Correspondence
X-Linked Wiskott–Aldrich Syndrome in a Girl
N Engl J Med 1998; 338:1850-1851June 18, 1998
- Article
To the Editor:
Parolini and coworkers (Jan. 29 issue)1 describe an eight-year-old girl who had the Wiskott–Aldrich syndrome associated with a nonrandom pattern of inactivation of the maternally derived X chromosome. In the accompanying editorial, Puck and Willard2 provide an elegant review of the mechanisms leading to a skewed pattern of X-chromosome inactivation in females. However, the reader may be left with the impression that unbalanced X-chromosome inactivation is a congenital feature, whether or not it is familial. We believe that the most prevalent form is indeed acquired and that this point has clinical relevance.
Recent studies by various laboratories have clearly shown that skewed lyonization can be an acquired pattern. In the study of peripheral-blood leukocytes by Busque et al.,3 the incidence of skewing was 1.9 percent in neonates, 4.5 percent in women who were 28 to 32 years old, and 22.7 percent in women who were 60 years of age or older. It is essentially in neutrophils that extreme skewing increases with age, with T lymphocytes showing less evidence of unbalanced X inactivation in the elderly. It can be estimated that in 30 to 40 percent of elderly women, hematopoietic cells (erythroid cells, granulocytic cells, monocytes, and megakaryocytes) have more than 90 percent expression of one parental X chromosome.
Acquired skewing in hematopoiesis may be responsible for late-onset manifestations in female carriers of X-linked disease. Cotter et al.4 described a previously unaffected 81-year-old woman in whom microcytic sideroblastic anemia developed. She was found to be heterozygous for a point mutation of the erythroid-specific 5-aminolevulinate synthase gene (i.e., the gene involved in the pathogenesis of X-linked sideroblastic anemia). The initial diagnosis was the myelodysplastic syndrome, but the recognition of the X-linked congenital sideroblastic anemia allowed successful treatment with pyridoxine. Clinicians should be aware that acquired skewing may be responsible for late-onset X-linked disorders in women.
4 ReferencesMario Cazzola, M.D.
Gaetano Bergamaschi, M.D.
Policlinico S. Matteo, 27100 Pavia, Italy1
Parolini O ,Ressmann G ,Haas OA , et al. X-linked Wiskott-Aldrich syndrome in a girl. N Engl J Med 1998;338:291-295
Full Text | Web of Science | Medline2
Puck JM ,Willard HF . X inactivation in females with X-linked disease. N Engl J Med 1998;338:325-328
Full Text | Web of Science | Medline3
Busque L ,Mio R ,Mattioli J , et al. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood 1996;88:59-65
Web of Science | Medline4
Cotter PD ,May A ,Fitzsimons EJ , et al. Late-onset X-linked sideroblastic anemia: missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts. J Clin Invest 1995;96:2090-2096
CrossRef | Web of Science | Medline
To the Editor:
In their editorial, Puck and Willard provide a lucid diagram (their Figure 1) of three different mechanisms whereby an extremely unbalanced pattern of somatic-cell mosaicism may be produced in women after X inactivation, and they cite examples of how each of these mechanisms may operate in different clinical conditions. There is at least one possible example of each of the three mechanisms at work in different women with the same condition — namely, glucose-6-phosphate dehydrogenase (G6PD) deficiency. Indeed, the first mechanism (the extreme end of a normal distribution curve after random X inactivation) was deemed the simplest explanation for the G6PD values in the fully deficient range reported by Rinaldi et al. in about 1 percent of genetically confirmed heterozygotes for the Mediterranean variant of G6PD deficiency.1 Semiquantitative data from heterozygotes for the electrophoretic variants G6PD B and G6PD A were first used by Nance,2 in 1964, to demonstrate the bell-shaped curve shown in the inset in Figure 1A.
The second mechanism (Figure 1B) could be called “somatic selection after X inactivation.” (We prefer this term to “nonrandom X inactivation,” because, in fact, X inactivation itself is still random.) This mechanism has been well characterized3 in many heterozygous mothers of patients with G6PD-deficiency mutations associated with severe clinical expression (i.e., chronic nonspherocytic hemolytic anemia). Here, the selection affects hematopoietic cells in a way that is analogous to what happens to lymphoid cells in the immunodeficiency syndromes cited by Puck and Willard.
As for the third mechanism, there is a report of one family with segregation for the rare mutation called G6PD Ilesha.4 Every heterozygous woman in the family had an extremely unbalanced X-inactivation pattern, which could not have resulted from selection against the cells with G6PD Ilesha, because in some members of the family, the imbalance favored the X chromosome with the normal G6PD allele, whereas in other members, it favored the X chromosome with the G6PD Ilesha allele. Although, at the time, the explanation favored by one of us was selection for cells expressing a selectable allele of some other X-linked gene, perhaps there was a defect in the X-inactivation process (Figure 1C). Since the X-inactivation–specific transcript (XIST) gene maps to Xq13 and G6PD maps to Xq28, one would predict an even chance of recombination, in keeping with what was observed in the family with the G6PD Ilesha mutation.
4 ReferencesLucio Luzzatto, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021Giuseppe Martini, Ph.D.
International Institute of Genetics and Biophysics, 80125 Naples, Italy1
Rinaldi A ,Filippi G ,Siniscalco M . Variability of red cell phenotypes between and within individuals in an unbiased sample of 77 heterozygotes for G6PD deficiency in Sardinia. Am J Hum Genet 1976;28:496-505
Web of Science | Medline2
Nance WE . Genetic tests with a sex-linked marker: G-6-PD. Cold Spring Harb Symp Quant Biol 1964;29:415-425
Web of Science | Medline3
Filosa S . Giacometti N, Wangwei C, et al. Somatic-cell selection is a major determinant of the blood-cell phenotype in heterozygotes for glucose-6-phosphate dehydrogenase mutations causing severe enzyme deficiency. Am J Hum Genet 1996;59:887-895
Web of Science | Medline4
Luzzatto L ,Usanga EA ,Bienzle U ,Esan GF ,Fusuan FA . Imbalance in X-chromosome expression: evidence for a human X-linked gene affecting growth of hemopoietic cells. Science 1979;205:1418-1420
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Author/Editor Response
The authors reply:
To the Editor: Cazzola and Bergamaschi correctly refer to the known fact that acquired skewing of X-chromosome inactivation can be observed in hematopoietic cells, in particular in elderly women.1 We would like to emphasize that the clinical manifestation of the Wiskott–Aldrich syndrome in a girl due to skewed X inactivation, as we described, is clearly different from such situations. First, acquired nonrandom X-chromosome inactivation in a female is usually restricted to a single target tissue,1,2 whereas in our study, not only hematopoietic cells but also epithelial cells showed a skewed pattern of X-chromosome inactivation, strongly suggesting a congenital defect in the regulation of X-chromosome inactivation.
Secondly, acquired unbalanced X-chromosome inactivation due to chance or occurring during aging usually does not result in a completely skewed pattern. Therefore, the manifestation of X-linked disorders in women due to acquired unbalanced X-chromosome inactivation is expected only when the defective gene associated with a disease does not affect cellular proliferation or survival. The Wiskott–Aldrich syndrome is known to cause a selective disadvantage to cells carrying the genetic defect.3 Thus, one would expect that even if a small proportion of lymphocytes had the normal X as the active X, these cells would have a selective advantage over precursors with the mutant X.
The fact that in the peripheral blood of our patient there were only cells carrying the defective Wiskott–Aldrich syndrome protein (WASP) allele on the active X chromosome strongly argues for the presence of completely skewed X inactivation. For the purposes of genetic diagnosis of X-linked diseases in females and genetic counseling, it is important to know whether the genetic defect is affecting the proliferation or survival of the cells in which it is expressed and to extend the analysis of X-chromosome inactivation to more than one tissue.
3 ReferencesOrnella Parolini, Ph.D.
Walter Knapp, M.D.
Institute of Immunology, A-1235 Vienna, AustriaWolfgang Holter, M.D.
St. Anna Children's Hospital, A-1090 Vienna, Austria1
Busque L ,Mio R ,Mattioli J , et al. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood 1996;88:59-65
Web of Science | Medline2
Gale RE ,Fielding AK ,Harrison CN ,Linch DC . Acquired skewing of X-chromosome inactivation patterns in myeloid cells of the elderly suggests stochastic clonal loss with age. Br J Haematol 1997;98:512-519
CrossRef | Web of Science | Medline3
Wengler G ,Gorlin JB ,Williamson JM ,Rosen FS ,Bing DH . Nonrandom inactivation of the X chromosome in early lineage hematopoietic cells in carriers of Wiskott-Aldrich syndrome. Blood 1995;85:2471-2477
Web of Science | Medline
