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Turner syndrome as a candidate pseudoautosomal disorder
Medical Hypotheses
Turner Syndrome as a Candidate Pseudoautosomal Disorder N. J. NUSBAUM Department of Medicine, Lee Streich Flow Cytometry Laboratory, Brookdale Hospital Medical Center and Health Science Center at Brooklyn, Brooklyn, NY 71212, USA (Reprint requests to NJN)
Abstract-Turner syndrome has been clearly associated with the absence of an X chromosome, but it remains uncertain how this deletion produces either the range of defects regularly associated with the syndrome or those only occasionally seen. It is of particular interest in this regard that the pseudoautosomal portion of the X chromosome has recently been identified as the location for the GM-CSF receptor gene. It is submitted that Turner syndrome, with its hemizygosity for the psuedoautosome, may be an important model for studying the GM-CSF receptor gene as well as other associated genetic material.
Clinical
background
Turner syndrome was described first as a clinical entity, with subsequent appreciation of its relationship to monosomy for the X chromosome. The mechanism by which monosomy for chromosome X could produce the full array of findings associated with Turner syndrome has never been fully elucidated. It is noteworthy in particular that while live-born children with Turner syndrome typically do quite well, studies of spontaneously aborted pregnancies demonstrate that monosomy for chromosome X is sharply detrimental to human fetal survival (1). Interestingly, X0 fetal mice do not suffer from the fetal mortality seen in X0 humans (2). Turner syndrome has been difficult to explain given what is known of the phenomenon of lyonization (3). While a patient with Turner syndrome will be hcmizygous for any typical X-linked recessive trait, the same is true of the typical XY male. Hemizygosity in Date received 18 November 1991 Date accepted 31 March 1992
the male is of course associated with the male predisposition to hemophilia and several other disorders, but it is not associated with either the high rate of fetal wastage of X-O fetuses or the stigmata of those children born with Turner syndrome. A more plausible explanation for the relationship between monosomy X and the Turner syndrome phenotype is offered by the pseudoautosomal portion of the X chromosome. Inasmuch as this genetic material is present also on the Y chromosome, a normal XY male and a normal XX female each have two copies of this genetic information. It is only the Turner syndrome patient who is able to survive being hemizygous for the pseudoautosomal material. Pseudoautosomy
and the GM-CSF receptor
Gene dosage effect may be important in Turner syndrome. The fact that the Turner patient has only a single copy of each of the pseudoautosomal genes
156
TURNER SYNDROME AS A CANDIDATE PSEUDOAUTOSOhJAL DISORDER
may help explain the consistent features of Turner syndrome. Short stature and gonadal dysgenesis may both be related to decreased dose of a gene product or products needed for growth and development. The fact that the GM-CSF receptor has recently been located on the pseudoautosome may be relevant in this regard (4). One wonders particularly if the GM-CSF receptor has a role in stimulating the growth of skeletal and gonadal tissue as well as that of the hemopoietic tissues. Such an effect could be mediated either by receptors on the target itself and/or by indirect effects of hematopoietic cells stimulated via the GM-CSF receptor. It is certainly a plausible hypothesis that the cytokine GM-CSF may display an even broader range of target tissues in the fetus than it does in postnatal life when cells have become more fully differentiated. Indeed, it may be that those X-O fetuses which are able to survive to term despite their hemizygosity for the pseudoautosome are in some way less severely affected either on the GM-CSF receptor gene or elsewhere. Such an issue could perhaps be addressed by studying GM-CSF receptor number and/or function in the parents of Turner syndrome children and comparing them to those parents whose X-O fetuses spontaneously abort. The pseudoautosome may also be important in explaining the more inconstant components of the Turner syndrome such as coarctation of the aorta. These variable components of the prcscntation ol Turner syndrome may represent the fact that the Turner syndrome patient is not protected by a second sex chromosome from any abnormal gents which she may be carrying on her pseudoautosome. One might consider aortic coarctation for example as due to a recessive mutation of some sort on the pseudoautosome. In this case, the parental source of her X chromosome could be a silent carrier of the mutation. Fcmale offspring of any consanguineous matings in such a family could include 46XX patients who did not have the Turner syndrome phenotype but who might have a coarctation as a homozygous pseudoautosomal recessive trait. It should be noted that the interpretation of gent dosage based on number of X chromosomes may be difficult. An earlier report regarding steroid sulphatase activity suggested that the locus for this gene on the inactive X chromosome showed just under half the activity coming from an X chromosome that was active (5). One presumes that even if there arc abnormaIities of GM-CSF receptor number found in Turner syndrome patients that a patient might he able to compensate for this in a variety of fashions, perhaps by increasing GM-CSF production and/or by rc-
157
lying on the production of other cytokines to stimulate her granulocyte and macrophage production. All these hypotheses should be readily testable. Potential pleiotropic effects of a GM-CSF receptor lesion GM-CSF receptor expression may be affected by GM-CSF itself. Further, there is cross-reactivity in humans between the IL-3/IL-3 receptor and the GMCSF/GM-CSF receptor systems (6). In a given Turner patient for different tissues, and at various points in development of a given tissue, cells may differ in GM-CSF receptor number and/or in their ability to compensate (via IL-3 or other mechanisms) for any decrease in GM-CSF receptor expression. Simply arranging for GM-CSF receptor number may be misleading, particularly if a cell is expressing a nonfunctional GM-CSF receptor (7). A point of particular interest is whether GM-CSF might be important in utero for lymphatic development, since abnormalities of the lymphatics have been thought to cause some of the stigmata of Turner syndromc (8). There is dispute in the literature regarding whether the GM-CSF receptor is expressed on human umbilical vein endothelial cells (9). In general, once the role played by the GM-CSF receptor in normal fetal dcvclopment is better defined, one could better study whether that function is aberrant in Turner syndromc. It is noteworthy in this regard that, although Turner syndrome individuals tend to fall below the third percentile in height, the shape of their early childhood growth curve tends to resemble that of 46XX prepubcrtal girls (10). One plausible explanation would be that skeletal precursor cells in utero rely in part on GM-CSF for their growth and development, so that the Turner syndrome patient’s postnatal growth pattern is the expression of a prior intrauterine GM-CSF receptor dcfcct. There is indeed some clinical suggestion of a link between postnatal hematopoietic functions and Turner syndrome. The co-occurrence of X monosomy and acute lcukcmia (myelogenous or lymphocytic) has been dcscribcd anccdotally (11, 12), and an association has also been suggested between chronic inllammatory bowel disease and Turner syndrome (13). Subclinical abnormalities of lymphocytes (14) and granulocytcs (I 5) have also been dcscribcd. Neither lcukopcnia nor leukocytosis have apparently been dcscribcd as typical components of Turner syndrome (3). On the other hand, Diamond and collcagucs report in their review of congenital hypoplas-
158 tic anemia that 7 of their patients (3 malts, 4 females) had the webbed neck typical of Turner, without the chromosome findings of Turner (16). One wonders if such patients with grossly normal chromosomes but partial phenotypic Turner syndrome might have a pseudoautosomal defect too small to be appreciated on their karyotype. Conclusion Turner syndrome can be looked upon as a natural genetic experiment, displaying the effect of hemizygosity in a female. As such, it can demonstrate the importance of dose effect on the expression of normal pseudoautosomal genes, and allow one to examine the effect of any mutations in pseudoautosomal genes. This may prove a useful model for study of the GM-CSF receptor, and study of receptor number and function in hematopoietic and other tissues would be particularly instructive. Indeed, some of the various genetic defects in Turner syndrome patients may suggest as yet unidentified loci on the pseudoautosome. Acknowledgements Research supporrin hematology/oncology has been provided by the Dworetz Wolf Leukemia Foundation, the Interboro Leukemia Organization, the Lee Stretch Memorial Fund, the Louis Berkowitz Family Foundation, and the Sadie Scheer Cancer Research Fund.
References 1. Robinson A. Demography and prevalence of Turner Syndrome. In: Rosenfield R G. Grumloeb M N. Turner Syndrome. Marcel Dekker, New York, 1991. 2. Ashworth A, Rastan S. LoveU-Badge R. Kay G. X-Chromosome inactivation may explain the difference in viability of X0 humans and mice. Nature 3.51: 406--108, 1991
MEDICAL HYPOTHESES
3. Engel E. Forbes A P. Cytogenetic and clinical findings in 48 patients with congenitaLly defective or absent ovaries. Medicine, 44: 135-164, 1965. 4. Gough N M, Gearing D P, Nicola N A, Baker E. Pritchard M, CaUen D F, Sutherland G R. Localization of the human GM-CSF receptor gene to the X-Y pseudoautosomal region. Nature, 345: 134-136, 1990. 5. Lykkesfeldt G, Lykkesfeldt A E, Skakkebaek N E. Steroid sulphatase in man: a non inactivated X-locus with partial gene dosage compensation. Hum Genet 65: 355-357, 1984. 6. Rrizzi M F, Avanzi G C. Pegoraro L. Hematopoietic growth factor receptors. International Journal of Cell Cloning, 9: 274-300, 1991. I. Baldwin G C, Golde D W, Widhopf G F, Economou F, Gasson J C. Identification and characterization of a low-affinity granulocyte-macrophage colony-stimulating factor receptor on primary and cultured human melanomal xells. Blood, 78: 609-615, 1991. 8. MostcUo D J. Bofinger M K. Siddiqi T A. Spontaneous resolution of fetal cystic hygroma and hydrops in Turner Syndrome. Obstetrics and Gynecology, 73: 862-865, 1989. 9. Yong K, Cohen H. Khwaja A, Jones H M, Linch D C. Lack of effect of granulocyte-macrophage and granulocyte colonystimulating factors on cultured human endothelial cells. Blood 11: 1675-1680, 1991. 10. Tuschy U. Spontaneous growth in Turner’s Syndrome. Pediatr Grenzgeb 29: 419-423. 1990. 11. Wertelecki W. Shapiro J R. 45,X0 Turner’s Syndrome and lcukaemia. Lancet i: 789-790, 1970. 12. Pawltger I) F, Barrow M, Noyes W D. Acute leukaemia and Turner’s Syndrome. Lancet i: 1345. 1970. 13. Price W H. High incidence of chronic inflammatory bowel disease in patients with Turner’s Syndrome. Journal of Medical Genetics, 16: 263-266, 1979. 14. Cacciari E, Masi M, Fantini M P et al. Serum immunoglobulins and lymphocyte subpopulations derangement in Turner’s Syndrome. Journal of Immunogenetics 8: 337-341. 1981. 15. Lopez-Osuna M, Vega-Avila E, Salamanca F, Kretschmer R R. Defective polymorphonuclear chemotaxis in patients with Turner’s Syndrome (45.X). Clinical Genetics 34: 165-171, 1988. 16. Diamond L K, Wang W C, Alter B P. Congenital hypoplastic anemia. Advances in Pediatrics 22: 349-377, 1976.
Turner Syndrome as a Candidate Pseudoautosomal Disorder N. J. NUSBAUM Department of Medicine, Lee Streich Flow Cytometry Laboratory, Brookdale Hospital Medical Center and Health Science Center at Brooklyn, Brooklyn, NY 71212, USA (Reprint requests to NJN)
Abstract-Turner syndrome has been clearly associated with the absence of an X chromosome, but it remains uncertain how this deletion produces either the range of defects regularly associated with the syndrome or those only occasionally seen. It is of particular interest in this regard that the pseudoautosomal portion of the X chromosome has recently been identified as the location for the GM-CSF receptor gene. It is submitted that Turner syndrome, with its hemizygosity for the psuedoautosome, may be an important model for studying the GM-CSF receptor gene as well as other associated genetic material.
Clinical
background
Turner syndrome was described first as a clinical entity, with subsequent appreciation of its relationship to monosomy for the X chromosome. The mechanism by which monosomy for chromosome X could produce the full array of findings associated with Turner syndrome has never been fully elucidated. It is noteworthy in particular that while live-born children with Turner syndrome typically do quite well, studies of spontaneously aborted pregnancies demonstrate that monosomy for chromosome X is sharply detrimental to human fetal survival (1). Interestingly, X0 fetal mice do not suffer from the fetal mortality seen in X0 humans (2). Turner syndrome has been difficult to explain given what is known of the phenomenon of lyonization (3). While a patient with Turner syndrome will be hcmizygous for any typical X-linked recessive trait, the same is true of the typical XY male. Hemizygosity in Date received 18 November 1991 Date accepted 31 March 1992
the male is of course associated with the male predisposition to hemophilia and several other disorders, but it is not associated with either the high rate of fetal wastage of X-O fetuses or the stigmata of those children born with Turner syndrome. A more plausible explanation for the relationship between monosomy X and the Turner syndrome phenotype is offered by the pseudoautosomal portion of the X chromosome. Inasmuch as this genetic material is present also on the Y chromosome, a normal XY male and a normal XX female each have two copies of this genetic information. It is only the Turner syndrome patient who is able to survive being hemizygous for the pseudoautosomal material. Pseudoautosomy
and the GM-CSF receptor
Gene dosage effect may be important in Turner syndrome. The fact that the Turner patient has only a single copy of each of the pseudoautosomal genes
156
TURNER SYNDROME AS A CANDIDATE PSEUDOAUTOSOhJAL DISORDER
may help explain the consistent features of Turner syndrome. Short stature and gonadal dysgenesis may both be related to decreased dose of a gene product or products needed for growth and development. The fact that the GM-CSF receptor has recently been located on the pseudoautosome may be relevant in this regard (4). One wonders particularly if the GM-CSF receptor has a role in stimulating the growth of skeletal and gonadal tissue as well as that of the hemopoietic tissues. Such an effect could be mediated either by receptors on the target itself and/or by indirect effects of hematopoietic cells stimulated via the GM-CSF receptor. It is certainly a plausible hypothesis that the cytokine GM-CSF may display an even broader range of target tissues in the fetus than it does in postnatal life when cells have become more fully differentiated. Indeed, it may be that those X-O fetuses which are able to survive to term despite their hemizygosity for the pseudoautosome are in some way less severely affected either on the GM-CSF receptor gene or elsewhere. Such an issue could perhaps be addressed by studying GM-CSF receptor number and/or function in the parents of Turner syndrome children and comparing them to those parents whose X-O fetuses spontaneously abort. The pseudoautosome may also be important in explaining the more inconstant components of the Turner syndrome such as coarctation of the aorta. These variable components of the prcscntation ol Turner syndrome may represent the fact that the Turner syndrome patient is not protected by a second sex chromosome from any abnormal gents which she may be carrying on her pseudoautosome. One might consider aortic coarctation for example as due to a recessive mutation of some sort on the pseudoautosome. In this case, the parental source of her X chromosome could be a silent carrier of the mutation. Fcmale offspring of any consanguineous matings in such a family could include 46XX patients who did not have the Turner syndrome phenotype but who might have a coarctation as a homozygous pseudoautosomal recessive trait. It should be noted that the interpretation of gent dosage based on number of X chromosomes may be difficult. An earlier report regarding steroid sulphatase activity suggested that the locus for this gene on the inactive X chromosome showed just under half the activity coming from an X chromosome that was active (5). One presumes that even if there arc abnormaIities of GM-CSF receptor number found in Turner syndrome patients that a patient might he able to compensate for this in a variety of fashions, perhaps by increasing GM-CSF production and/or by rc-
157
lying on the production of other cytokines to stimulate her granulocyte and macrophage production. All these hypotheses should be readily testable. Potential pleiotropic effects of a GM-CSF receptor lesion GM-CSF receptor expression may be affected by GM-CSF itself. Further, there is cross-reactivity in humans between the IL-3/IL-3 receptor and the GMCSF/GM-CSF receptor systems (6). In a given Turner patient for different tissues, and at various points in development of a given tissue, cells may differ in GM-CSF receptor number and/or in their ability to compensate (via IL-3 or other mechanisms) for any decrease in GM-CSF receptor expression. Simply arranging for GM-CSF receptor number may be misleading, particularly if a cell is expressing a nonfunctional GM-CSF receptor (7). A point of particular interest is whether GM-CSF might be important in utero for lymphatic development, since abnormalities of the lymphatics have been thought to cause some of the stigmata of Turner syndromc (8). There is dispute in the literature regarding whether the GM-CSF receptor is expressed on human umbilical vein endothelial cells (9). In general, once the role played by the GM-CSF receptor in normal fetal dcvclopment is better defined, one could better study whether that function is aberrant in Turner syndromc. It is noteworthy in this regard that, although Turner syndrome individuals tend to fall below the third percentile in height, the shape of their early childhood growth curve tends to resemble that of 46XX prepubcrtal girls (10). One plausible explanation would be that skeletal precursor cells in utero rely in part on GM-CSF for their growth and development, so that the Turner syndrome patient’s postnatal growth pattern is the expression of a prior intrauterine GM-CSF receptor dcfcct. There is indeed some clinical suggestion of a link between postnatal hematopoietic functions and Turner syndrome. The co-occurrence of X monosomy and acute lcukcmia (myelogenous or lymphocytic) has been dcscribcd anccdotally (11, 12), and an association has also been suggested between chronic inllammatory bowel disease and Turner syndrome (13). Subclinical abnormalities of lymphocytes (14) and granulocytcs (I 5) have also been dcscribcd. Neither lcukopcnia nor leukocytosis have apparently been dcscribcd as typical components of Turner syndrome (3). On the other hand, Diamond and collcagucs report in their review of congenital hypoplas-
158 tic anemia that 7 of their patients (3 malts, 4 females) had the webbed neck typical of Turner, without the chromosome findings of Turner (16). One wonders if such patients with grossly normal chromosomes but partial phenotypic Turner syndrome might have a pseudoautosomal defect too small to be appreciated on their karyotype. Conclusion Turner syndrome can be looked upon as a natural genetic experiment, displaying the effect of hemizygosity in a female. As such, it can demonstrate the importance of dose effect on the expression of normal pseudoautosomal genes, and allow one to examine the effect of any mutations in pseudoautosomal genes. This may prove a useful model for study of the GM-CSF receptor, and study of receptor number and function in hematopoietic and other tissues would be particularly instructive. Indeed, some of the various genetic defects in Turner syndrome patients may suggest as yet unidentified loci on the pseudoautosome. Acknowledgements Research supporrin hematology/oncology has been provided by the Dworetz Wolf Leukemia Foundation, the Interboro Leukemia Organization, the Lee Stretch Memorial Fund, the Louis Berkowitz Family Foundation, and the Sadie Scheer Cancer Research Fund.
References 1. Robinson A. Demography and prevalence of Turner Syndrome. In: Rosenfield R G. Grumloeb M N. Turner Syndrome. Marcel Dekker, New York, 1991. 2. Ashworth A, Rastan S. LoveU-Badge R. Kay G. X-Chromosome inactivation may explain the difference in viability of X0 humans and mice. Nature 3.51: 406--108, 1991
MEDICAL HYPOTHESES
3. Engel E. Forbes A P. Cytogenetic and clinical findings in 48 patients with congenitaLly defective or absent ovaries. Medicine, 44: 135-164, 1965. 4. Gough N M, Gearing D P, Nicola N A, Baker E. Pritchard M, CaUen D F, Sutherland G R. Localization of the human GM-CSF receptor gene to the X-Y pseudoautosomal region. Nature, 345: 134-136, 1990. 5. Lykkesfeldt G, Lykkesfeldt A E, Skakkebaek N E. Steroid sulphatase in man: a non inactivated X-locus with partial gene dosage compensation. Hum Genet 65: 355-357, 1984. 6. Rrizzi M F, Avanzi G C. Pegoraro L. Hematopoietic growth factor receptors. International Journal of Cell Cloning, 9: 274-300, 1991. I. Baldwin G C, Golde D W, Widhopf G F, Economou F, Gasson J C. Identification and characterization of a low-affinity granulocyte-macrophage colony-stimulating factor receptor on primary and cultured human melanomal xells. Blood, 78: 609-615, 1991. 8. MostcUo D J. Bofinger M K. Siddiqi T A. Spontaneous resolution of fetal cystic hygroma and hydrops in Turner Syndrome. Obstetrics and Gynecology, 73: 862-865, 1989. 9. Yong K, Cohen H. Khwaja A, Jones H M, Linch D C. Lack of effect of granulocyte-macrophage and granulocyte colonystimulating factors on cultured human endothelial cells. Blood 11: 1675-1680, 1991. 10. Tuschy U. Spontaneous growth in Turner’s Syndrome. Pediatr Grenzgeb 29: 419-423. 1990. 11. Wertelecki W. Shapiro J R. 45,X0 Turner’s Syndrome and lcukaemia. Lancet i: 789-790, 1970. 12. Pawltger I) F, Barrow M, Noyes W D. Acute leukaemia and Turner’s Syndrome. Lancet i: 1345. 1970. 13. Price W H. High incidence of chronic inflammatory bowel disease in patients with Turner’s Syndrome. Journal of Medical Genetics, 16: 263-266, 1979. 14. Cacciari E, Masi M, Fantini M P et al. Serum immunoglobulins and lymphocyte subpopulations derangement in Turner’s Syndrome. Journal of Immunogenetics 8: 337-341. 1981. 15. Lopez-Osuna M, Vega-Avila E, Salamanca F, Kretschmer R R. Defective polymorphonuclear chemotaxis in patients with Turner’s Syndrome (45.X). Clinical Genetics 34: 165-171, 1988. 16. Diamond L K, Wang W C, Alter B P. Congenital hypoplastic anemia. Advances in Pediatrics 22: 349-377, 1976.