Case 2 -

Hurler Syndrome with Coronary Arterial Stenosis and Valvular Involvement Alan G. Rose

Clinical History 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. [1]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-α-glucosamidose Acetyl-CoA-α-glucosamide N-acetyl- transferase N-acetyl transglucosamine-6-sulfate sulfatase AR AR 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. [2] 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. [3] 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 syndrome. 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: Mucolipidoses 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. Glycoproteinoses 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. Lipidoses 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 [4] (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. [2, 5] 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 Lipidoses 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 Gangliosidoses GM1 Gangliosidosis β-galactosidase GM1 & other oligosaccharides GM2 Gangliosidosis 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 + + +   Gangliosidoses 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 [7] (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. [8] 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. [9]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. [10] References 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.