Cases from Virginia:
A Neonate and an Infant
with Splenomegaly
Lauren Youell MD
Chief Resident
UVA Pediatrics
Patient 1: C.M.
Patient C.M.
Term male
G3, now P3 mother
No pregnancy complications
Fetal decels during labor, thin meconium
ROM 12 hours
Apgars of 7 and 8
Patient admitted to the newborn nursery
Maternal Labs
Blood type O+, Ab negative
RPR NR
Hepatitis B negative
GC negative
Chlamydia treated during pregnancy with test of
cure during first trimester
HIV negative
GBS negative
Rubella immune
First exam
BW 2674g (10th %)
Length 50cm (50th %)
HC 33 cm (10th %)
Exam normal
– palpable liver edge 2 fingers below costal
margin
NBN Course
Initial hypoglycemia that resolved with
feeds
Persistent jitteriness
Mild hypocalcemia
Hyperbilirubinemia requiring phototherapy
DOL 5
Liver noted to be 2.5cm below costal
margin
Spleen enlargement also noted on exam
Patient otherwise doing well
Further Labs and Studies
WBC 7, HCT 50, PLT 69
BMP normal except potassium of 5.7
ALP 392, ALT 14, AST 55
Abdominal U/S- Liver not enlarged,
caudate lobe prominent. Spleen
prominent (6.5cm in length). Small ascites,
GB contracted.
Differential of Hepatosplenomegaly
in the Neonate
Congenital Infections
Elevated portal pressures (CHF, hepatic
vein thrombosis)
Obstruction (tumors, stones, cysts)
Storage disease (glycogen, lipids, metals,
abnormal proteins)
Infiltration (neoplasms, metastases,
extramedullary hematopoiesis)
Algorithm for the Work-up of Neonates with Hepatomegaly
Wolf, A. D. et al. Pediatrics in Review 2000;21:303-310
Copyright ©2000 American Academy of Pediatrics
Differential of Thrombocytopenia
in the Neonate
Non-immune platelet destruction
Immune platelet destruction
Decreased platelet production
Non-Immune Platelet Destruction
Disseminated intravascular coagulation
Bacterial sepsis
Intrauterine viral infection
Pregnancy induced hypertension
Necrotizing enterocolitis
Drugs/toxins
Immune Thrombocytopenia
Maternal Immune Thrombocytopenia
Neonatal Alloimmune Thrombocytopenia
(NAIT)
Maternal Systemic Lupus Erythematosus
Decreased Platelet Production
Thrombocytopenia absent radii (TAR)
syndrome
Neonatal leukemia
Aplastic anemia
Merging the Differentials
Congenital Infection
Metabolic disease with sequestration
Congenital Infection- CMV
Most common
Risk of transmission greatest with primary
maternal infection
10% of congenitally infected infants will
have clinical evidence of disease
– IUGR
– Hepatosplenomegaly
– Hematologic abnormalities(thrombocytopenia)
– CNS changes
CNS Changes
of CMV
Microcephaly
Ventriculomegaly
Cerebral atrophy
Chorioretinitis
Sensorineural
hearing loss
Intracerebral calcifications (periventricular)
Toxoplasmosis
Infection during 1st trimester
– Chorioretinitis
– Encephalitis with
intracerebral calcifications
– Microcephalus
– Hydrocephalus
– Hepatosplenomegaly
– Maculopapular rash
– Thrombocytopenic purpura
Our Patient
Urine CMV negative
Toxoplasmosis IgG positive, IgM negative
Head U/S- no calcifications
Eye exam- no evidence of chorioretinitis
(or cherry red macule)
Hematology Consult
BM biopsy to rule out leukemia
– Trilineage hematopoiesis with normal
cellular maturation
– No evidence of lipid storage disease or
neoplasm
Prolonged bleeding time after the BM
biopsy
A Definitive Diagnosis
Liver biopsy necessary for tissue
diagnosis
Not without risks
– Age
– Platelet dysfunction?
– Liver disease
Pathology calls…
Foam Cells
Niemann-Pick Disease
Heterogeneous group of lysosomal lipid
storage diseases
All have autosomal recessive inheritance
Niemann-Pick Disease
Niemann-Pick Type A and B
– Acid Sphingomyelinase deficiencyabnormal
storage of sphingomyelin
– Type A=neuronopathic, earlier onset
– Type B=non-neuronopathic, milder course
Niemann Pick Disease
Niemann-Pick Type C
– Impaired cholesterol esterification
– Sequestration of unesterified cholesterol in
lysosomes
– Acid Sphinogmyelinase is secondarily
reduced
– Can present in infants, children or adults
Age at Time of Diagnosis
Vanier and Millat, Clinical Genetics, 2003; 64:269-281
Niemann-Pick Type C
Classic presentation
– 60-70% of cases
– Mid-late childhood
– Insidious onset
– Death typically occurs in the second or third
decade
Classic Niemann-Pick Type C
First manifestation- often ataxia
Neurologic onset- typically decreased
school performance, fine motor skills
Organomegaly- up to 90%
Cataplexy- 20%
Seizures- about 50%
Dysphagia is also common
Exam Clues
Massive HSM (not required)
Vertical supranuclear gaze palsy
Cherry red spot on macula
Niemann-Pick Type C
Perinatal onset
– Liver disease is major sign
– May have history of fetal ascites or hydrops
– May also have prolonged cholestatic jaundice
– Most children with “rapidly fatal neonatal
cholestatic form” die before age of 6 months
Niemann-Pick Type C
Infantile onset
– Can present with ascites, severe liver disease
or respiratory failure
– Infants without liver or lung involvement may
have just hypotonia and developmental delay
Niemann-Pick Type C
Adult onset
– More likely to present with progressive
dementia or psychiatric symptoms
– Movement disorders
– Organomegaly less common
Diagnosis
Biochemical testing
Most have mutations in the NPC1 gene
Molecular gene testing of NPC1 and
NPC2 will detect mutations in
approximately 94% of individuals with
NPC
Our Patient
Homozygous gene mutation in the NPC1
gene
Particular mutation not previously reported
in the literature or disease specific
databases
Management
Largely symptomatic
– Treat seizures, dystonia
– Physical therapy
– Gastrostomy tube
– Aggressively treat
intercurrent infections
Managing our Patient
Required NG feeds at discharge
Family counseled and decided against Gtube placement
Actigall for cholestasis
Palliative care involved at discharge
Update on C.M.
Now 5 months of age
Followed by genetics and palliative care
Not requiring NG feeds, growing well
Continues to be very hypotonic on exam
with massive hepatosplenomegaly
Remains on actigall for cholestasis
Patient 2: A.B.
Patient A.B.
6 mo female
Full term
PMH: bronchiolitis at 1 month of age,
feeding difficulties with emesis x 1 week
Developmental: +social smile, not rolling
over yet, sits with assistance per mom
Splenomegaly noted by PCP
Admit Exam
Weight: 6.64 kg (25%)
Length: 64 cm (25-50%)
HC: 41.5 cm (25%)
Exam normal except for:
– Thrush
– Spleen palpable 4 cm below costal margin
Admit Labs and Studies
WBC 6, Hgb 10, PLT 98
Smear: microcytosis
Upper GI series: positive for reflux, no
structural abnormalities
Abdominal U/S: confirms splenomegaly,
otherwise normal
Infectious Work-up
EBV
CMV
Parvovirus
All serologies negative
Hematology consulted
Family history of hereditary spherocytosis
on paternal side
Osmotic fragility testing-normal
Bone marrow biopsy performed
– Trilineage hematopoiesis
– Lipid laden macrophages
Gaucher Cells
Gaucher Disease
Glucocerebrosidase deficiency
Represents a continuum of disease
Autosomal recessive inheritance
Gaucher Disease- Type 1
“Adult-type”-may present in childhood
Bone disease
Hepatosplenomegaly
Anemia
Thrombocytopenia
Lung disease
**No CNS disease
Gaucher Disease-Type 2
Neuropathic
Onset before age of 2 years
Limited development
Rapidly progressive course
Death by age 2-4 is common
Gaucher Disease-Type 3
Neuropathic
Onset may also be before 2 years
Slowly progressive
May live into the third or fourth decade
Subtype
Type 1
Primary CNS
Involvement
No
Type 2
(acute or infantile)
Bulbar signs
Pyramidal signs
Cognitive impairment
Type 3 (subacute;
juvenile)
Oculomotor apraxia
Seizures
Progressive myoclonic
epilepsy
Bone
Disease
Other
Yes
Splenomegaly
Hepatomegaly
Cytopenia
Pulmonary disease
No
Hepatomegaly
Splenomegaly
Cytopenia
Pulmonary disease
Dermatologic changes
Yes
Hepatomegaly
Splenomegaly
Cytopenia
Pulmonary disease
Diagnosis
Characteristic bone marrow changes
Demonstration of deficient enzyme activity
in peripheral blood leukocytes
Identification of 2 disease causing alleles
in GBA (only gene linked to Gaucher
disease)
Our Patient
Presented with concerns for neurologic
involvement in the first year of life
Gene testing positive for mutation in GBA
Type 2 disease diagnosed based on
clinical presentation
Management
Enzyme replacement therapy
– Decreases spleen size
– Does not affect neurologic deterioration
Partial or total splenectomy
Analgesics, oral bisphosphonates and
calcium for bone changes in Type 1
Update on A.B.
Now 2 ½ years old
Being treated with enzyme therapy
Tracheostomy and G-tube dependent
Frequent pulmonary infections
Seizure disorder
Global developmental delay
Final Thoughts