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Clinicopathological conference One-year-old infant with hepatosplenomegaly and developmental delay.

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American Journal of Medical Genetics 28:411-431 (1987)
ClinicopathologicalConference:
One-Year-OldInfant With Hepatosplenomegaly
and Developmental Delay
Lewis A. Barness, Sandra Wiederhold, Sunita Chandra, Gerard B.
Odell, Nasrollah T. Shahidi, and Enid F. Gilbert
Department of Pediatrics, University of South Florida, Tampa, Florida
(L.A.B.); Departments of Pediatrics (S. W., G.B. O., N. T.S., E.F.G.) and
Pathology (S.C., E.F. G.), University of Wisconsin, Madison, Wisconsin
CLINICAL PRESENTATION
Dr. Sandra Wiederhold, Resident in Pediatrics
A 12-month-old-white male was referred to the University of Wisconsin Hospital for
evaluation of hepatosplenomegaly.
He was born at term after a normal pregnancy. Mother was 22 years old and this
was her first pregnancy. Birth weight was 2.8 kg. The parents were of German and Polish
descent and there was no known consanguinity. The neonatal course was remarkable for
transient hyperbilirubinemia that responded to phototherapy. Physical examination at the
time of discharge was unremarkable.
He was a healthy infant with no medical problems until age 3 months when he was
seen by his physician for lethargy. Examination showed only “some eye muscle dysfunction.” He was referred to an ophthalmologist, who confirmed strabismus and recommended intermittent patching.
At 8 months he was referred to a pediatrician for evaluation of his abnormal facial
appearance. Developmental assessment showed that he had rolled from front to back at 2
months, from back to front at 4 months, was scooting and eating some finger foods. He was
found to have a prominent forehead, a wide nasal bridge, left esotropia, a prominent
abdomen, and slender arms and legs. His liver was palpable 4 cm below the right costal
margin and the spleen was 3 cm below the left costal margin.
Received for publication January 5, 1987; revision received April 6, 1987
Address reprint requests to Dr. Lewis A. Barness, Professor and Chairman, Department of Pediatrics, University
of South Florida, Tampa, FL 33612.
0
1987 Alan R. Liss, Inc.
412
Barness et al
TABLE 1. Hyperbilirubinemia in the
Newborn Infant With
HepatosplenomegalyWith Progressive
DeteriorationOver 2 Years
Galactosemia
Tyrosinemia
Hypothyroidism
Maple syrup urine disease
fl-Thalassemia
Mannosidosis
Fructose intolerance
He was seen 2 months later with a diagnosis of otitis media and persistent
hepatosplenomegaly. His hematocrit was 30%, white blood cell (WBC) count 9,600/mm3
with 43% segmented, 3% bands, 3% eosinophils, 50% lymphocytes, and 1% monocytes.
There was slight anisocytosis and an apparently normal number of platelets. Serum Na
level was 140, K 4.7, C1 110, CO, 20 mEq/L, cholesterol 173 mg/dl, triglycerides 380
mg/dl, SCOT 416 unit/L, LDH 306 unit/L, bilirubin 0.3 mg/dl, G G T 116 unit/L,
alkaline phosphatase 243 unit/L. He was referred to University of Wisconsin Hospital for
further evaluation.
On physical examination the weight was 8.3 kg (5th centile), length 69.8 cm (5th
centile), and OFC 36 cm (5th centile). He was an irritable child with prominent forehead,
hypertelorism, epicanthal folds, and left esotropia. There were no cataracts and a normal
red reflex, There was gingival hyperplasia but no lymphadenopathy. His liver was palpable
1 1 cm below the right costal margin and spleen 6 cm below the left costal margin. He had
hypotonia and inability to sit or bear weight with assistance. There was a marked lumbar
kyphosis while sitting and slight limitation of extension at the elbows, knees and hips.
A liver biopsy was performed. Urine and blood were obtained for metabolic studies.
A skeletal survey was obtained.
Over the next year the infant suffered a progressive downhill course with several
bouts of pneumonia, increase in his lethargy, and massive hepatosplenomegaly. At 23
months he had developed pitting edema and rales. He died one month later of presumed
respiratory arrest.
DISCUSSION
Dr. Lewis Barness, Professor and Chairman, Department of Pediatrics,
University of South Florida
A 12-month-old child who presents with hepatosplenomegaly, first noted 4 months
previously, should suggest the presence of a malignancy, chronic infection, certain
metabolic diseases, some hematologic disorders, or a number of storage diseases.
At birth, the patient had hyperbilirubinemia (Table I). Of the metabolic diseases,
galactosemia at this age could cause hyperbilirubinemia and hepatosplenomegaly but
would be more likely to cause cirrhosis and severe neurological deficits if lactose feedings
persisted. Tyrosinemia and several other amino acid disorders also may cause hyperbilirul
binemia but would be more likely to accompany signs of hyperammonemia and cirrhosis.
Some children with hypothyroidism have persistent jaundice neonatally and, if untreated,
may develop hepatosplenomegaly.
Clinicopathological Conference: Hepatosplenomegaly
413
TABLE 11. Considerationsof Diagnosis of
Heptosplenomegaly in 12-Month-Old Child With Progressive
Deterioration
Malignancy
Neuroblastoma
Leukemia
Lymphoma
Chronic infection
Tuberculosis
Parasites
Metabolic disorders
Galactose
Hematologic disorders
Thalassemia
Iron deficiency
Storage diseases
Mucopolysaccharides
Glycogen
I-cell (mumlipid)
Aspartylglucosaminuria
Gaucher
Niernann-Pick
Mannosidosis
Fucosidosis
Lactosylceramidosis
Gangliosidosis
At age 3 months, lethargy and strabismus were noted. Without a dietary history and
laboratory results, galactosemia, other inborn errors of metabolism, hypothyroidism, or
anemia might be considered. If the lethargy and strabismus are of recent onset, some
studies might have been indicated. Increased intracranial pressure, infection, retinoblastoma, muscle diseases, hypoglycemia or some of the storage diseases that cause strabismus
early such as Hurler, Hunter, Niemann-Pick or Gaucher disease should at least be
considered.
At 8 months, normal development and abnormal facial appearance are described.
Though we have no photographs, the prominent frontal area, wide nasal bridge, prominent
abdomen and hepatosplenomegaly might suggest one of the mucopolysaccharidoses or the
recently described infant born of a mother with AIDS [Marion et al, 19861, I-cell disease,
or aspartylglucosaminuria. Some of the other storage diseases previously mentioned also
present a similar appearance.
In spite of the abnormal facial appearance, one of the first considerations in an
infant with a large liver with or without splenomegaly is a malignancy. Neuroblatsoma,
leukemia, or lymphoma commonly present at this age with hepatosplenomegaly only. No
tests for any of these diseases are reported (Table 11).
At age 10 months, the CBC apparently makes leukemia or a hemoglobinopathy
such as thalassemia unlikely. The absence of cataracts and no mention of deafness
probably makes consideration of Hurler or Hunter mucopolysaccharidoses less likely,
though these are not expected findings at 6 months. Good ophthalmologists pick up
corneal clouding in some by the ages of death in such children. The absence of tight skin
and the very large spleen decrease the likelihood of a mucolipidosis. Even though the face,
especially the frontal bossing and flat nasal bridge, resembles that of a child with Hunter
syndrome, the relatively small head, 36 cm (less than 5th centile), and slender arms and
legs argue against any of the mucopolysaccharidoses.
At this point we would examine the urine for amino acids and mucopolysaccharides;
a bone marrow for malignant cells, foam cells, and inclusion bodies; a fasting blood sugar;
and roentgenograms of the long bones.
The gingival hyperplasia might suggest glycogen storage disease. Consideration of
this diagnosis was eliminated because of the normal heart size, the normal sugar, and the
child’s unusual appearance. The very large spleen without evidence of hypersplenism
militates against such a diagnosis. The epicanthal folds are important diagnostically only
414
Barness et al
for some of the trisomies and other syndromes which are not at all consistent with the
course in this patient.
Children with Gaucher disease would probably have in addition to strabismus,
trismus and retroflexion of the head and probably hypersplenism. Mannosidosis, fucosidosis, and lactosylceramidosis as well as the gangliosidoses would probably have more
evidence of white matter disease such as hyperactive reflexes and hypertonicity.
Otitis media and apparent respiratory involvement, irritability, hypotonia, early
jaundice, and the apparent storage phenomena described over the next year are consistent
with Niemann-Pick disease. While the parents are German and Polish, only 50% of the
cases are reported to be in Jewish families and no mention is made of their religious
affiliation. About 50% have a cherry-red spot; if this were present, it would have helped in
making the diagnosis. I would expect to find foam cells in the marrow and in other organs.
The diagnosis could be made by determining the lack of sphingomyelinasein white cells or
in other tissues [Brady, 19831. For any of the diseases discussed, the definitive diagnosis
rests on enzyme determinations. While hypercholesterolemia has been described in
Niemann-Pick and similar lipid storage diseases, this child had a normal serum cholesterol
with elevated triglycerides. I am unable to explain the latter. My final diagnosis then is
Niemann-Pick disease type A .
RADIOLOGICAL FINDINGS
Dr. Mary Ellen Peters, Professor of Radiology
At age 11 months, the patient had a roentgenological survey of his skeleton; it
demonstrated generalized osteoporosis, mild undertubulation of the long bones, and
widening of the fifth metacarpals (Figs. 1, 2). Skull radiographs showed the sutures to be
split undoubtedly related to brain infiltration (Fig. 3). A diffuse, reticular nodular pattern
was present on the chest film; also, the right upper lobe was atelectatic (Fig. 4).
The radiographic manifestations of Niemann-Pick disease depend on the type and
severity of the disease and the longevity of the patient [Lachman et al, 19731. Bone
changes include osteoporosis, thinning of the cortices, undertubulation of the diaphyses,
splaying of the metaphyses, metacarpal widening, and a delay in bone maturation
[Lachman et al, 1973; Grunebaum, 1976; Gildenhorn and Amromin, 19613. Anterior
notching of vertebrae at the thoracolumbar junction has also been described [Lachman et
al, 1973; Swischuk, 19701. This has been postulated to be the result of exaggerated
kyphosis secondary to hypotonia that also is the cause of coxa valga in these patients
[Lachman et al, 1973; Swischuk, 19701. A reticular nodular pattern that can progress to
honeycombing is often seen on chest radiographs [Lachman et al, 19731. Enlargement of
the spleen, liver, and kidney can also be observed [Lachman et al, 1973; Grunebaum,
1976; Gildenhorn and Amromin, 19611. Small bowel changes that include dilatation,
delayed transit time, and loss of mucosal folds have been reported in type A disease
[Gildenhorn and Amromin, 19611.
PATHOLOGICAL FINDINGS
Dr. Enid Gilbert, Professor of Pathology and Pediatrics
A liver biopsy performed one month before death indicated presence of a storage
disease. On frozen section coarse granules were seen in the hepatocytes which stained
deeply with hematoxylin (Fig. 5). The appearance suggested the presence of mucopolysac-
Clinicopathological Conference: Hepatosplenomegaly
415
Fig. I . AP roentgenogram of hand showing osteoporosis and widening of the fifth metacarpal. The bone age is
appropriate for age.
charides; however, staining procedures by anion extraction failed to identify mucopolysaccharides. A reaction with lipid stains could be obtained; however, multiple stains to
identify the nature of the storage material gave inconclusive results.
At autopsy this 2-year-old white boy weighed 13 kg and measured 78 cm. Minor
anomalies were present but not specific (Fig. 6). The heart and lungs together weighed 370
g (normal 175 g). The heart was not remarkable. The lungs contained multiple small white
nodules measuring up to 1.0 cm in diameter (Fig. 7). On microscopic examination these
nodules contained clusters of foamy histiocytes (Fig. 8) that stained with oil red 0 for lipid
and with Lux01 fast blue for phospholipid. In addition, the osmium tetroxide alpha
naphthylamine (OTAN) stain after treatment with NaOH was positive, identifying the
storage material as sphingomyelin. A histochemical profile of the staining reactions is
shown in Table 111. The differential staining reaction of glycolipids, phospholipids, and
neutral lipid is shown in Table IV.
The liver was enlarged and weighed 950 g (normal 395 g), and the cut surface was
pale and yellow (Fig. 9). Microscopic sections showed foamy hepatocytes and Kupffer
cells that contained storage material (Fig. 10) identified histochemically as sphingomyelin
(Fig. 11). The spleen weighed 450 g (normal 35 g) (Fig. 12). Microscopically, foamy
histiocytes filled the splenic sinusoids. These cells also stained histochemically for
sphingomyelin. Each kidney weighed 50 g (normal 45 8). The cut surfaces showed
indistinct corticomedullary demarcation. Occasional foamy histiocytes were seen in the
glomeruli and renal tubules (Fig. 13). The brain weighed 910 g (normal 1,000 g) and was
symmetrical with some gyral atrophy. On coronal section, atrophy of gyri and deep sulci
416
Barnes et al
Fig. 2. AP roentgenogram of tibiae and fibulae showing osteoporosis and mild undertubulation of the
diaphyses.
was seen, and the ventricles were dilated (Fig. 14). On microscopic examination the
neurons were large and foamy (Fig. 15) and contained lipid storage material that stained
predominantly for phospholipid (Fig. 16). The bone marrow contained large foamy
histiocytes with a “soap bubble” cytoplasm (Fig. 17) demonstrated by Giemsa staining.
These cells had the appearance of “sea blue histiocytes” (Fig. 18).
Electron microscopic examination of the storage cells in the liver, spleen, and bone
marrow showed pleomorphic lipid profiles frequently with electron lucent tangled
membranes or electron dense cores (Fig. 19).The neurons contained principally concentric
membranous bodies resembling gangliosides (Fig. 20) with electron-dense cores.
Biochemical studies of the tissues were performed by Dr. John Callahan, University
of Toronto. A deficiency of sphingomyelinase was present. Results are shown in Table V.
PATHOLOGICAL EXAMINATION OF FETUS
Dr. Sunita Chandra, Assistant Professor of Pathology
Twenty-one months after the death of this patient his mother terminated a
pregnancy at 22 weeks. Cultured amniocytes from an amniocentesis at 16 weeks and
Clinicopathological Conference: Hepatosplenomegaly
Fig. 3.
417
Lateral skull film showing split sutures. The sellar shape is within normal limits for age.
Fig. 4. AP film of chest showing diffuse, fine, reticular nodular pattern. Right upper lobe is atelectatic.
Fig. 5. Microscopic frozen section of liver biopsy showing coarse granularity of the cytoplasm of the
hepdtocytes staining deeply with hematoxylin. Hemdtoxyhn and eosin (H&E). x 100.
Fig. 6 . Appearance of the patient.
Fig. 7. Cut surface of lung showing multiple firm white nodules.
Clinicopathological Conference: Hepatosplenomegaly
Fig. 8.
419
Microscopic appearance of the lung showing large foamy histiocytes. H&E. x 100.
TABLE 111. HistochemicalProfile in Niemann-Pick Disease
Neural tissue
Luxol fast blue
PAS
After NaOH
After KBr
Sudan black B
Oil red 0
After hot acetone
After cold acetone
OTAN
OTAN NaOH
Ferric hemdtoxylin
After NaOH
Schultze reaction for
cholesterol
AZO dye reaction for
acid phosphatase
Autofluorescence
Visceral organs
Bond marrow
++
+++
+++
++
++
++
++
+
+
+
+
+
++
++
++
+++
+++
+++
+
++++
++++
+++
++
+
+
+
+
+
++++
++++
+
++
++
++
+++
++
++
++
++
+
+
+
+
f++
+
420
Barness et al
TABLE IV. Histochemical Identification of Lipids
Glycolipids
Oil-soluble dyes
(oil red 0)
Extracted with cold acetone
Extracted with hot acetone
Extracted in hot pyradine
PAS
OTAN
Phospholipids
Neutral lipids,
cholesterol,
triglycerides,
fatty acids
+
+
+
No
YeS
Yes
POS
Neg
No
No
YeS
Neg
Yes
YeS
Yes
Neg
Neg
POS
Fig. 9. Gross appearance of the cut surface of the liver. The parenchyma is uniformly pale
cultured fetal fibroblasts showed extremely low levels of sphingomyelinase activity in a
female fetus (Table VI).
No obvious external abnormalities were seen. The liver was slightly enlarged and
weighed 30 g (normal 24 8). Microscopic sections of the brain showed normal hepatic
architecture with the usual amount of extramedullary hematopoiesis. The hepatocytes
were distended by foamy cytoplasm and contained eccentric nuclei (Fig. 21). The spleen
was slightly enlarged and weighed 5.0 g (normal 0.5 to 2.5 8). The sinusoids contained
large foamy cells with eccentric nuclei and vacuolated cytoplasm (Fig. 22). No other
pathological changes were noted. A diagnosis of Niemann-Pick disease type A was made
and was confirmed by biochemical studies.
FINAL PATHOLOGICAL DIAGNOSIS: NIEMANN-PICK DISEASE TYPE A
COMMENT
Dr. Gerard Odell, Professor of Pediatrics
Dr. Barness is to be congratulated for his perceptive differential diagnosis. Unfortunately, 1 was not so wise. I was more impressed by the patient’s physical findings at the
Clinicopathological Conference: Hepatosplenomegaly
421
Fig. 10. Microscopic section of the liver. There is vacuolization of the hepatocytes. H&E. x40
Fig. 1 I . Microscopic appearance of the liver showing deep staining of the cytoplasm for sphingomyelin.
Osmium tetroxide alpha naphthylamine (OTAN) stain after NaOH. x 100.
time of his University Hospital admission, namely, his prominent forehead, delayed
development of the naso-orbital ridge, and coarse facial appearance. The additional
findings of thoracolumbar kyphosis and inability to extend the arms at the elbows to 180°
lead me to favor a diagnosis of Hunter or Hurler syndrome involving lysosomal storage of
mucopolysaccharides. The very impressive hepatosplenomegaly in the presence of minor
elevations of serum transaminases and a normal serum bilirubin concentration indicated a
storage disease rather than a primary hepatocellular disorder. Given such an orientation
the needle aspiration biopsy of the liver included not only formalin fixation but also a
sample for electron microscopy as well as a snap-frozen section before fixation to permit
histochemical identification of storage material that might otherwise be lost during
fixation and paraffin embedding. Indeed, the frozen sections showed storage-laden cells
422
Bpraessetal
Fig. 12. Gnss appearance of the cut surface of thc spleen. The parenchyma is pale and glistening.
Fig. 13. Microscopic section of the kidney. Scattered vacuolated histiocytes are present in the glomeruli and
tubules. H&E. x 100.
which stained with the hematoxylin but we were unable to further identify the material at
the time and the electron micrographs showed large abnormal lysosomes.
We were fortunate to have as our Chief Resident Dr. William Gahl, who was able to
culture fibroblasts for sphyngomyelinase activity from a skin biopsy. We sent them to Dr.
John F. OBrien’s laboratory at the UCSD/LaJolla for a more definitive diagnosis; a
“sulfate-chase’’ could not establish a diagnosis of mucopolysaccharidosis.
COMMENT
Dr. Nasrollah T. Shahidi, Professor of Pediatrics
Sea-blue histiocytes are large cells measuring up to 60 pm in diameter and
containing a single, usually eccentrically located nucleus. When stained with Wright or
Giemsa stain the cytoplasm exhibits numerous sea-blue or blue-green homogeneous
granules. The granules also stain with Sudan black, periodic acid-Schiff (PAS), and
acid-fast stains. Ultrastructural investigations indicate that these granules consist of
ClinicopathologicalConference: Hepatosplenomegaly
423
Fig. 14. Coronal section of the brain. There is atrophy of gyri and dilatation of the lateral ventricles.
Fig. 15. Microscopic section of the brain showing many distended neurons in the cortex. H & E . x 100.
lamellae of lipid molecules. Their major chemical constitucnt is thought to be ceroid.
Sea-blue histiocytes are seen in the spleen and the bone marrow in a variety of acquired
disorders such as idiopathic thrombocytopenic purpura and chronic myelogenous leukemia
as well as hereditary disorders such as Fabry disease, Niemann-Pick disease, Tangier
disease, and Hallervordcn-Spatz disease.
DISCUSSION OF PATHOLOGICAL FINDINGS
Dr. Enid F. Gilbert, Professor of Pathology and Pediatrics
Sphingomyelin lipidosis is associated with deficiency of isoelectric forms of sphingomyelinase. Six types of this disorder have been characterized. Four of these (types A-D)
were first differentiated clinically by Crocker [ 196 1 1. Type A is the infantile form in which
hepatosplenomegaly and CNS degeneration begin within the first year of life. Type B
[Fredrickson and Sloan, 1978; Gal et al, 19751 is the non-neuronopathic form and is less
severe than type A. Type C [Fredrickson and Sloan, 1978; Crocker and Farber, 19581, the
424
Barness et a1
Fig. 16. Microscopic section of the brain showing large distended neurons. Lux01 fast blue stain for
phospholipid. x 100.
Fig. 17. Large foamy histiocytes in bone marrow showing typical “soapbubble” appearance of the cytoplasm
of a Niemann-Pick cell. H&E. x 1,000.
“juvenile form,” is characterized by CNS degeneration beginning after the first year of life
with less severe hepatosplenomegaly than is found in type A and often accompanied by
predominance of cerebellar symptoms. Type D occurs in patients of Nova Scotian ancestry
[ Fredrickson and Sloan, 1978; Crocker and Farber, 1958; Vethamany et al, 19721 who
otherwise have a course similar to patients with type C . Type E has been included as an
indeterminate form in adults [Pilz, 1970; Attal et al, 19771 and biochemically appears to
be closely related to type C . Type F is characterized by childhood onset of splenomegaly,
lack of neurological involvement, diminished activity of a heat-labile sphingomyelinase,
and “sea-blue’’ histiocytes [Schneider et al, 19781.
Many variant types have been reported [Norman et al, 1967; Wenger et al, 1977;
Clinicopathological Conference: Hepatosplenomegaly
425
Fig. 18. Sea-blue histiocytes in bone marrow. Giemsa stain. x400.
Fig. 19. Electron micrograph of the liver showing pleomorphic lipid profiles frequently with tangled
membranes and electron dense cores. Uranyl acetate and citrate. ~8,000.
Hagberg et al, 1978; Wiedemann et al, 19721 that do not clearly fit into any type in the
current classification for Niemann-Pick disease (NPD) because the classification for
N P D [Crocker, 196 1; Fredrickson and Sloan, 1983; Crocker and Farber, 19581 has relied
almost entirely on the clinical manifestations and the total absence of sphingomyelinase
activity. A form of lipid storage disease was described by Wiedemann et al [ 19721 in which
4 sibs with a slowly progressive lipidosis had marked hepatosplenomegaly. Three of these
patients began to show mental and motor deterioration in the second and fourth years of
life with hepatosplenomegaly present a t birth in one infant. One child died at age 9 years,
and another 14-year-old girl with splenomegaly and foam cells in the marrow had entirely
normal mental and physical development. A glycerophospholipid was identified in liver
426
Barnes et al
Fig. 20. Electron micrograph of a neuron. Lipid profiles are abundant with concentrically laminated
membranes with occasional electron dense cores. Uranyl acetate and lead citrate. x 15,000.
TABLE V. Sohineomvelinase Levels in Control and Niemann-Pick Tissues*
Liver
Brain
1
30
L
21
54
22
Spleen
Normal control
3
Niemann-Pick type A
30
0.4
-
2.6
44
21
21
0.3
*All values expressed as nmol sphingomyelin hydrolyzed per hour per mg protein and are average values based on
assays run at 4 different protein concentrations.
and spleen in a child who died with a visceral sphingomyelinosis with decreased activity of
sphingomyelinase. Wiedemann et al [ 19721 considered these cases to be another variant
form of NPD.
Another variant of sphingomyelin lipidosis has been reported with unexplained
cirrhosis, involvement of the central nervous system and vertical supranuclear ophthalmoplegia [Wenger et al, 1977; Witzleben et al, 19861. One case was associated with
hepatocellular carcinoma [Witzleben et al, 19861. Biochemical analysis of cultured skin
fibroblasts obtained from one of the children showed that sphingomyelinase activity was
42% of control values. The association of hepatic storage and cirrhosis in infants or
children should prompt bone marrow examination for the presence of such histiocytes.
Further biochemical studies with more specific characterization of isoelectric forms
of sphingomyelinase should continue to define other variant forms of sphingomyelin
storage disease.
Pathologically, light and electron microscopic changes are similar in all forms of
NPD. The storage cell ranges in diameter from 20 to 90 pm, and the cytoplasm is filled
with lipid droplets that impart a “soap bubble” appearance with the nucleus displaced to
the periphery. Some cells in the viscera may contain lipofuscin pigment, sphingomyelin,
and lesser quantities of cholesterol and gangliosides [Elleder et al, 197.51. The histochemical staining reactions confirm the presence of a complex phospholipid. The cells stain
Clinicopathological Conference: Hepatosplenomegaly
427
TABLE VI. Sphingomyelin Activity in
Fetus From Cultured Fibroblasts
Control
Amniocentesis
Fetal fibroblasts
0.3
0.6
2.6
133
96
Fig. 21. Microscopic appearance of the liver in the aborted 22-week fetus showing large foamy hepatocytes.
H&E. x100.
positively with oil red 0, Nile blue sulphate, and Luxol-fast blue and the O T A N reaction
after pretreatment with NaOH. The ultrastructural appearance of the lipid inclusions
consists of concentrically laminated, myelinlike figures with a periodicity of approximately
50 A, resembling membranous cytosomes in the nervous system and other pleomorphic
lipid profiles. In the viscera lipid inclusions are frequently membrane bound and contain
stacked membranes, concentrically laminated membranes, and pleomorphic profiles with
both electron-dense and electron-lucent cores [Gilbert et al, 1981; Vethamany et al, 1972;
Luse, 1967; Lazarus et al, 1967; Lynn and Terry, 1964; Gumbians et al, 19751. Cultured
fibroblasts have similar inclusions and cultured amniotic cells contain storage material.
Unlike other lipid storage disorders in which the predominant storage substance is
the substrate of the deficient enzyme responsible for the disease, many of the lipids that
accumulate in N P D are not substrates for sphingomyelinase. In addition to sphingomyelin,
cholesterol, bis-(monoacylglyceryl)phosphate, and glycosphingolipids (eg, glucocerebroside, GM2, GM3) are also significantly elevated in types A and C NPD.
In 1966, Brady et al [ 19661 first demonstrated that sphingomyelinase activity was
low in tissues from patients with the infantile form of NPD. Callahan and co-workers
[ 1974, 1975, 19761 and Besley [ 19771 have separated, by isoelectric focusing, multiple
components of sphingomyelinase. The most acidic ones are the major forms in the liver and
brain, but 3 minor components with more alkaline pH values were also found [Callahan et
al, 1975; Callahan and Khalil, 19761. It has been postulated that the deficiency of a
portion of the enzyme pool must be of sufficient severity so that the catabolic demand
428
Barness et a1
Fig. 22. Microscopic appearance of the spleen in the aborted 22-week fetus showing distended foamy
histiocytes in the sinusoids. H&E. x 100.
outweighs the capacity for breakdown of sphingomyelin [Callahan et al, 19751. This leads
to lipid storage in visceral tissue.
Some workers utilizing ''C-sphingomyelin or a chromogenic analogue of sphingomyelin have demonstrated sphingomyelinase activities between 5 1% and 63% of normal in
cultured skin fibroblasts from patients with type C N P D [Gal et al, 19751. The
chromogenic analogue of sphingomyelin has been used successfully in the diagnosis of type
A NPD [Gal et al, 1975; Gal and Fash, 19761 and is hydrolyzed by the enzyme purified
from placenta [Pentchev et al, 19771.
So far there has been a dearth of studies of brain neutral glycolipids in NPD type A.
Of 2 such reports, the one by Greenbaum et al [ 19761, documented that total extracts
contain increased levels of glucosylceramide, di- and trihexoside as well as G M2, changes
identical with findings in some cases of N P D type C. Kamoshita et al [1969] found a
glucocerebroside together with GM2 and GM3. However, the distribution of the lipid
stored has as yet not been studied in type A brains. In type A, there is mostly neuronal, less
so vascular, sphingomyelin storage, while neutral glycolipid dominates in the vascular wall
[Elleder and jirisek, 198 11. In type C, it is a glycolipid which is stored in the neurons, that
is in a location different from that in type A.
Schoenfeld et al [ 19851 have reported placental ultrasonographic biochemical and
histochemical studies in human fetuses affected with NPD type A. Differences in the echo
pattern of the placental tissue have been described [Winsberg, 1973; Fox, 1963, 1975,
1978; Fisher et al, 19761 but these usually appear in late pregnancy, near term. Focal,
opaque, strong echoes in placental tissue with thick and irregular chorionic plates as early
as 18.5 weeks in placentae of N P D fetuses have been observed [Schoenfeld et al, 19851.
An animal model of NPD has been described in Siamese cats [Snyder et al, 1982;
Crisp et al, 1970; Percy and Jortner, 1971 1. The disease results from a profound deficiency
of lysosomal sphingomyelinase activity, with resultant accumulations of sphingomyelin,
cholesterol, and gangliosides in neurons and visceral cells of the mononuclear phagocyte
system [ Wenger, 19771. Kittens that are affected have progressive neurologic deteriora-
Clinicopathological Conference: Hepatosplenornegaly
429
tion, starting at about age 4 months; they usually die before they reach age one year
[ Wenger et al, 19801.
The earliest recognized clinical manifestation of feline NPD are retarded growth
and occasional knuckling over in the rear legs. As the disease progresses, there is increased
incoordination in the rear limbs, splaying of legs, and involvement of forelimbs. Later there
is depression, apparent blindness, anorexia, and continuous bobbing movements of the
head. Eventually total paresis and anorexia lead to death.
In the cat at autopsy all lymph nodes in the body are enlarged and yellow to tan. The
liver is markedly swollen, pale yellow, and greasy. The spleen is enlarged and pale, and
lymphoid tissue is indistinct. The central and peripheral nervous systems are characterized
by loss of Nissl substance, cytoplasmic swelling, and vacuolation of neurons, most marked
in Purkinje cells of the cerebellum and neurons of the cerebellar roof nuclei and
hippocampus, and in dorsal root and peripheral ganglion cells. Large mononuclear cells
with foamy cytoplasm are found most prominently in lymph nodes, liver, and spleen, but
also are found readily in the bone marrow, adrenals, and lungs. In addition, endothelial
cells in most organs have cytoplasmic swelling, and most lymphocytes and monocytes in
blood smears contain clear cytoplasmic vacuoles.
Thus, feline sphingomyelinosis is analogous to human NPD type A, and the clinical,
morphologic, and biochemical characteristics of the respective diseases are virtually
identical [Wenger et al, 1980; Brady and King, 19731. One alteration in human NPD not
yet found in affected cats is the macular “cherry-red spot” seen ophthalmoscopically
[Cogan and Kuwabara, 19681. The genetic basis for the disease in cats is not yet fully
established. However, an autosomal recessive mode of inheritance is suspected.
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Edited by John M. Opitz and James F. Reynolds
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