e., disorders of anterior horn cell, peripheral nerve, neuromuscular junction, or skeletal muscle)

Commonly Associated Conditions

  • Respiratory problems (apnea/hypoventilation)
  • Feeding/swallowing difficulties
  • Hip dislocation/contractures/joint laxity
  • Seizure disorder
  • Cognitive/developmental delay
  • Hypersomnolence

Diagnosis

History and physical exam findings used to categorize patients as having central, peripheral, or combined hypotonia.

History

  • Pregnancy and deliveryPregnancyMaternal illnessDrug or teratogen exposureAbnormalities on prenatal ultrasoundPolyhydramnios (poor prenatal swallow)Reduced fetal movements (neuromuscular disorders)DeliveryGestational age and presentationBirth trauma, anoxia, or complicationsShortened umbilical cordLow Apgar scoresMaternal perinatal infection
  • Medical historySeizuresApneaFeeding difficultiesReview of systems for associated malformations or health conditionsDelayed motor milestonesDelayed social, fine motor, or language milestones point to CNS defect.
  • Course of hypotoniaAge at onsetImproved or worsened
  • Family historyParental consanguinityThree-generation pedigree specifically inquiring about history of neuromuscular disease, birth defects, intellectual disability, and recurrent infantile deaths

Physical Exam

Exam findings will help determine if hypotonia is suggestive of an upper motor neuron versus a lower motor neuron problem or both. Perform the following:

  • General physical examDysmorphic features (may lead to particular syndromic diagnosis)Alertness: Infants with neuromuscular disease are typically alert.Poor spontaneous movementsAbnormal head size and/or shapeHigh-arched palate (neuromuscular disorders)Tongue fasciculations (anterior horn cell)Large tongue (storage disorders)Ophthalmologic exam: cataracts (peroxisomal disorders), pigmentary retinopathy (peroxisomal disorders), cherry red spot (storage disorders), lens dislocation (sulfite oxidase/molybdenum cofactor deficiency)Abnormal fat pads, inverted nipples (congenital disorders of glycosylation)Cardiac enlargement and signs of cardiac failure (Pompe disease)Visceral enlargement (storage disorders)Arthrogryposis (central, neuromuscular, or connective tissue disorders)Hip dislocation (intrauterine hypotonia)Joint laxity (connective tissue disorders)
  • Neurologic examStrengthLow-pitched or progressively weaker cryPoor suckPaucity of facial expression ("myopathic" facies) indicates facial weakness (myotonic dystrophy, congenital muscular dystrophy, congenital myopathies).Ptosis and external ophthalmoplegia (congenital myasthenic syndromes, congenital myopathies, and congenital muscular dystrophies)Regional strength differences: Spinal muscular atrophy (SMA) spares diaphragm, face muscles, and pelvic sphincters. Neuropathies present with distal limb weakness and proximal sparing. Myasthenic syndromes affect bulbar and oculomotor muscles.Muscle toneAbnormal resting posture (abducted, externally rotated legs, flaccid arms) and prominent head lag with pull-to-sitFisting indicates spasticity.Abnormal posture and tone in supine position, ventral and horizontal suspension, and tractionElbow may easily extend beyond midsternum (scarf sign).Generalized hypotonia with increased tone in thumb adductors, wrist pronators, and hip adductors: early cerebral palsyFatigability: cardinal feature of myasthenic syndromes but may occur in other neuromuscular diseasesDTRsHyperreflexia implies central dysfunction.Diminished DTRs in proportion to degree of weakness in myopathic diseasesAbsent DTRs in setting of minimal weakness typical of neuropathic disease
  • Examination of the motherSigns of myotonia (myotonic dystrophy)Handgrip myotonia (inability to release handgrip quickly)Percussion myotonia (inability to release muscle tapped with reflex hammer), including tongue myotonia, a more reproducible feature than handgrip myotoniaAction myotonia (delayed muscle relaxation after voluntary contraction)

Diagnostic Tests & Interpretation

Lab

  • Initial tests may include the following:Electrolytes (including Ca and Mg)Thyroid function testsCreatine kinase (normal in central, may be high in peripheral or combined cases)Arterial blood gas
  • Toxoplasmosis, other viruses, rubella, cytomegalovirus, or herpes (TORCH) screen; blood, urine, and CSF cultures (infection)
  • Screen for inborn error of metabolism:Ammonia (high in urea cycle defects, organic acidemias, fatty acid oxidation disorders)Lactate in blood, urine, CSF (high in carbohydrate metabolism and mitochondrial disorders)Quantitative amino acid analysis in blood and urine (aminoacidopathies)Plasma acylcarnitine profiles and urine organic acid analysis (organic acidemias, fatty acid oxidation defects)Plasma very-long-chain fatty acids (peroxisomal disorders)Uric acid (low in molybdenum cofactor deficiency)Transferrin isoelectric focusing (abnormal pattern seen in congenital disorders of glycosylation)7-dehydrocholesterol (high in Smith-Lemli-Opitz syndrome)WBC lysosomal enzyme assaysUrine GAA/GMT(creatine deficiency disorders)Urine purine/pyrimidine (purine/pyrimidine metabolism disorders)CSF neurotransmittersStools for Clostridium toxin when botulism suspected (endemic in Pennsylvania, some Northwestern states)
  • Molecular studiesKaryotype (Down syndrome)Microarray/SNP array (microdeletion/microduplication syndromes)DNA methylation/MS-MLPA (Prader-Willi/Angelman syndrome)DNA-based molecular testingExome sequencing

Imaging

  • MRI for structural brain abnormalities; CT for intracranial calcifications
  • Magnetic resonance spectroscopy (MRS): assesses neuronal integrity (N-acetylaspartate [NAA] peaks), intracerebral accumulation of unusual metabolites (lactate, glycine), or deficiency of a key metabolite (creatine)
  • Muscle imaging: used in some centers to delineate a neuromuscular problem
  • Abdominal/pelvic ultrasound: Assess other organ involvement.

Diagnostic Procedures/Other

  • Evaluation of vision and hearing
  • Echocardiography
  • Anticholinesterase administration in suspected myasthenia may be diagnostic.
  • Electromyography (EMG) and nerve conduction velocity: useful tools to assess the lower motor unit and localize involved site
  • EEG: if seizures are suspected
  • Skin biopsy: for lysosomal enzyme assay in fibroblasts and electron microscopy for abnormal organelles, inclusions, or storage material (Pompe disease)
  • Muscle biopsy: for histopathology, electron microscopy and respiratory chain studies (congenital myopathies, storage myopathies [Pompe disease], or muscular dystrophies)

Differential Diagnosis

Generalized nonneurologic conditions including the following:

  • Acute systemic disordersSepsisTraumaMalnutritionGI obstruction or bleedToxic (hyperbilirubinemia, maternal sedative, analgesic, and/or anesthetic exposure)
  • Chronic systemic disordersCongenital heart diseaseEndocrinopathies (hypothyroidism, rickets, hypercalcemia)Renal tubular acidosisCystic fibrosisMalabsorptionConnective tissue disordersEhlers-Danlos syndromeMarfan syndromeLoeys-Dietz syndromeOsteogenesis imperfectaChondrodysplasiaBenign joint laxity

Neurologic diagnoses including the following:

  • Central hypotoniaDisorders involving cerebral cortex, cerebellum, and brainstemStructural brain abnormalities (lissencephaly, holoprosencephaly)Hypoxic-ischemic encephalopathyIntracranial hemorrhageInfections (meningitis, encephalitis)Chromosomal disordersDown syndromeWilliams syndromePrader-Willi syndromeAngelman syndromeSingle-gene disordersFragile X syndromeRett/Rett-like syndromePTEN-related disordersSmith-Lemli-Opitz syndromePeroxisomal disorders (Zellweger syndrome, infantile Refsum, neonatal adrenoleukodystrophy)Congenital disorders of glycosylationCreatine deficiency disordersPurine/pyrimidine metabolism disordersDisorders of spinal cordMyelodysplasias (meningomyeloceles, diplomyelia, diastematomyelia)Benign congenital hypotonia: mild transient hypotonia without dysmorphology; weakness; or other neurologic, physical, or laboratory abnormalities
  • Peripheral hypotoniaDisorders of anterior horn cell including the following:Spinal muscular atrophy (SMA)SMA with respiratory distress (SMARD)Arthrogryposis multiplex congenitaPompe disease (glycogen storage type II)Neonatal poliomyelitisDisorders of peripheral nerveDejerine-Sottas diseaseGuillain-Barr © syndromeCharcot-Marie-Tooth diseaseFamilial dysautonomiaDisorders of neuromuscular junctionMyasthenia gravis (congenital, transient)Infantile botulismToxic (hypermagnesemia, antibiotics [especially aminoglycosides], nondepolarizing neuromuscular blockers)Disorders of muscleCongenital myotonic dystrophyCongenital muscular dystrophiesCongenital structural myopathies: central core, nemaline, centronuclear myopathyMetabolic myopathies (mitochondrial and storage disorders)Organic aciduria (Barth syndrome)Fatty acid oxidation disorders
  • Combined hypotoniaDystroglycanopathiesLeukodystrophies (Canavan disease, Pelizaeus-Merzbacher disease)Marinesco-Sj ¶gren syndromeMitochondrial encephalomyopathies

Treatment

Medication

  • Anticholinesterase inhibitors and 3,4-diamino-pyridine in congenital myasthenic syndromes
  • IV immunoglobulin and plasmapheresis have been used in treatment of infants with Guillain-Barr © syndrome.

Additional Therapies

General Measures

  • Address apnea, hypoventilation, hypoxia:Intubation or positive pressure devices may be required.Chest physiotherapy, antibiotics, bronchodilators, and oxygen may be needed.Hypermagnesemia can cause apnea.Weak infants in car seats may be at risk for acute respiratory problems.
  • Underlying toxic or metabolic causes should be addressed and treated appropriately.

Complementary & Alternative Therapies

  • Physical therapyMay help maintain maximum muscle function and reduce secondary deformitiesOrthopedic consultation to evaluate hips and contractures
  • Occupational therapy
  • Speech therapy

Surgery/Other Procedures

Surgical intervention in later childhood to correct primary as well as secondary deformities

Inpatient Considerations

Admission Criteria

Respiratory insufficiency, feeding intolerance, failure to thrive, metabolic abnormality

Ongoing Care

Follow-up Recommendations

Individualized multidisciplinary care including specialists in neurology, pulmonology, orthopedics, development, physiotherapy, and nutrition; attention to vision and hearing; as well as psychosocial support to caregivers/families

Diet

Feeding and swallowing difficulties may necessitate nutritional supplementation and/or feeding tube placement.

Prognosis

Many of the paralytic hypotonias are quite variable in their clinical course. Severity of disease depends on underlying cause and associated respiratory and nutritional factors.

Complications

  • Respiratory insufficiency/recurrent pneumonia
  • Orthopedic deformities
  • Poor nutritional status

Additional Reading

  • Bodensteiner JB. The evaluation of the hypotonic infant. Semin Pediatr Neurol. 2008;15(1):10-20. [View Abstract]
  • Harris SR. Congenital hypotonia: clinical and developmental assessment. Dev Med Child Neurol. 2008;50(12):889-892. [View Abstract]
  • Lisi E, Cohn R. Genetic evaluation of the pediatric patient with hypotonia: perspective from a hypotonia specialty clinic and review of the literature. Dev Med Child Neurol. 2011;53(7):586-599. [View Abstract]
  • Peredo DE, Hannibal MC. The floppy infant: evaluation of hypotonia. Pediatr Rev. 2009;30(9):e66-e76. 19726697. [View Abstract]
  • Prasad A, Prasad C. Genetic evaluation of the floppy infant. Semin Fetal Neonatal Med. 2011;16(2):99-108. [View Abstract]

Codes

ICD09

  • 781.99 Other symptoms involving nervous and musculoskeletal systems
  • 779.89 Other specified conditions originating in the perinatal period

ICD10

  • P94.2 Congenital hypotonia

SNOMED

  • 33010005 Floppy infant syndrome (disorder)

FAQ

  • Q: By what age should one expect resolution of benign congenital hypotonia?
  • A: Hypotonia typically resolves by the time the infant is walking, up to 18 months of age.
  • Q: What clinical sign can help distinguish between SMA and infantile botulism?
  • A: Tongue fasciculations are seen in SMA. Also, decreased pupillary light reflex is seen in botulism.