Grand Rounds: “Two patients with splenomegaly: what is the diagnosis?”

January 17, 2008

Bellevue AmphitheaterCommentary by Noga Chlamtac MD, PGY 3

This weeks grand rounds was delivered by Dr. Pramod Mistry, Professor of Pediatrics and Medicine, and Chief of the Section of Pediatric Gastroenterology, Hepatology and Nutrition at Yale School of Medicine. Dr. Mistry received his Ph.D degree from the St. Thomas Hospital Medical School at the University of London in 1979 and his clinical training at the Royal Free Hospital and the Royal College of Physicians. Starting in 1998, he served as the Director of the Comprehensive Gaucher Disease Treatment Center at Mt. Sinai School of Medicine until 2001, when began his current position as Director of the National Gaucher Disease Treatment Center. Dr. Mistry’s research has focused on inherited metabolic liver diseases.

Dr. Mistry began his talk by describing two patients with Gaucher’s disease (GD). The first case was a 4 year old boy who presented with failure to thrive and massive splenomegaly. The patient was treated with enzyme replacement therapy and grew up to be a healthy, normal appearing and functioning adult. The second case demonstrated the perils of a missed diagnosis. A ten-year old boy who presented with massive splenomegaly was originally given the diagnosis of infectious mononucleosis. He presented with a bone crisis at age 15. At age 25 he did truly suffer from infectious mononucleosis, and experienced rapid enlargement of his spleen, which then ruptured, nearly killing him. He later developed a rare bone tumor. An earlier diagnosis of GD as well as targeted therapy might have prevented some of these bad outcomes. Indeed, misdiagnosis is not infrequent – 25 percent of all patients affected by GD have a delayed diagnosis of up to 10 years. GD is the most common lysosomal storage disease, occurring in approximately 1/75,000 births in the general population, with a much higher incidence (1/850) in Ashkenazi Jews. (Of note, the carrier state is 1/10 in this high risk population — the selective advantage has been hypothesized to protect against infection or malnutrition, but remains to be fully elucidated).
In 1882 in France, Dr.Gaucher performed an autopsy of a patient who had initially presented with cachexia and massive hepatosplenomegaly. Autopsy revealed large cells in the liver, which he mistook for cancer cells. In 1965 Dr. Brady at the NIH defined the disease as inherited autosomal recessive mutation in the glucocerebrosidase gene. Lysosomes of macrophages fill with lipid material, which subsequently accumulate in the spleen, liver, bone marrow, and bone. These cells have a characteristic tissue-paper appearance on microscopy, and are now termed “Gaucher cells”.

Phenotypically, the disease is variable and complex. In a study of 1,500 children, Dr. Mistry and his colleagues found that most patients at a young age present with hepatosplenomegaly, growth failure, anemia, and thrombocytopenia. In contrast, in patients older than 50 years, the typical presenting symptom is not liver disease, rather skeletal disease characterized by osteopenia. Affected patients may have painful crises, osteolytic lesions, pathologic fractures, vertebral compression and osteonecrosis. Patients with GD who first present with bone disease, are frequently misdiagnosed as having, for example, frozen shoulder or osteoporosis. This is a dangerous misdiagnosis, not only because the bone disease progresses, but also because there is an increased incidence of cancer in this population. The risk of multiple myeloma is a staggering 37 times higher in those with GD, for example. There appears to be an indirect relationship between the phenotypic disease severity of GD and the incidence of cancer.

Possible therapies for Gaucher’s include BMT, liver transplant, substrate deprivation therapy, and enzyme enhancement therapy, the latter being the standard of care. This therapy has only been widely available in recombinant form over the last 10-12 years. Deficiency of glucocerebrosidase leads to accumulation of glucocerebroside and other glycolipids within the lysosomes of macrophages. ERT works by reducing substrate accumulation. While we have recently seen great improvements in therapy, we have yet to understand how different phenotypes of disease occur. To target this issue, scientists are now studying glucocerebrosidase gene knockout mice. Dr. Mistry believes that genome studies conducted in association between Yale and NYU will elucidate what the genetic modifications are responsible for the variability in the GD phenotype.