How Can a Female Have an X-Linked Disease?
ABSTRACT & COMMENTARY
Synopsis: A female presented with clinical and genetic features of the Wiskott-Aldrich Syndrome, which is usually transmitted as an X-linked genetic trait. Genetic studies showed that this female was heterozygous for the W-A gene but had non-random inactivation of her X chromosomes due to a second mutation.
Source: Parolini O, X-linked Wiskott-Aldrich Syndrome in a girl. N Engl J Med 1998;338:291-295.
The wiskott-aldrich (w-a) syndrome is a rare genetic disorder characterized by thrombocytopenia, eczema, and immunologic abnormalities. The disease is caused by mutations on the X chromosome that are responsible for the synthesis of the Wiskott-Aldrich protein (WASP). Female carriers of X-linked disorders usually have no clinical symptoms because random inactivation of their X chromosomes (lyonization) leads to a roughly 50/50 mixture of cells with normal or abnormal X chromosomes. In W-A Syndrome, after lyonization, there is a positive selection for hematopoietic cells that contain the normal gene, so the descendent lymphoid and hematopoietic cells are normal.
The patient described by Parolini and associates had the onset of thrombocytopenia, repeated infections, and eczema in early life. Extensive study of this girl and her parents revealed two genetic mutations that resulted in her manifesting the disease. The first was a spontaneous mutation in the X-chromosome of the father. This was a missense mutation in the WASP gene. A second mutation was detected in the mother that caused non-random inactivation of lyonization so that a majority of the hematopoietic cells carried the father's mutant WASP gene.
This report should alert clinicians to the possibility of recessive X-linked diseases in female children. The pattern of X-chromosome inactivation can be identified.
COMMENT BY MARGRETTA SEASHORE, MD, FAAP
There are a number of mechanisms that may be involved in the appearance of diseases thought to be X-linked recessive in females.1 In some instances, this is a result of mutations in autosomal chromosomes, which have the same clinical effects as a mutant gene on the X chromosome. This appears to be the basis of many cases of autosomally transmitted chronic granulomatous disease.
I have seen a few girls with clinical diseases that are thought to be transmitted as X-linked recessive disorders. One was a girl with severe Factor VIII hemophilia whose father had hemophilia and whose mother was a carrier for hemophilia. (They had met at a Family Program for hemophiliacs!) Thus, the girl was obviously homozygous for the hemophilia gene. I also know of a girl who had chronic granulomatous disease who also had XO Turner Syndrome. Her one X chromosome carried and expressed the CGD gene.
The more usual reason for females expressing X-linked recessive diseases involves non-random lyonization of X chromosomes (unequal lyonization). If a majority of the inactivated X chromosomes carry the normal as opposed to the mutant gene, a deficiency of gene product may result in clinical expression of the disease.
The family described in this report demonstrates an unusual reason for the child's disease that involved two mutations: a mutation of the WASP gene of the father's sperm cell and a separate mutation in the mother that prevented random lyonization of the X-chromosomes of the child. If this seems complicated, it is. The take-home message is that X-linked recessive diseases can rarely occur in girls. When they do, there are modern techniques of DNA analysis that can usually define the mechanism. (Dr. Seashore is Professor of Pediatrics and Human Genetics, Yale University School of Medicine.)
Reference
1. Puck J, Willard HF. X inactivation in females with X-linked disease. N Engl J Med 1988;338:325-328.
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