Autosomal-dominant giant platelet syndromes: a hint of the same genetic defect as in Fechtner syndrome owing to a similar genetic linkage to chromosome 22q11-13

Families with 3 different syndromes characterized by autosomal dominant inh eritance of low platelet count and giant platelets were studied. Fechtner s yndrome is an autosomal-dominant variant of Alport syndrome manifested by n ephritis, sensorineural hearing loss, and cataract formation in addition to macrothrombocytopenia and polymorphonuclear inclusion bodies. Sebastian pl atelet syndrome is an autosomal-dominant macrothrombocytopenia combined wit h neutrophil inclusions that differ from those found in May-Hegglin syndrom e or Chediak-Higashi syndrome or the Dohle bodies described in patients wit h sepsis, These inclusions are, however, similar to those described in Fech tner syndrome. Other features of Alport syndrome, though, including deafnes s, cataracts, and nephritis, are absent in Sebastian platelet syndrome. Eps tein syndrome is characterized by macrothrombocytopenia without neutrophil inclusions, in addition to the classical Alport manifestations-deafness, ca taracts, and nephritis-and it is also inherited in an autosomal-dominant mo de. We mapped the disease-causing gene to the long arm of chromosome 22 in an Italian family with Fechtner syndrome, 2 German families with the Sebast ian platelet syndrome, and an American family with the Epstein syndrome. Fo ur markers on chromosome 22q yielded an LOD score greater than 2.76. A maxi mal 2-point LOD score of 3.41 was obtained with the marker D22S683 at a rec ombination fraction of 0.00. Recombination analysis placed the disease-caus ing gene in a 3.37-Mb interval between the markers D22S284 and D22S693, The disease-causing gene interval in these 3 syndromes is similar to the inter val described recently in an Israeli family with a slightly different Fecht ner syndrome than the one described here. Recombination analysis of these 3 syndromes refines the interval containing the disease-causing gene from 5. 5 Mb to 3.37 Mb. The clinical likeness and the similar interval containing the disease-causing gene suggest that the 3 different syndromes may arise f rom a similar genetic defect. (C) 2000 by The American Society of Hematolog y.