clinical pathological conference 三軍總醫院小兒科部王志堅主任 / r3 田炯璽

Clinical Pathological Conference

三軍總醫院小兒科部

王志堅主任 /R3 田炯璽

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.

Case PresentationPersonal 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 PresentationPhysical Examination

Skin: Hypo-pigmentation noted

Genitalia: bilateral cryptorchitism

Neurological: primitive reflexes : depressed ; DTRs : depressed ; muscle tone: hypotonic ; poor crying.

Case PresentationRadiologic & Lab Findings

Chest film: mild infiltration over bilateral lung fields.

Total or Free?

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.

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………

Major Problems

Hypotonia - Poor crying - Poor swallowingRespiratory distressDysmorphic appearances - High arched palate - Elongated face - Slender long digitsDepressed deep tendon

reflexes.Poor eye movement

(ophthalmoplegia)

Large head circumference

Hypersomnolence status

Airway compromise

Ptosis (bilateral)

Asymmetric chest wall

Skin hypo-pigmentation

Hearing impairmentCryptorchitism

Minor Problems

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 NO

Brain MRI Generalized Distinct level of sensory/ motor

MRI of spine

Dysmorphic feature

NOYESNormal Abnormal

To be continued…..

Hypotonic Infants (From: Pediatric Decision-making Strategies)

Brain MRI

Brain malformationStatic encephalopathy (Post hypoxic-ischemia) (Post congenital infection) (Post trauma) (Post intracranial hemorrhage)Progressive encephalopathy (Leukodystrophy) (Mitochondrial disease)

Spinal muscular atrophyMyasthesia gravisHypothyroidismMetabolic disorderPrader Willi syndromeDown syndrome

Consider CK, EMG, muscle biopsy ± additional genetic

or metabolic workup

Normal Abnormal



History Physical Examinations

Signs or symptoms suggestive of a cerebral disorder

YES NO

Brain MRI Generalized Distinct level of sensory/ motor

MRI of spine

Dysmorphic feature

NOYESNormal Abnormal


Seizure, impaired consciousness, jitteriness, fisting of hands, brisk tendon reflexes, clonus, autonomic dysfunction


Prader Willi syndrome Down syndrome NO

Generalized

Classical dysmorphic

featuresNO (?)YES

YESMaternal weakness present

Transient neonatal myasthenia gravisCongenital myotonic dystrophy

Systemic disorder/ illness BotulismConnective tissue diseaseCongenital-infantile myasthenia gravisSpinal muscular atrophyCongenital myotonic dystrophy Myopathy

Prader Willi SyndromeDeletion 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 SyndromeMajor Diagnostic Criteria

1.Neonatal and infantile central hypotonia with poor suck, gradually improving with age2.Feeding problems in infancy with need for special feeding techniques and poor weight

gain/failure to thrive3.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 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.


Prader Willi syndrome (?) Down syndrome NO

Generalized

Classical dysmorphic

featuresNO YES




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 InfantsIngestion 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 AtrophyProgressive 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 AtrophyCK 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 DystrophyA 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 DystrophyClassical 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.


Prader Willi syndrome (?)Down syndrome

NO

Generalized

Dysmorphic features

NO YES




Myopathies Associated with Hypotonia

Myotubular myopathyCongenital muscle fiber-type DisproportionNemaline rod myopathyCentral core diseaseMetabolic myopathies Glycogenoses Mitochondrial myopathies Lipid myopathies

Myotubular MyopathyMaturation 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 MyopathyCK 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 MyopathyRod-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 DiseaseAbnormal 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.

GlycogenosisType 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

GlycogenosisType III : most common but least severe - hypotonia, weakness, hepatomegaly, fasting hypoglycemia. - resolves spontaneously and become asymptomatic in

adulthoodType 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

Genetic molecular markeror

Muscle biopsy

Diagnostic Procedure

Thanks For Your Attention !!

clinical pathological conference 三軍總醫院 小兒科部 王志堅 主任 / r3 田炯璽

Documents

clinical pathological conference 三軍總醫院小兒科部王志堅主任 / r3 田炯璽