Transcript Hypotonic Infants (From: Pediatric Decision

Clinical
Pathological
Conference
三軍總醫院 小兒科部
王志堅 主任/R3 田炯璽
Case Presentation
Present Illness
A male newborn was born to a healthy 30-year-old mother via
cesarean section at gestational age 40 weeks due to fetal
distress.
The baby had respiratory distress and poor limbs movement
upon delivery.
Apgar scores were 7 to 7 at 1st minute and 5th minute,
respectively.
He was immediately transferred to NICU.
Case Presentation
Personal and Family History
Birth history: BW: 2784gm (10~25th percentile)
Body length: 50cm (50~ 75th percentile)
Head circumference: 36cm ( >90th percentile)
Maternal history: Parity: 1011(previous ectopic pregnancy)
No reduction in fetal movement noted during pregnancy.
Polyhydramnios: (-).
Family history: no history of neuromuscular disease or
consanguimity.
Case Presentation
Physical Examination
Skin: Hypo-pigmentation noted
Genitalia: bilateral cryptorchitism
Neurological: primitive reflexes : depressed ; DTRs : depressed ;
muscle tone: hypotonic ; poor crying.
Case Presentation
Radiologic & Lab Findings
Chest film: mild infiltration over bilateral lung fields.
Total or Free?
Case Presentation
Hospital Course-I
Initially nasal CPAP was applied due to respiratory distress.He
was treated as neonatal infection then.
Throughout neonatal period, he usually in hyper-somnolence
status, needed NG-tube feeding, and had difficulty
maintaining his airway because of profuse sputum and
required frequent oral suction.
Two times of RUL pneumonia happened to him before age of
one month, and recovered under supportive treatment.
His breathing got better since age of one month, and he could
be weaned off CPAP intermittently.
His proximal limbs developed some anti-gravity power
although less active movements.
Case Presentation
Hospital Course-II
Poor of eye movement and facial expression was noted.
Bilateral mild ptosis, high arched palate, elongated face,
slender long digits, asymmetric of chest wall and absence of
tendon reflexes were found.
Electrophysiological studies including NCV and EEG were
normal.
ABR from left ear was abnormal.
Brain MRI was normal.
The diagnostic procedure was made………
Major Problems
Hypotonia
- Poor crying
- Poor swallowing
Respiratory distress
Dysmorphic appearances
- High arched palate
- Elongated face
- Slender long digits
Depressed deep tendon
reflexes.
Poor eye movement
(ophthalmoplegia)
Minor Problems
Large head circumference
Hypersomnolence status
Airway compromise
Ptosis (bilateral)
Asymmetric chest wall
Skin hypo-pigmentation
Hearing impairment
Cryptorchitism
Questions
How was the patient during clinical follow-up? Was
there any further improvement in his muscle power
and/or tendon reflexes?
Any other metabolic studies? Lactic acid? Amino acids
in urine?
Hypotonic Infants (From: Pediatric Decision-making
Strategies
accompanied by Nelson)
History
Physical Examinations
Signs or symptoms
suggestive of a
cerebral disorder
YES
Brain MRI
NO
Distinct level of
sensory/ motor
Generalized
Dysmorphic
feature
Normal
Abnormal
YES
NO
To be continued…..
MRI of spine
Hypotonic Infants (From: Pediatric Decision-making
Strategies)
Brain MRI
Normal
Abnormal
Consider CK, EMG, muscle
biopsy ± additional genetic
or metabolic workup
Spinal muscular atrophy
Myasthesia gravis
Hypothyroidism
Metabolic disorder
Prader Willi syndrome
Down syndrome
Brain malformation
Static encephalopathy
(Post hypoxic-ischemia)
(Post congenital infection)
(Post trauma)
(Post intracranial hemorrhage)
Progressive encephalopathy
(Leukodystrophy)
(Mitochondrial disease)
To be continued…..
Hypotonic Infants (From: Pediatric Decision-making
History
Physical Examinations
Seizure, impaired consciousness,
jitteriness, fisting of hands, brisk
tendon reflexes, clonus,
autonomic dysfunction
Signs or symptoms
suggestive of a
cerebral disorder
YES
Brain MRI
Strategies)
NO
Distinct level of
sensory/ motor
Generalized
Dysmorphic
feature
Normal
Abnormal
YES
NO
To be continued…..
MRI of spine
Hypotonic Infants (From: Pediatric Decision-making
Strategies)
Generalized
YES
Classical
dysmorphic
features
Prader Willi syndrome
Down syndrome
Systemic disorder/ illness
Botulism
Connective tissue disease
Congenital-infantile myasthenia gravis
Spinal muscular atrophy
Congenital myotonic dystrophy
Myopathy
NO
NO (?)
Maternal
weakness
present
YES
Transient neonatal
myasthenia gravis
Congenital myotonic
dystrophy
Prader Willi Syndrome
Deletion or disruption of genes or maternal disomy in the
proximal arm of chromosome 15.
Decreased fetal movement or infantile lethargy or weak cry in
infancy, neonatal and infantile central hypotonia with poor
suck, gradually improving with age(often after 12 mo. old).
Feeding problems in infancy, and turns into hyperphagia after
three years old.
Characteristic facial features
Hyposcrotal hypoplasia, undescended testes, small penis
and/or testes in males.
Skin hypopigmentation is one of the minor diagnostic criterias.
Prader Willi Syndrome
Major Diagnostic Criteria
1.Neonatal and infantile central hypotonia with poor suck, gradually improving with age
2.Feeding problems in infancy with need for special feeding techniques and poor weight
gain/failure to thrive
3.Excessive (crossing two centile channels) or rapid weight gain on weight-for-length
chart after 12 months and before age 6; central obesity in the absence of intervention.
4.Characteristic facial features with dolichocephaly in infancy, narrow face or bifrontal
diameter, almond-shaped eyes, small-appearing mouth with thin upper lip,
downturned corners of the mouth (three or more of these characteristics required).
5.Hypogonadism-includes any of the following, depending on age:
a. Genital hypoplasia (in males: scrotal hypoplasia, undescended testes, small penis
and/or testes; in females: absence or severe hypoplasia of labia minora and/or clitoris).
b. Delayed or incomplete gonadal maturation with delayed pubertal signs after age 16
(in males: small gonads, decreased facial and body hair, lack of voice change; in
females: no or infrequent menses).
6.Global developmental delay in a child younger than 6 years; mild to moderate mental
retardation or learning problems in older children.
7.Hyperphagia (excessive appetite)/food foraging/obsession with food.
8.Deletion 15q 11-13 (>650 bands, preferably confirmed by fluorescence in situ
hybridization) or other appropriate molecular abnormality in this chromosome region,
including maternal disomy.
Prader Willi Syndrome
Minor Diagnostic Criteria
1.Decreased fetal movement or infantile lethargy or weak cry in infancy,
improving with age.
2.Characteristic behavior problems, temper tantrums, violent outbursts, and
obsessive/compulsive behavior; tendency to be argumentative,
oppositional, rigid, manipulative, possessive, and stubborn; perseverating,
stealing, and lying (five or more of these symptoms required).
3.Sleep disturbance or sleep apnea.
4.Short stature for genetic background by age 15 (in absence of growth
hormone intervention)
5.Hypopigmentation-fair skin and hair compared with other family members.
6.Small hands (less than 25th percentile) and/or feet (less than 10th
percentile) for height age.
7.Narrow hands with straight ulnar border (outer edge of hand).
8.Eye abnormalities (esotropia, myopia).
9.Thick, viscous saliva with crusting at corners of the mouth.
10.Speech articulation defects.
11.Skin picking.
Hypotonic Infants (From: Pediatric Decision-making
Strategies)
Generalized
YES
Classical
dysmorphic
features
Prader Willi syndrome (?)
Down syndrome
Systemic disorder/ illness
Botulism
Connective tissue disease
Congenital-infantile myasthenia gravis
Spinal muscular atrophy
Congenital myotonic dystrophy
Myopathy
NO
NO
Maternal
weakness
present
YES
Transient neonatal
myasthenia gravis
Congenital myotonic
dystrophy
Systemic Illnesses Associated
With Hypotonia
Sepsis
Malnutrition
Cyanotic heart disease
Renal acidosis
Hypercalcemia
Hypermagnesemia
Rickets
Cystic fibrosis
Intestinal obstruction
(intussusception,
volvolus)
Considering obtain ：
Septic workups (？)
Electrolytes (N)
BUN and creatinine (N)
Glucose (N)
Calcium (？)
Magnesium (？)
Thyroid function tests (N)
Urine for amino acids and organic
acid (？)
Botulism in Infants
Ingestion of food containing the toxin of Clostridium
botulinum. Honey is a frequent source.
The incubation period could be as short as a few hours.
Initiates with nausea, vomiting and diarrhea.
Dysphagia, weak suck, ptosis, masklike face, weak cry, and
absent gag reflex.
Generalized hypotonia and weakness then develop and may
cause respiratory failure.
Neuromuscular blockage is documented by EMG with
repetitive nerve stimulation.
Collagen Diseases Associated
With Hypotonia
Ehlers- Danlos syndrome (autosomal recessive ocular type):
- joint hyperextensibility, hypotonia, kyphoscoliosis, fragile
cornea, keratoconus, skin hyperelasticity, fragile bone.
Marfan syndrome (infantile) :
- hypotonia, arachnodactyly, joint laxity and dislocation,
flexion contracture, long face, lax skin, large ear, etc.
Osteogenesis imperfecta ( especially type I) :
- fragile bone, blue sclera, early deafness (triad), easy
bruising, joint laxity, recurrent fracture, hypotonia, short
stature, etc.
Congenital Infantile
Myasthenia Gravis
Immune-mediated neuromuscular blockage.
Congenital myasthenia gravis :
- feeding difficulty, ptosis, facial weakness, poor head control,
rapid fatigue of muscles.
- progressive.
- tendon stretch reflexes may be diminished but are rarely lost.
- Unique diagnostic EMG pattern; CK is normal.
Transient neonatal myasthenia gravis :
- baby born to myasthenic mother;
- respiratory insufficiency, poor swallowing and sucking,
generalized hypotonia and weakness for days or weeks;
- patients regain normal strength after abnormal maternal
antibodies disappear.
Spinal Muscular Atrophy
Progressive degenerative disease of motor neuron.
Type I (Werdnig-Hoffmann):
- severe hypotonia, generalized weakness, thin muscle mass,
absent stretch tendon reflexes, lie flaccid with little
movement, unable to overcome gravity.
- sparing extraocular muscle and sphincters.
- respiratory distress and unable to feed.
Type II :
- usually able to suck and respiration is adequate in infancy.
- progressive weakness.
Type III (Kugelberg-Welander) :
- mildest, may appear normal in infancy.
- progressive weakness is proximal in distribution.
Spinal Muscular Atrophy
CK is normal or mild elevated.
NCV of motor neuron showed characteristic mild slowing in
terminal stage of the disease.
EMG shows fibrillation potentials and other signs of
denervation of muscle.
Definite diagnostic test is molecular genetic marker of blood
for SMN gene by DNA probe.
Myotonic Muscular Dystrophy
A genetic defect causing dysfunction in multiple organ system
(GI tract, cardiac, endocrine, immunologic, ocular).
Severe neonatal form :
- minority, infants born to mothers with myotonic dystrophy.
- generalized hypotonia and weakness after birth.
- may need gavage feeding or even ventilation support.
- one or both leaves of diaphragm may be nonfunctional.
- prominent facial wasting, characteristic dysmorphic face
with V-shaped upper lip, thin cheek, and concave
temporalis muscles.
- palate may be high, and head is narrow.
- tendon reflexes are usually preserved.
Myotonic Muscular Dystrophy
Classical EMG is not found in infancy but in later time.
Diagnostic test is a DNA analysis of blood for the abnormal
expansion of CTG repeat on chromosome 19q13 locus.
Hypotonic Infants (From: Pediatric Decision-making
Strategies)
Generalized
Dysmorphic
features
YES
Prader Willi syndrome (?)
Down syndrome
Systemic disorder/ illness
Botulism
Connective tissue disease
Congenital-infantile myasthenia gravis
Spinal muscular atrophy
Congenital myotonic dystrophy
Myopathy
NO
NO
Maternal
weakness
present
YES
Transient neonatal
myasthenia gravis
Congenital myotonic
dystrophy
Myopathies Associated
with Hypotonia
Myotubular myopathy
Congenital muscle fiber-type Disproportion
Nemaline rod myopathy
Central core disease
Metabolic myopathies
Glycogenoses
Mitochondrial myopathies
Lipid myopathies
Myotubular Myopathy
Maturation arrest of fetal muscle during the myotubular stage
of development at 8~15 gestational age.
Decrease fetal movement may occur, polyhydramnios in late
pregnancy is common.
Severe generalized hypotonia, diffused weakness.
Respiratory insufficiency may need ventilator support.
Gavage feeding is needed due to poor suck and deglutition.
The testes are often undesended; the palate may be high.
Facial weakness may present but no characteristic feature of
myotonic dystrophy; ophthalmoplegia presents but few.
Case analysis (1995, Joseph et al.) reported large head
circumference in 70%, narrow elongated face in 80%, and
slender long digits in 60 % of cases
Not associated with cardiomyopathy or CNS or other systems.
Myotubular Myopathy
CK levels are normal.
EMG are usually normal or nonspecific myopathic feature.
NCV may be slow but usually normal.
Muscle biopsy is diagnostic even at birth. The molecular
genetic marker of blood also confirms the diagnosis and
could be provided for prenatal diagnosis.
X-linked recessive inheritance is most common; point
mutation or deletion of critical MTM1 gene on the Xq28
site could be identified.
Congenital Muscle Fiber-type
Disproportion (CMFTD)
An abnormal suprasegmental influence on the developing
motor unit during the stage of histochemical differentiation
of muscle between 20 ~ 28 weeks of gestational age.
Could be an isolated congenital myopathy or associated with
various disorders, ex: cerebellar hypoplasia, glycogenoses,
etc.
As an isolated condition, CMFTD is nonprogressive and
present at birth. Generalized hypotonia, and weakness is not
severe; respiratory distress and dysphagia are rare.
Dolichocephaly, facial weakness, high palate arch are usually
presented.
Serum CK level, ECG, EMG and NCV are normal in simple
CMFTD. Diagnostic muscle biopsy should be performed.
Nemaline Rod Myopathy
Rod-shaped inclusion-like abnormal structure in muscle fibers,
and the formation may be an unusual reaction of muscle
fibers to injury.
Severe infantile and juvenile forms are known.
Generalized hypotonia, weakness including bulbar-innervated
and respiratory muscles, and a very thin muscle mass are
characteristic.
Decreased fetal movements are reported by the mother.
The head is dolichocephalic, the palate is high arched, or even
cleft, dysphagia and arthrogryposis develops.
Mouth are usually open due to weak masseters; The
extraocular muscles are spared.
CK level is normal; Muscle biopsy shows CMFTD or at least
type I fiber predominance with nemaline rods.
Central Core Disease
Abnormal genetic disease at the 19q13.1 locus, cause central
core in muscle fibers contains only amorphous granular
cytoplasm without myofibrils and organelles.
Infantile hypotonia, proximal weakness, muscle wasting, and
involvement of facial and neck flexor muscles.
Nonprogressive, and weakness is not usually disabling.
Congenital hip dislocation and skeletal deformities are
common.
Serum CK level is normal. Muscle biopsy shows characteristic
pathologic picture.
Glycogenosis
Type I : not a true myopathy.
- hypoglycemia, lactic acidosis in neonatal period; more
commonly present at 3~4 months old with hepatomegaly or
seizures.
- classical appearance : doll-like faces with fat cheeks, thin
extremities, short stature, protuberant abdomen.
- hypoglycemia, lactic acidosis, hyperuricemia,
hyperlipidemia.
Type II (Pompe disease):
- infantile form with generalized myopathy and
cardiomyopathy.
- cardiomegaly and hepayomegaly, diffused hypotonia and
weakness
- serum CK level greatly elevated
Glycogenosis
Type III : most common but least severe
- hypotonia, weakness, hepatomegaly, fasting hypoglycemia.
- resolves spontaneously and become asymptomatic in
adulthood
Type IV :
- amylopectin in liver reticuloendothelial and cardiac and
skeletal muscle
- hypotonia, weakness, muscle wasting, contracture.
- most patient die because of hepatic or cardiac failure.
Type V : muscle phosphorylase deficiency
- exercise intolerance is the cardical clinical feature.
- CK slightly elevated only after exercises.
Type VII : phosphofructokinase deficiency
- similar to type V.
Lipid Myopathies
Muscle carnitine deficiency :
- proximal myopathy with facial, pharyngeal and cardiac
involvement.
- clinical course may be of sudden exacerbation of weakness
or a progressive muscular dystrophy; usually begins in late
childhood.
Systemic carnitine deficiency :
- similar to myopathy above but onset earlier.
- episodes of acute hepatic encephalopathy may occur.
- hypoglycemia and metabolic acidosis
Final Diagnosis
Prader-Willi syndrome
or
Myotubular Myopathy
Diagnostic Procedure
Genetic molecular marker
or
Muscle biopsy
Thanks For Your Attention !!