Clinical Pathological Conference

1
Clinical Pathological Conference

• ????? ????
• ??? ??/R3 ???

2
Case PresentationPresent 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.

3
Case PresentationPersonal and Family History

• Birth history BW 2784gm (1025th percentile)
• Body length 50cm (50 75th
  percentile)
• Head circumference 36cm (
  gt90th 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.

4
Case PresentationPhysical Examination

• Skin Hypo-pigmentation noted
• Genitalia bilateral cryptorchitism
• Neurological primitive reflexes depressed
  DTRs depressed muscle tone hypotonic poor
  crying.

5
Case PresentationRadiologic Lab Findings

• Chest film mild infiltration over bilateral lung
  fields.

Total or Free?
6
Case PresentationHospital 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.

7
Case PresentationHospital 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

8
Major Problems
Minor 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)

• Large head circumference
• Hypersomnolence status
• Airway compromise
• Ptosis (bilateral)
• Asymmetric chest wall
• Skin hypo-pigmentation
• Hearing impairment
• Cryptorchitism

9
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?

10
Hypotonic Infants (From Pediatric
Decision-making Strategies accompanied by Nelson)
History Physical Examinations
Signs or symptoms suggestive of a cerebral
disorder
YES
NO
Distinct level of sensory/ motor
Brain MRI
Generalized
Dysmorphic feature
MRI of spine
NO
YES
Normal
Abnormal
To be continued..
11
Hypotonic Infants (From Pediatric
Decision-making Strategies)
Brain MRI
Normal
Abnormal
Brain malformation Static encephalopathy (Post
hypoxic-ischemia) (Post congenital infection)
(Post trauma) (Post intracranial
hemorrhage) Progressive encephalopathy
(Leukodystrophy) (Mitochondrial disease)
Consider CK, EMG, muscle biopsy additional
genetic or metabolic workup
Spinal muscular atrophy Myasthesia
gravis Hypothyroidism Metabolic disorder Prader
Willi syndrome Down syndrome
To be continued..
12
Hypotonic Infants (From Pediatric
Decision-making Strategies)
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
NO
Distinct level of sensory/ motor
Brain MRI
Generalized
Dysmorphic feature
MRI of spine
NO
YES
Normal
Abnormal
To be continued..
13
Hypotonic Infants (From Pediatric
Decision-making Strategies)
Generalized
Classical dysmorphic features
NO (?)
YES
Prader Willi syndrome Down syndrome
Maternal weakness present
NO
YES
Transient neonatal myasthenia
gravis Congenital myotonic dystrophy
Systemic disorder/ illness
Botulism Connective tissue disease Congenital
-infantile myasthenia gravis Spinal muscular
atrophy Congenital myotonic dystrophy Myopathy
14
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.

15
Prader Willi SyndromeMajor 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 (gt650 bands, preferably
  confirmed by fluorescence in situ hybridization)
  or other appropriate molecular abnormality in
  this chromosome region, including maternal disomy.

16
Prader Willi SyndromeMinor 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.

17
Hypotonic Infants (From Pediatric
Decision-making Strategies)
Generalized
Classical dysmorphic features
NO
YES
Prader Willi syndrome (?) Down syndrome
Maternal weakness present
NO
YES
Transient neonatal myasthenia
gravis Congenital myotonic dystrophy
Systemic disorder/ illness
Botulism Connective tissue disease Congenital
-infantile myasthenia gravis Spinal muscular
atrophy Congenital myotonic dystrophy Myopathy
18
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 (?)
19
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.

20
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.

21
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.

22
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.

23
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.

24
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.

25
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.

26
Hypotonic Infants (From Pediatric
Decision-making Strategies)
Generalized
Dysmorphic features
NO
YES
Prader Willi syndrome (?) Down syndrome
Maternal weakness present
NO
YES
Transient neonatal myasthenia
gravis Congenital myotonic dystrophy
Systemic disorder/ illness
Botulism Connective tissue disease Congenital
-infantile myasthenia gravis Spinal muscular
atrophy Congenital myotonic dystrophy Myopathy
27
Myopathies Associated with Hypotonia

• Myotubular myopathy
• Congenital muscle fiber-type Disproportion
• Nemaline rod myopathy
• Central core disease
• Metabolic myopathies
• Glycogenoses
• Mitochondrial myopathies
• Lipid myopathies

28
Myotubular Myopathy

• Maturation arrest of fetal muscle during the
  myotubular stage of development at 815
  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.

29
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.

30
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.

31
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.

32
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.

33
Glycogenosis

• Type I not a true myopathy.
• - hypoglycemia, lactic acidosis in neonatal
  period more commonly present at 34 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

34
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.

35
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

36
Final Diagnosis

• Prader-Willi syndrome
• or
• Myotubular Myopathy

Diagnostic Procedure
Genetic molecular marker or Muscle biopsy
37
Thanks For Your Attention !!