A Tribute to Jan

Returning to the University of Uppsala after 1 year in ON DECEMBER 1, 1996, the world lost one of this century’s giants in hematology. Jan Gosta WaldenMunich, he studied diseases associated with an elevation of the erythrocyte sedimentation rate (ESR). Waldenström ström was born the son and grandson of physicians in Stockholm, Sweden, on April 17, 1906. During his long and distindescribed three patients with an elevated ESR who had hyperproteinemia and petechiae of their lower extremities withguished career, he made seminal observations in hematology that provided a framework for understanding diseases such out evidence of malignancy. Although he coined the term ‘‘purpura hyperglobulinaemica,’’ this entity is now recogas porphyria, hemosiderosis, macroglobulinemia, and the monoclonal gammopathies. After obtaining his M.D. degree nized as benign hypergammaglobulinemic purpura of Waldenström (BHPW). Subsequent studies have shown that at the University of Uppsala, Waldenström studied organic chemistry in the laboratory of Hans Fischer at the Technische rheumatoid factor was present in all and intermediate complexes ranging from 7 S to 19 S were found on ultracentrifuHochschule in Munich. This led to his classical monograph entitled ‘‘Studien Über Porphyrie’’ in which he demongation. The purpura can be precipitated by increases in hydrostatic pressure. Moreover, we now know that BHPW strated the excessive excretion of uroporphyrinogen III in the urine in patients with acute intermittent porphyria (AIP). occurs frequently in autoimmune diseases and rarely with multiple myeloma. AIP is characterized by recurrent episodes of abdominal pain, vomiting, constipation, hypertension, tachycardia, and Over the years, Waldenström’s clinical insights lead to the recognition of several other disease states. He reported neurologic involvement including muscle weakness, mental changes, and even seizures. Since this early observation, the association of liver cirrhosis and hypergammaglobulinemia, which is now recognized as chronic active hepatitis. specific inherited deficiencies of enzymes within the heme synthetic pathway have been delineated that allow improved He demonstrated frequent iron deficiency in otherwise healthy women and was the first to recognize pulmonary understanding of classification, pathogenesis, and genetic screening. AIP, for example, is characterized as an autosomal hemosiderosis. Together with colleagues, he noted the skin flushing characteristic of metastatic carcinoid tumors. Imdominant condition resulting from decreased levels of porphobilinogen (PBG) deaminase or hydroxymethylbilane portantly, he described an early case of sex-linked hypogammaglobulinemia (Bruton’s hypogammaglobulinemia), an (HMB) synthase. area in which rapid progress has recently been achieved. Specifically, the gene for X-linked agammaglobulinemia (XLA) has now been mapped to Xq21.3-q22, and it is hypothesized that the pre-B cells that use the X chromosome with the XLA defective gene fail to develop into mature B cells. Most excitingly, the genetic defect at this locus has been shown to be due to defective gene expression of a B-cell–specific cytoplasmic protein tyrosine kinase, B-cell progenitor kinase, or agammaglobulinemia tyrosine kinase.