Reply to Kosaki et al.

To the Editor:The letter from Kosaki et al. (2001xFemale patient showing hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID). Kosaki, K, Shimasaki, N, Fukushima, H, Hara, M, Ogata, T, and Matsuo, N. Am J Hum Genet. 2001; 69: 664–665Abstract | Full Text | Full Text PDF | PubMed | Scopus (26)See all References2001 [in this issue]) reports the first instance of immunodeficiency in a female heterozygous for a hypomorphic mutation of the X-linked NEMO gene. NEMO hypomorphic mutations result, in males, in the disorder hypohidrotic ectodermal dysplasia with immunodeficiency (HED-ID) (Zonana et al. 2000xA novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Zonana, J, Elder, ME, Schneider, LC, Orlow, SJ, Moss, C, Golabi, M, Shapira, SK, Farndon, PA, Wara, DW, Emmal, SA, and Ferguson, BM. Am J Hum Genet. 2000; 67: 1555–1562Abstract | Full Text | Full Text PDF | PubMed | Scopus (326)See all References2000; Aradhya et al. 2001xAtypical forms of incontinentia pigmenti in male individuals result from mutations of a cytosine tract in exon 10 of NEMO (IKK-γ). Aradhya, S, Courtois, G, Rajkovic, A, Lewis, R, Levy, M, Israel, A, and Nelson, D. Am J Hum Genet. 2001; 68: 765–771Abstract | Full Text | Full Text PDF | PubMed | Scopus (102)See all References2001; Doffinger et al. 2001xX-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-κB signaling. Doffinger, R, Smahi, A, Bessia, C, Geissmann, F, Feinberg, J, Durandy, A, Bodemer, C et al. Nat Genet. 2001; 27: 277–285Crossref | PubMed | Scopus (502)See all References2001; Jain et al. 2001xSpecific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Jain, A, Ma, CA, Liu, S, Brown, M, Cohen, J, and Strober, W. Nat Immunol. 2001; 2: 223–228Crossref | PubMed | Scopus (268)See all References2001). In the 17 families previously reported, only males have had clinical immunodeficiency. As expected, owing to Lyonization, carrier females either were normal or had defects of their teeth, skin, or hair. A single female carrier, heterozygous for the same mutation reported in the family studied by Kosaki et al., had an elevated immunoglobulin A level (Zonana et al. 2000xA novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Zonana, J, Elder, ME, Schneider, LC, Orlow, SJ, Moss, C, Golabi, M, Shapira, SK, Farndon, PA, Wara, DW, Emmal, SA, and Ferguson, BM. Am J Hum Genet. 2000; 67: 1555–1562Abstract | Full Text | Full Text PDF | PubMed | Scopus (326)See all References2000) but did not have immunodeficiency.Null mutation of the NEMO gene generally results in prenatal lethality in hemizygous males and in incontinentia pigmenti in heterozygous females. Affected females are immunologically normal, presumably owing to preferential survival and proliferation of cells expressing the normal allele (skewed X inactivation). Female carriers with hypomorphic mutations have shown both random and skewed X inactivation, indicating that at least some of the mutations do not affect T- and B-cell survival or proliferation (Aradhya et al. 2001xAtypical forms of incontinentia pigmenti in male individuals result from mutations of a cytosine tract in exon 10 of NEMO (IKK-γ). Aradhya, S, Courtois, G, Rajkovic, A, Lewis, R, Levy, M, Israel, A, and Nelson, D. Am J Hum Genet. 2001; 68: 765–771Abstract | Full Text | Full Text PDF | PubMed | Scopus (102)See all References2001; Doffinger et al. 2001xX-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-κB signaling. Doffinger, R, Smahi, A, Bessia, C, Geissmann, F, Feinberg, J, Durandy, A, Bodemer, C et al. Nat Genet. 2001; 27: 277–285Crossref | PubMed | Scopus (502)See all References2001; Jain et al. 2001xSpecific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Jain, A, Ma, CA, Liu, S, Brown, M, Cohen, J, and Strober, W. Nat Immunol. 2001; 2: 223–228Crossref | PubMed | Scopus (268)See all References2001). Rarely, females can fully manifest X-linked recessive disorders, including other X-linked immunodeficiencies, such as Wiskott-Aldrich syndrome (Puck and Willard 1998xX inactivation in females with X-linked disease. Puck, JM and Willard, HF. N Engl J Med. 1998; 338: 325–328Crossref | PubMedSee all References1998). However, in contrast to the patient reported by Kosaki et al., cases not due to cytogenetic abnormalities demonstrate skewed X inactivation, presumably of cells expressing the mutant allele. In these instances, the mutations do not impair cell proliferation or survival but still do cause cellular dysfunction.It is difficult to reconcile Kosaki et al.'s finding of random X inactivation in the peripheral blood leukocytes with their patient’s clinical manifestations. We would expect to find skewed X inactivation in which the X chromosome expressing the mutant allele is predominant. It is possible that a functionally important subset of B or T cells (Jain et al. 2001xSpecific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Jain, A, Ma, CA, Liu, S, Brown, M, Cohen, J, and Strober, W. Nat Immunol. 2001; 2: 223–228Crossref | PubMed | Scopus (268)See all References2001) would have displayed skewed X inactivation if Kosaki et al. had sorted the leukocytes into separate populations before analysis. Another remote possibility is that, unlike the patient’s presumably heterozygous mother and sister, who had ectodermal findings but no immunodeficiency, the patient had a loss of her normal NEMO allele. The existence of a highly homologous NEMO pseudogene on the X chromosome makes it very difficult to distinguish hemizygosity from true heterozygosity.Kosaki et al.’s findings are unique, but, as in other examples, fully manifesting females with X-linked recessive disorders—such as Duchenne muscular dystrophy and hemophilia B—usually represent rare events (Puck and Willard 1998xX inactivation in females with X-linked disease. Puck, JM and Willard, HF. N Engl J Med. 1998; 338: 325–328Crossref | PubMedSee all References1998). Families should still be counseled that generally, in HED-ID, only males manifest clinically significant immunodeficiency. Further cases of immunodeficient females with HED-ID must be described before such counseling should be altered.