Atypical Presentation of Wiskott-Aldrich Syndrome: Diagnosis in Two Unrelated Males Based on Studies of Maternal T Cell X Chromosome Inactivation zy By zyxwvutsrqpon Jennifer M. Puck, Katherine A. Siminovitch, Mortimer Poncz, Cheryl R. Greenberg, Menochem Rottem, and Marv Ellen Conley Congenital thrombocytopenia may occur in isolation or accompanied by eczema and immunodeficiency, as part of the X-linked hereditary Wiskott-Aldrich syndrome (WAS). Because the clinical and immunologic picture of WAS is variable, particularly early in life, definite diagnosis cannot always be made in cases with a negative family hisotry. Two unrelated males with sporadic congenital thrombocy- topenia had only questionable immunologic abnormalities as infants, making them clinically indistinguishable from cases of isolated thrombocytopenia, although one devel- oped episodic neutropenia and the other began to manifest a multisystem autoimmune disease at 2 years of age. Evaluation of X chromosome inactivation in the T cells of ISKOTT-ALDRICH syndrome (WAS) is an X- W linked disease of unknown pathogenesis character- ized by developmental defects of platelet, lymphocyte, and possibly other bone marrow-derived cell lineages.'-' Boys with typical WAS present in infancy with bleeding and a history of similarly affected male maternal relatives. They subsequently manifest immunodeficiency with development of eczema, recurrent infections, and, in 10% to 20% of cases, lymphoreticular malignancy.' However, as with all X-linked recessive genetic lethal diseases, over one third of cases of WAS are expected to be the first manifestation of a new mutation.6 In the absence of a positive family history WAS must be distinguished from other causes of thrombocytope- nia, including maternally derived or autologous anti-platelet antib~dies,~.' congenital cytomegalovirus9 and human immu- nodeficiency virus (HIV)," and other genetic defects. De- creased mean platelet volume," alterations in lymphocyte glycoprotein CD43 (gpL1 15),'2-'5 and morphologicabnormal- ities detected by scanning electron microscopy'6 have been reported in WAS; when present, these abnormalities can aid in diagnosis, but it is not known how they are related to the primary genetic lesion, which has been mapped to the proximal short arm of the X chromosome."^'* Recent advances in the management of WAS, including bone marrow transplantation" and carrier dete~tion,~,'*'~.'* increase the clinical relevance of early diagnosis. Therefore, it is important to clarify whether WAS and simple X-linked thrombocytopenia represent separate entities,20-22 or are variant forms of the same disease, as suggested by reports of immune dysfunction in the latter.23s24 We and others have previously studied X chromosome inactivation in female carriers of X-linked immunodeficiency diseases. In the cell lineages primarily targeted by the gene defect, the X chromosome that bears the mutation is consis- tently inactive, as opposed to the normal pattern of random X inactivation. Thus, the B cells, but not other cell types, of mothers of boys with X-linked agammaglobulinemia (XLA) have only the normal X active,25s26 while skewed X inactiva- tion is specific to T and B cells of carriers of X-linked severe combined immunodeficiency (SCID).27,28 Similarly, nonran- dom X inactivation is found in several bone marrrow derived both patients' mothers showed each of these women to have the same highly skewed X chromosome inactivation pattern seen in carriers of typical familial WAS. A T-cell defect was subsequently directly demonstrated in the second patient, whose lymphocytes failed to proliferate to periodate and anti-CD43. Taken together, these data suggest the presence of T cell immunodeficiency consis- tent with WAS in these patients. Furthermore, their mothers were found to have a very high likelihoodof being carriers, lending support to the diagnosis of a hereditary disease in these boys and making possible genetic predic- tion in other family members and subsequent pregnancies. zy 0 zyxwv 1990 zyxwv by The American Society of Hematology. cell lineages, including T cells, of obligate carriers of WAS.'-' This report describes two unrelated boys who presented with isolated sporadic thrombocytopenia. Testing maternal T cells for nonrandom X inactivation provided a means to establish the hereditary nature of the disorder in each case. Moreover, the evidence that their mothers carried a primary T-cell defect supported the concept that these boys had a form of WAS, and one of the boys was subsequently shown to have defective lymphocyte activation via CD43. Together, these findings suggest that at least some cases of X-linked thrombocytopenia represent an attenuated form of WAS. zy PATIENTS AND METHODS This term infant of Middle Eastern extraction was the first son of a woman with two daughters, eight sisters, and one brother, all in good health. At 2 weeks of age, he developed rectal bleeding and was found to have platelet counts as low as 58,00O/pL. At 3 months, although developing well, he had persistent rectal bleeding and petechiae; bone marrow examination showed normal megakaryocytes. Coombs' test, antinuclear antibodies, and rheuma- toid factor were negative, but platelet-associated antibodies were zy Patient 1. From the Department of Pediatrics, University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia, Philadelphia, PA: the Department of Medicine, University of Toronto, Ontario, Canada: the Department of Pediatrics. University of Manitoba, Winnipeg, Manitoba, Canada: the Department of Pediatrics, University of Tennessee College of Medicine and St. Jude Children's Research Hospital, Memphis, TN. Submitted October 25, 1989; accepted March 1. 1990. Supported by National Institutes of Health Physician Scientist Award No. HDO0567 to J.M.P. and Grants No. HD23679 and AI25129: March of Dimes Basic Research Grant No. 1077; and the Immune Deficiency Foundation. Address reprint requests to Jennifer M. Puck, MD. Division of Infectious Diseases, Children's Hospital of Philadelphia, I Chil- dren's Center, Philadelphia, PA 19104. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact. 6 I990 by The American Society of Hematology. 0006-4971/90/7512-0025%3.00/0 Blood, Vol 75, No 12 (June 151. 1990: pp 2369-2374 zyxwvuts 2369 Downloaded from http://ashpublications.org/blood/article-pdf/75/12/2369/602265/2369.pdf by guest on 06 March 2023