An autopsy is being performed on a 4-year-old boy who recently died from a myocardial infarction. The child had a history of intellectual disability. Autopsy shows a prominent forehead and broad nose. There is a diffuse haze over the corneas bilaterally. The heart, liver, and spleen are enlarged. Sampling of the coronary arteries is most likely to reveal intimal accumulation of which of the following substances?
Mucopolysaccharidoses* | ||||
Diagnosis | Inheritance | Deficiency | Accumulated | Key features |
Hurler | AR | α-L-iduronidase | Dermatan & heparan sulfate |
|
Hunter | XLR | Iduronate sulfatase |
| |
| * Subtype of lysosomal storage disorder. AR = autosomal recessive; XLR = X-linked recessive | ||||
This patient most likely had Hurler syndrome (type I mucopolysaccharidosis), an autosomal recessive disorder characterized by severe intellectual disability, corneal clouding, and coarse facial features (eg, frontal bossing, broad nose, flat midface). Hepatosplenomegaly and heart disease are also typical findings.
Mucopolysaccharidoses are lysosomal storage disorders resulting from the defective metabolism of glycosaminoglycans (GAGs). GAGs are long, unbranched polysaccharides that are an important component of the ground substance within the extracellular matrix of connective tissues. Hurler syndrome is caused by a deficiency of alpha-L-iduronidase, which hydrolyzes dermatan and heparan sulfate. Hunter syndrome, a less severe disease than Hurler syndrome, also results in an accumulation of dermatan and heparan sulfate but characteristically does not cause corneal clouding.
Patients with Hurler syndrome have a shortened life expectancy. Death, typically in early childhood, is usually caused by cardiac complications (eg, myocardial infarction); this child's death from coronary artery disease was likely due to deposition of dermatan and heparan sulfate within the vessels.
(Choice A) Premature coronary artery disease is seen with familial hypercholesterolemia. Cholesterol deposits can lead to tendon xanthomas, xanthelasmas (ie, eyelid plaques), and/or corneal arcus (ie, gray ring around the cornea) but not coarse facial features, intellectual disability, or a diffuse corneal haze.
(Choice B) Accumulation of glucocerebroside within mononuclear cells is seen in Gaucher disease, an autosomal recessive defect in beta-glucocerebrosidase. This condition is characterized by bruising due to thrombocytopenia, hepatosplenomegaly, progressive neurologic deterioration, and severe bone pain. Premature coronary artery disease does not occur.
(Choice C) Glycogen storage diseases cause defective metabolism of glycogen in the liver and/or muscles. The presentation can include hypoglycemia, lactic acidosis, hepatomegaly, growth retardation, and/or muscle fatigue/cramping. Cardiomegaly can occur with Pompe disease, but corneal clouding is not a feature.
(Choice E) Niemann-Pick disease results from a deficiency of sphingomyelinase, which leads to the accumulation of sphingomyelin within phagocytes. This disease is characterized by hepatosplenomegaly and progressive neurologic deterioration, but eye findings include a cherry-red spot on the macula, not corneal clouding.
Educational objective:
Hurler syndrome is a mucopolysaccharidosis caused by a deficiency of alpha-L-iduronidase, which hydrolyzes dermatan and heparan sulfate. Accumulation of these substances results in the characteristic features of intellectual disability, coarse facial features, corneal clouding, and hepatosplenomegaly. Early death due to cardiac complications (eg, myocardial infarction) is expected.