Selected Arterial and Venous Diseases
Case 2 -
Hurler Syndrome with Coronary Arterial Stenosis and Valvular Involvement
Alan G. Rose
This 28-month-old female child was treated with Busulphan and Cytoxan prior to undergoing an unrelated
allogeneic bone marrow transplant (BMT) for Hurler syndrome (dwarfism, mental retardation, skeletal
malformations, hepatosplenomegaly and corneal opacities). A week post BMT she developed severe
respiratory problems and lung biopsy showed idiopathic interstitial pneumonia and fibrosis. Refractory
graft-versus-host disease of the skin and hypertension were additional problems. She also had gram
negative septicemia and peritonitis. Terminally the patient was hypotensive with multiorgan failure.
Autopsy revealed the presence of Hurler syndrome (mucopolysaccharidosis type I; previously gargoylism,
lipochondrodystrophy). Gross external features included scaphocephaly, depressed nasal bridge, widely
spaced eyes, widely spaced and poorly developed teeth with gingival hypertrophy. Other features of
Hurler syndrome found at autopsy included intimal fibrosis of rare medium sized pulmonary arteries,
concentric intimal thickening (Figure 1) of the proximal coronary arteries and intimal thickening of the
proximal aorta causing partial obstruction of the coronary ostia. In addition, there was yellow-white,
nodular thickening of the mitral and tricuspid leaflets and their chordae tendineae. Changes due to
Hurler syndrome were minimal in the myocardium, mild in the endocardium and moderate in the heart valves
with greater involvement of the mitral valve compared to the tricuspid. Intimal thickening affected all
of the epicardial coronary arterial branches.
Case 2 - Figure 1 - Severe intimal thickening due to the accumulation of Hurler cells and fibrosis has led to sub-total luminal occlusion of this major coronary artery
Case 2 - Figure 2 - Relatively normal LAD and diagonal branches of LCA in a 17 year old girl in whom bone marrow transplantation prevented significant coronary arterial disease
Case 2 - Figure 3 - Higher power view of the diagonal branch
Histopathology of the heart revealed the presence of numerous 'Hurler cells' and increased fibrosis
and interstitial mucopolysaccharide accumulation in the intima of the major coronary arteries and
moderately affecting the atrioventricular valves. The aorta also showed numerous vacuolated, AMP rich
Hurler cells in the intima and the media. Electron microscopy of the bone marrow and the liver showed no
storage material within the relevant cells. The brain showed widespread neuronal storage of
mucopolysaccharide and sclerosis around the white matter perivascular spaces.
The mucopolysaccharidoses have been divided into 7 major types (Tables 1 and 2) based on the
particular deficient enzyme responsible for each disorder. These disorders carry such eponyms as Hurler,
Scheie, Hurler-Scheie, Hunter, Sanfilippo, Morquio, Maroteaux-Lamy and Sly. Diagnosis of the
different mucopolysaccharidoses is made by identification of a combination of typical physical features,
assaying cells or tissues for the specific enzyme deficiency or by polymerase chain reaction techniques
to determine the mutation.
Table 1: Classification of the Mucopolysaccharidoses
|Type ||Eponym ||Enzyme Deficiency ||Inheritance|
|I-H ||Hurler syndrome ||α-L-iduronidase || AR|
|I-S (V) ||Scheie syndrome ||α-L-iduronidase || AR|
|II ||Hunter syndrome ||Sulfoiduronide sulfatase || XLR|
|IIIA ||Sanfilippo syndrome ||Heparan sulfatase |
N-acetyl transglucosamine-6-sulfate sulfatase
|IVA ||Morquio syndrome ||Galactosamine-6-sulfate sulfatase ||AR|
|IVB ||Morquio syndrome ||β-galactosidase ||AR|
|VI ||Maroteaux-Lamy Syndrome ||Aryl sulfatase B || AR|
|VII ||Sly ||β-glucuronidase ||AR|
AR = autosomal recessive
XLR = X-linked recessive
Mucopolysaccharidosis Type I includes Hurler, Hurler-Scheie and Scheie syndromes. All three are
autosomal recessive traits caused by a deficiency of α-L-iduronidase, a lysosomal hydrolase that
participates in the catabolism of mucopolysaccharides (glyosaminoglycans). Iduronidase deficiency
results in the accumulation of heparan sulfate and dermatan sulphate.  The undegraded
glycosaminoglycans accumulate in lysosomes and affect tissue function. Hurler syndrome (MPS-I) is an
autosomal recessive trait found on chromosome 22 (22q11) that occurs in about 1 in 40,000 people. Like
the Hunter syndrome both dermatan and heparan sulfate are found in high concentrations in the urine;
childhood myocardial infarction is seen.
Cardiovascular involvement in the mucopolysaccharidoses is summarized in Table 2. All may show
myocardial involvement and involvement of the aorta has led to coarctation of the abdominal aorta in some
cases. Coronary arterial and valvular involvement is common.
Bone marrow transplantation slowed the disease progression in two patients.  The histology
of a patient who lived 17 years with Hurler syndrome following bone marrow transplantation illustrates
how this procedure may prevent significant arterial disease (Figures 2 and 3). This latter patient is
the first to have autopsy documented evidence that BMT may prevent coronary arterial disease in Hurler
Table 2: Cardiovascular Involvement in the Mucopolysaccharidoses
| Mucopolysaccharidoses ||Elastic arts ||Coronary arts ||Valves|
|All may have myocardial involvement |
|Type 1 |
|Hurler, || + || + || +|
|Hurler-Scheie || || + || +|
|Scheie || + || + || +|
|Type II |
|Hunter || + || + || +|
|Type III |
|Sanfillipo || || ||+|
|Type IV |
|Morquio || || + ||+|
|Type VI |
|Maroteaux-Lamy || || + ||+|
|Type VII |
|Sly || + || || |
Cardiovascular Involvement in Other Inborn Errors of Metabolism:
I-Cell Disease (mucolipidosis II) is an autosomal recessive
trait resulting from a deficiency of N-acetyl-gluosamine-1-phosphotransferase. Phenotypically similar to
Hurler syndrome, but present earlier and lack urinary excretion of mucopolysaccharides. Stenotic aortic
and mitral valves, left ventricular hypertrophy, and aortic involvement.
Pseudo-Hurler Polydystrophy (mucolipidosis type III) is
related to I-cell disease (milder). Affects mitral and aortic valves, and one may have absent peripheral
pulses. Histopathology of the heart and peripheral arteries has not yet been reported.
α-Mannosidosis. Deficiency of α-mannosidase in glycoprotein
catabolism leads to accumulation of mannose-rich compounds within lyosomes in myocardium, endocardium,
cardiac valves and conduction system.
Fucosidosis, which results from a deficiency of α-fucosidase,
affects the myocytes.
Neuraminidase deficiency (sialidosis): type II sialidosis
has caused mitral valve disease.
Acid Lipase Deficiency
Deficiency of the lysosomal enzyme acid lipase may lead to 2 phenotypically distinct disorders: (1)
Wolman disease (WD) and (2) cholesterol ester storage disease (CESD). Autosomal recessive inheritance.
WD cases die in infancy or early childhood  (due to diarrhea and adrenal gland calcification),
whereas CESD may present only in the second decade of life. Clinical cardiovascular dysfunction has not
been reported in WD. Lipids (cholesterol esters and triglycerides) are deposited within the myocardium
and vascular endothelium, including the aorta. Autopsies in 3 patients have shown focal concentric
intimal deposits in the pulmonary arteries and arterioles, aorta, and coronary arteries. The deposits
comprised foam cells, extracellular lipid and fibrosis. Ischemic heart disease has not been reported,
but can be expected.
We have observed myocardial necrosis in a child with Wolman disease.
Wolman disease has been successfully treated by bone marrow transplantation, which leads to long-term
continued remission. [6 ]
Table 3: Summary of Enzyme Defects in Lipidoses & Gangliosidoses
|Disease || Enzyme defect || Accumulation of|
|Wolman || Acid lipase || Cholesterol esters|
|CESD || Acid lipase ||triglycerides|
|Farber's || Acid ceramidase ||Ceramide|
|Niemann-Pick || Sphingomyelinase ||Sphingomyelin|
|Gaucher || Glucocerebrosidase || Sphingolipids|
|Fabry's || α-galactosidase A || Glycosphingolipids|
|GM1 Gangliosidosis || β-galactosidase ||GM1 & other oligosaccharides|
|Tay-Sachs || Hexosaminidase A || Gangliosides|
|Sandhoff || Hexosaminidase A and B || Gangliosides|
Table 4: Cardiovascular Involvement in the Lipidoses and Gangliosidoses
| Lipidoses ||Elastic arts ||Coronary arts || Myocardium ||Valves|
|Acid lipase deficiency|
| Wolman's disease || + || + || + || |
| CESD || + || + || || |
|Farber's disease || || || || +|
|Niemann-Pick disease || - || - || - || -|
|Gaucher's disease || - || - || + || +|
|Fabry's disease || + || || + || +|
|GM1 Gangliosidosis || ! || +|| + || +|
|GM2 Gangliosidosis || ! || + || + || +|
Idiopathic Arterial Calcification of Infancy
The differential diagnosis of arterial narrowing in young individuals should include idiopathic
arterial calcification of infancy  (IACI), which is characterized by calcification of the
internal elastic lamina plus intimal fibrous proliferation with resultant luminal narrowing. Arteries
throughout the body (apart from the brain) may be affected. Calcific arteriopathy of infancy most often
affects infants less than 6 months of age with a mortality rate of 85%. Coronary arterial narrowing
leads to death because of myocardial ischemia. The aorta may also be involved with calcification of the
elastic lamellae, smooth muscle and collagen components of the medial lamellar units. The condition may
be diagnosed clinically by palpation of the hardened superficial arteries and by soft tissue radiography,
e.g. of the neck and limbs. Whilst the pathology is reminiscent of metastatic calcification, most cases
do not have uremia.
Idiopathic Calcification of the Aorta in Young Women
Idiopathic calcification of the aorta has also been reported in isolated instances in young women, in
whom it may mimic healed Takayasu's aortitis. 
Kawasaki (Mucocutaneous Lymph Node) Syndrome
Kawasaki disease is an acute multisystemic vasculitis of infancy and early childhood, which presents
with fever, rash, conjunctivitis, mucosal inflammation, erythematous induration of the palms and soles,
and cervical lymphadenopathy. The pathology is similar to that of polyarteritis nodosa. Up
to 20% of cases develop single or multiple coronary arterial aneurysms, particularly affecting the left
anterior descending coronary artery. Death may result from coronary thrombosis or aneurysmal rupture.
In addition to arteritis of medium-sized and small arteries, the aorta and veins may also be affected.
The condition is the most frequent cause of acquired heart disease in the United States. It is believed
that in a genetically susceptible person, an infectious agent (probably a virus) may trigger a vasculitis
mediated by an immunoregulatory defect. The defective reaction may involve activation of macrophages and
T-cells, cytokine secretion, hyperactivity of polyclonal B-cells, and the formation of autoantibodies to
endothelial cells and smooth muscle cells. Fibrinoid necrosis is said to be less obtrusive than in
polyarteritis nodosa. 
- Towbin JA, Greenberg F. Genetic syndromes and clinical molecular genetics. In: The Science and Practice of Pediatric Cardiology, 2nd Ed, edited by Garson A Jr, Bricker JT, Fisher DJ, and Neish SR. Baltimore, Williams & Wilkins, 1998, pp 2627-2699.
- Gelb BD, Abdenur J. Metabolic heart disease. In The Science and Practice of Pediatric Cardiology, 2nd Ed, edited by Garson A Jr, Bricker JT, Fisher DJ, and Neish SR. Baltimore, Williams & Wilkins, 1998, pp 1895-1898.
- Hopwood JJ, Vellodi A, Scott HS, et al. Long-term clinical progress in bone marrow transplanted mucopolysaccharidosis type I patients with a defined genotype. J Inherit Metab Dis 1993; 16: 1024-1033.
- Wolman M, Sterk VV, Gatt S, Frenkel M. Primary familial xanthomatosis with involvement and calcification of the adrenals: report of two more cases in siblings of a previously described infant. Pediatr 1961; 28: 742-757.
- Beaudet AL, Ferry GD, Nichols BL Jr, Rosenberg HS. Cholesterol ester storage disease: clinical, biochemical and pathological studies. J Pediatr 1977; 90: 910-914.
- Krivit W, Peters C, Dusenberry K, Ben-Yoseph Y, Ramsay NKC, Wagner JE, Anderson R. Wolman disease successfully treated by bone marrow transplantation. Bone Marrow Transplantation 2000; in press.
- Moran JJ. Idiopathic arterial calcification of infancy: A clinicopathologic study. Cardiovascular pathology Decennial 1966-1975. SC Sommers (ed). Appleton- Century- Crofts, New York, 1975, pp 47-71).
- Rose AG, Forman R. Idiopathic aortitis with calcification of ascending aorta, and aortic and mitral valves. Brit Heart J 1976; 38: 650-652.
- Gilbert-Barness E, Debich-Spicer D. Cardiovascular system. In Gilbert-Barness, E. (ed): Potter's Atlas of Fetal and Infant Pathology.Mosby, St Louis, 1998, pp 143-165.
- Robbins Pathologic Basis of Disease. Cotran RS, Kumar V, Collins T (eds). W B Saunders Company, Philadelphia, 1999, p 521.