The WT syndrome--a "new" autosomal dominant pleiotropic trait of radial/ulnar hypoplasia with high risk of bone marrow failure and/or leukemia

Abstract

We report 2 families with an autosomal dominant syndrome of limb and hematologic abnormalities. The W Family was ascertained through AW, a 13-year-old girl, who was purportedly born without congenital anomalies and who was normal until 11 1/2 years when she developed acute lymphoblastic leukemia. She died 2 years later with CNS involvement. Her chromosomes, studied in the first weeks after diagnosis of the disease, were apparently normal. Her father had clinodactyly of both 5th fingers and was found to have panmyelocytopenia refractory to all treatment at 26 years. He died within a year of the onset of his anemia. This man's oldest brother was born with congenital malformations of the elbows and the hands and was healthy until 38 years when he was also found to have an "idopathic anemia" and panmyelocytopenia which was refractory to treatment except for transfusions; he died at age 42 years. Both men were initially thought to have the Fanconi anemia syndrome. Their mother died at 71 years of leukemia. DT, the propositus of the second family, was noted to have malformations of both hands at birth. At 21 months he had anemia for which he received transfusions. Family history reveals that several people on the paternal side have severe hand anomalies and a history of childhood anemia. The paternal grandfather died at age 51 of acute monocytic leukemia. Barring genetic heterogeneity, we think that the trait in the W and T families in the same. It is a pleiotropic autosomal dominant mutant which affects radial and ulnar development of the upper limbs and is associated with a relatively high risk of transient or permanent bone marrow arrest with or without leukemia. We propose the hypothesis that apparently increased risk of leukemia to Fanconi heterozygotes actually represents admixture with the WT syndrome and that Fanconi heterozygotes may not have an increased risk of leukemia.