Approach to the infant with hypotonia and weakness

INTRODUCTION — Hypotonia and weakness in early infancy may be a sign of a central nervous disorder (eg, cerebral palsy), a primary neuromuscular disorder (table 1), or a genetic syndrome associated with hypotonia (eg, Down syndrome, Prader-Willi syndrome). However, these signs also commonly occur as a consequence of common neonatal conditions such as congenital infections, bacterial sepsis, hypothyroidism, hypoglycemia, intracranial hemorrhage, and drug toxicity (eg, perinatal magnesium sulfate exposure). If these more common conditions can be excluded, genetic syndromes or a primary neuromuscular disorder should be considered.

Assessment of the infant with hypotonia and weakness is reviewed here. Hypotonia and weakness caused by peripheral nerve and muscle diseases (table 1) and the evaluation of specific neuromuscular disorders are discussed elsewhere. (See "Overview of peripheral nerve and muscle disorders causing hypotonia in the newborn" and "Neuromuscular junction disorders in newborns and infants" and "Congenital myopathies".)

CAUSES — The causes of hypotonia and weakness in infancy are diverse:

●Ill-appearing infant – Hypotonia may be part of an overall ill appearance of the infant. Infection is an important cause of ill appearance in infancy; other causes are summarized in the table (table 2). The approach to evaluating and managing ill-appearing infants is discussed separately. (See "Approach to the ill-appearing infant (younger than 90 days of age)".)

●Genetic syndromes – Hypotonia is a feature of numerous genetic syndromes. Some common examples include:

•Down syndrome (see "Down syndrome: Clinical features and diagnosis")

•Prader-Willi syndrome (see "Prader-Willi syndrome: Management")

•Trisomy 18 (Edwards syndrome) (see "Congenital cytogenetic abnormalities", section on 'Trisomy 18 syndrome')

•Trisomy 13 (Patau syndrome) (see "Congenital cytogenetic abnormalities", section on 'Trisomy 13 syndrome')

•Achondroplasia and other skeletal dysplasias (see "Achondroplasia" and "Skeletal dysplasias: Specific disorders")

●Inborn errors of metabolism – Hypotonia is a feature of many inborn errors of metabolism. Examples include:

•Tay-Sachs disease

•Congenital disorders of glycosylation (see "Inborn errors of metabolism: Classification", section on 'Congenital disorders of glycosylation')

•Carnitine cycle defects and other fatty acid oxidation defects (see "Overview of fatty acid oxidation disorders")

•Disorders of creatine metabolism (see "Congenital disorders of creatine synthesis and transport")

•Glycogen storage diseases and other disorders of glycogen metabolism (see "Overview of inherited disorders of glucose and glycogen metabolism")

•Organic acidemias (see "Organic acidemias: An overview and specific defects")

•Peroxisomal disorders (see "Peroxisomal disorders")

•Urea cycle defects (see "Urea cycle disorders: Clinical features and diagnosis")

●Endocrine abnormalities – Common endocrine abnormalities that may present with hypotonia and weakness in infancy include:

•Congenital hypothyroidism (see "Clinical features and detection of congenital hypothyroidism")

•Hypoglycemia (eg, as a consequence of maternal diabetes) (see "Infants of mothers with diabetes (IMD)" and "Causes of hypoglycemia in infants and children")

•Congenital adrenal hyperplasia (see "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children")

●Primary neuromuscular disorders – Neuromuscular disorders that can present with hypotonia and weakness in infancy are summarized in the table and are discussed in greater detail separately (table 1). (See "Overview of peripheral nerve and muscle disorders causing hypotonia in the newborn" and "Neuromuscular junction disorders in newborns and infants" and "Congenital myopathies".)

●Cerebral palsy (CP) – Though CP is typically characterized by increased tone (spasticity and/or dystonia), some affected infants may exhibit low tone in early infancy. CP does not represent a specific cause of abnormal tone; rather, it is a heterogeneous group of conditions resulting from abnormalities of the developing fetal or infantile brain due to a variety of causes. Causes of CP are summarized in the table and are discussed separately (table 3). (See "Cerebral palsy: Epidemiology, etiology, and prevention", section on 'Specific causes and risk factors'.)

HISTORY — The obstetric and perinatal history may provide information that supports the diagnosis of a neuromuscular disorder. Affected infants frequently have a history of polyhydramnios (caused by decreased fetal swallowing), fetal akinesia (paucity of movement), and malpresentation (often in the breech position) [1].

Delivery may be complicated by birth trauma or perinatal depression. Although these complications can occur in normal infants, infants with congenital neuromuscular disorders may be less able to tolerate the stress associated with labor and delivery and, thus, be more susceptible to birth depression.

A family history of neuromuscular abnormalities may be informative because many disorders are inherited. Examples of familial neuromuscular diseases include:

●Congenital myotonic dystrophy (see "Myotonic dystrophy: Etiology, clinical features, and diagnosis")

●Spinal muscular atrophy (see "Spinal muscular atrophy")

●Familial dysautonomia (see "Hereditary sensory and autonomic neuropathies", section on 'HSAN3 (Familial dysautonomia)')

●Many metabolic disorders (eg, disorders of mitochondrial metabolism, acid alpha-glucosidase deficiency [Pompe disease]) (see "Mitochondrial myopathies: Clinical features and diagnosis" and "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features")

PHYSICAL EXAMINATION — The physical examination of an infant with weakness or hypotonia begins with an assessment of the infant's general appearance and includes clinical evaluation to identify features suggestive of a specific systemic or neuromuscular disorder. This evaluation includes assessment of:

●Dysmorphic features – Dysmorphic features and congenital defects should be identified. Characteristic dysmorphic features may be observed in many genetic disorders associated with hypotonia, including:

•Down syndrome (see "Down syndrome: Clinical features and diagnosis", section on 'Dysmorphic features')

•Trisomy 18 (Edwards syndrome) (see "Congenital cytogenetic abnormalities", section on 'Trisomy 18 syndrome')

•Trisomy 13 (Patau syndrome) (see "Congenital cytogenetic abnormalities", section on 'Trisomy 13 syndrome')

•Peroxisomal disorders (see "Peroxisomal disorders")

•Congenital disorders of glycosylation (see "Overview of congenital disorders of glycosylation")

●Standard measurements – Weight, length, and head circumference should be measured, and the data obtained plotted, against standard references. (See "The pediatric physical examination: General principles and standard measurements", section on 'Standard measurements'.)

●Findings suggestive of a possible neuromuscular disorder – Certain physical findings may be helpful in making the diagnosis of a specific neuromuscular disorder. These findings, and examples of specific conditions, include:

•Skin pallor, bruising, petechiae, or evidence of trauma (eg, traumatic myelopathy) (see "Overview of peripheral nerve and muscle disorders causing hypotonia in the newborn", section on 'Traumatic myelopathy')

•Abnormalities of respiratory rate, pattern, or diaphragmatic movement (eg, congenital myopathies) (see "Congenital myopathies")

•Cardiomyopathy (eg, carnitine deficiency, fatty acid oxidation disorders) (see "Specific fatty acid oxidation disorders", section on 'Carnitine cycle defects')

•Anomalies of the genitalia, including hypogonadism or hypospadias (eg, Smith-Lemli-Opitz syndrome) (see "Evaluation of the infant with atypical genital appearance (difference of sex development)" and "Causes of primary adrenal insufficiency in children", section on 'Defects in cholesterol biochemistry')

•Contractures or laxity of the hips or other joints (eg, Ehlers-Danlos syndrome, arthrogryposis multiplex congenita) (see "Overview of peripheral nerve and muscle disorders causing hypotonia in the newborn", section on 'Arthrogryposis multiplex congenita')

•Skeletal dysplasia, including rhizomelic shortening of extremities and lumbar kyphosis (see "Achondroplasia" and "Skeletal dysplasias: Specific disorders")

NEUROLOGIC EXAMINATION — A complete neurologic examination should be performed with particular attention given to the extent of hypotonia and weakness, whether the hypotonia is central (supraspinal/suprasegmental) or peripheral (segmental or motor unit), and the possible presence of other findings that may indicate a specific disorder [1,2].

The examination includes the following:

●Strength and tone – Assessment of muscle strength (maximum voluntary resistance to movement) and muscle tone (resistance to passive movement) (see 'Assessment of muscle tone' below). The former is challenging to evaluate in newborns and young infants and may require multiple attempts [2].

●Motor reflexes – Deep tendon reflexes may help distinguish between upper and lower motor neuron lesions. Abnormally brisk reflexes with clonus suggest involvement of the upper tract, whereas absent reflexes are consistent with a neuropathic lesion or severe myopathy. Primary neonatal reflexes, including the Moro reflex, tonic neck response, palmar grasp, and placing and stepping reactions, should be evaluated.

●Eye movements – Eye movements are assessed as part of the cranial nerve examination. Spontaneous movements, such as fixation on objects and following them, can be observed in response to the examiner's face or a red ball. Eye movements also can be induced by gentle rotation of the head (oculocephalogyric reflex). Absent fixation or following with a positive oculocephalogyric reflex suggests a lesion above the level of the brainstem.

●Facial movements and tongue fasciculations – Facial diplegia occurs in some neuromuscular disorders (eg, congenital myotonic dystrophy). It also can be associated with severe acute basal ganglia damage (eg, mitochondrial disease, Leigh syndrome). The tongue should be examined for fasciculations, which typically are associated with spinal muscular atrophy. However, they also are seen with hypoglossal motor nerve damage that occurs in conditions including glycogen storage diseases, hypoxic-ischemic injury, and infantile neuronal degeneration.

●Crying, sucking, and swallowing – The character of the cry should be noted. A weak cry is characteristic for some congenital muscular dystrophies (eg, Fukuyama congenital muscular dystrophy) [3]. The infant's ability to suck and swallow should be assessed; difficulty with swallowing may lead to pooling of secretions.

●Sensation – Sensation should be tested by the withdrawal to a stimulus such as touching the patient with a small brush. Abnormalities in sensation associated with neonatal hypotonia can result from conditions such as hereditary sensory neuropathy (eg, familial dysautonomia) [4]. (See "Hereditary sensory and autonomic neuropathies".)

The neurologic examination in newborns is discussed in greater detail separately. (See "Neurologic examination of the newborn".)

ASSESSMENT OF MUSCLE TONE — Assessment of muscle tone is performed as part of the complete physical examination (see "The pediatric physical examination: Back, extremities, nervous system, skin, and lymph nodes", section on 'Neurologic examination'). The patient with hypotonia is distinguished readily from an infant with normal muscle tone [2].

When assessing the infant's tone, it is important to recognize that muscle tone is decreased in preterm compared with term infants. Flexor tone in preterm infants diminishes with decreasing gestational age [5]. Maneuvers to test muscle tone and the corresponding findings that reflect normal tone versus hypotonia are as follows (these maneuvers should not be performed when cervical spine injury is present or if the infant is in severe distress):

●Observe the infant's posture in the supine position:

•Normal muscle tone – In the normal term infant, both the upper and lower limbs have predominantly flexor tone. Normal posture in the supine position includes flexion of the hips at approximately 70º to 90º and abduction at 10º to 20º, and the child has active movement of the limbs.

•Hypotonia – The hypotonic infant lies supine in a frog-like position with the hips abducted and the limbs abnormally extended [2]. Spontaneous activity is decreased.

●Assess the resistance to passive movement of the joints or to gentle shaking of an arm or leg (eg, passive response):

•Normal muscle tone – Resistance is met at approximately 90º to passive extension of the legs at the knees.

•Hypotonia – No resistance is met to passive extension of the legs at the knees.

●Hold the infant under the arms:

•Normal muscle tone – The infant will assume a sitting position; truncal resistance allows the infant to be easily supported without slipping through the examiner's hands.

•Hypotonia – The legs will be extended; decreased tone of the shoulder girdle allows the infant to slip through the examiner's hands.

●Hold the infant in horizontal suspension:

•Normal muscle tone – The infant flexes the limbs, straightens the back, and maintains the head in the midline for a few seconds.

•Hypotonia – The back hangs over the examiner's hand, and the limbs and head hang loosely.

●Pulling the infant from the supine to sitting position:

•Normal muscle tone – Only a slight head lag is expected; the head should wobble in the midline for a few seconds when the sitting position is reached.

•Hypotonia – The head lags and continues to lag when the sitting position is reached (picture 1).

Additional findings may be observed during the assessment and may provide additional information. For example, spontaneous fisting or an abnormal primitive reflex in response to handling may suggest cerebral dysfunction.

DISTINGUISHING AMONG DISORDERS

Narrowing the differential — Based on the history and physical examination, the list of diagnostic possibilities usually can be narrowed considerably. The pattern of hypotonia and the relative changes in tone, muscle strength, and antigravity activity may help distinguish among disorders.

●Central hypotonia – Central hypotonia is generally characterized by the following [6]:

•Tone is reduced relatively more than is muscle strength

•Hypotonia is typically mild to moderate

•Limbs typically retain antigravity power

•There may be some head lag

•Deep tendon reflexes are present (may be decreased or increased)

•Positive Babinski sign

•Persistent neonatal reflexes

If the pattern of hypotonia is chiefly central, a central nervous system disorder is most likely (eg, cerebral palsy or Leigh syndrome). The latter is predominantly a central nervous system disorder, though some patients may have associated myopathy and peripheral neuropathy. Cerebral palsy (CP) is typically characterized by increased tone (spasticity and/or dystonia); however, some affected infants may exhibit low tone in early infancy. CP does not represent a specific cause of abnormal tone; rather, it is a heterogeneous group of conditions resulting from abnormalities of the developing fetal or infantile brain due to a variety of causes. Causes of CP are summarized in the table and are discussed separately (table 3). (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Leigh syndrome' and "Cerebral palsy: Epidemiology, etiology, and prevention", section on 'Specific causes and risk factors'.)

●Peripheral hypotonia – Peripheral hypotonia is generally characterized by the following:

•Weakness is the most significant finding

•Absent or extremely reduced antigravity movements

•Significant head lag

•Absent deep tendon reflexes

•Negative Babinski sign

•Absence neonatal reflexes

If the pattern of weakness and hypotonia is predominantly peripheral, a neuromuscular disorder is most likely (table 1).

However, numerous exceptions occur, as illustrated by the following examples:

●Some disorders that are primarily central may present with both profound hypotonia and weakness. They include Prader-Willi syndrome, which accounts for up to 11 percent of cases of hypotonia in infancy and is not associated with obesity at this early age [7], and acute conditions such as hemorrhage or infarction of the deep central gray matter of the brain or spinal cord. (See "Prader-Willi syndrome: Management".)

●Disorders that affect both the central and peripheral nervous systems can present with hypotonia. Examples include congenital muscular dystrophy, congenital myotonic dystrophy, cervical spinal cord injury, alpha glucosidase deficiency (Pompe disease), and some mitochondrial and peroxisomal disorders. (See "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Congenital muscular dystrophies' and "Peroxisomal disorders" and "Overview of peripheral nerve and muscle disorders causing hypotonia in the newborn".)

●Infants with a mild congenital myopathy can retain antigravity power in the limbs. (See "Congenital myopathies".)

Evaluation — Laboratory testing may be warranted in the evaluation in select patients. This may include metabolic testing if an inborn error of metabolism is suspected or measuring creatine kinase if there is concern for a muscular dystrophy. (See "Inborn errors of metabolism: Identifying the specific disorder" and "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis", section on 'Evaluation and diagnosis'.)

If a specific disorder is suspected based on the history and physical examination, a focused diagnostic evaluation for that disorder should be performed. For example, testing for Prader-Willi syndrome is appropriate in an infant presenting with profound hypotonia and weakness, poor feeding, poor weight gain, and cryptorchidism. (See "Prader-Willi syndrome: Clinical features and diagnosis", section on 'Diagnosis'.)

The yield of other routine laboratory tests is generally low. Similarly, electromyography (EMG) and muscle biopsy have limited value. Genetic testing generally provides greater diagnostic information than EMG and muscle biopsy. In patients in whom the etiology of hypotonia remains uncertain after a thorough clinical evaluation, genetic testing using next-generation sequencing methods may have some utility [8,9]. Such testing should only be performed under the direction of a neurologist and clinical geneticist. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

SUMMARY AND RECOMMENDATIONS

●Causes – Hypotonia and weakness in early infancy may be caused by several conditions. These include common neonatal conditions such as congenital infections, hypoglycemia, intracranial hemorrhage, and drug toxicity (eg, perinatal magnesium sulfate exposure). If these conditions can be excluded, genetic syndromes, inborn errors of metabolism, other endocrine abnormalities, primary neuromuscular disorders (table 1), or cerebral palsy (table 3) should be considered. (See 'Introduction' above and 'Causes' above.)

●History – Infants with neuromuscular disorder frequently have a history of polyhydramnios, fetal akinesia, and malpresentation. Delivery may be complicated by birth trauma or perinatal depression. A family history of neuromuscular abnormalities may be present. (See 'History' above.)

●Examination findings – Physical findings that may be helpful in making the diagnosis of a specific neuromuscular disorder include dysmorphic features, bruising or petechiae, respiratory abnormalities, cardiomyopathy, organomegaly, defects of the genitalia (including hypogonadism), and joint contractures or laxity. (See 'Physical examination' above.)

●Neurologic evaluation – A thorough neurological examination should be performed to assess the degree of hypotonia and weakness. This includes screening for evidence of cranial nerve dysfunction (facial diplegia, eye movements, suck and cry) and asymmetries or abnormalities in deep tendon and neonatal reflexes, motor function, and sensation. (See 'Neurologic examination' above and 'Assessment of muscle tone' above and "Neurologic examination of the newborn".)

●Evaluation – The pattern of hypotonia, muscle strength, and antigravity activity may help distinguish among disorders. In a central nervous system disorder, tone is typically reduced relatively more than muscle strength. By contrast, neuromuscular disorders are more likely to exhibit profound weakness, manifested by inability to move the limbs against gravity. However, exceptions occur. (See 'Distinguishing among disorders' above.)

•Laboratory testing may be warranted in the evaluation of select patients. This may include metabolic testing if an inborn error of metabolism is suspected.

•If a specific disorder is suspected based on the history and physical examination, a focused diagnostic evaluation for that disorder should be performed.

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Geoffrey Miller, MD, who contributed to earlier versions of this topic review.