Saturday, December 03, 2016

What are X & Y Chromosome Variations?


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In 1956, Drs. Joe Tjio and Albert Lavan confirmed that there were 23 pairs of chromosomes in humans.  Up until that time, it had been thought that there were 48 chromosomes, but using a more sensitive technology, Tjio and Lavan were able to confirm that there were, in fact, only 46. (1)  This discovery by Tjio and Lavan is generally considered to be the beginning of modern “cytogenetics,” which is the study of chromosomes and the diseases caused by either numerical and/or structural abnormalities in them.

Because it was thought that all men had 22 pairs of autosomes plus one X and one Y sex-determining chromosomes, they were (and still are) referred to as 46,XY; and because it was thought that all women had the same 22 pairs of automsomes plus two X chromosomes, they were (and still are) referred to as 46,XX.

Three years after Tjio and Lavan’s confirmation of 46 chromosomes in humans, in 1959, a young English researcher named Patricia Jacobs and her associate described the first chromosmal abnormality in man, the extra X chomosome in an estimated 80% of the men with Klinefelter syndrome and all of the men who are 47,XXY.  Later than year, Dr. Jacobs identified the extra X in Trisomy X (47,XXX). (2)  As technology has continued to improve, scientists have been able to identify conditions involving a greater or lesser number of chromosomes, as well as to find persons who have a mixture of chromosomal number, which is referred to as “mosaicism” and in which, for example, some cells may contain 45 or 46 chromosomes, and other cells may obtain 47 or more chromosomes.

How common are variations in the number of X and/or Y chromosomes?

It is estimated that between 10% and 30% of all fertilized human eggs have either more or less than 46 chromosomes, resulting in approximately one-third of all miscarriages, and in turn the leading known cause of pregnancy loss. (3) Most people have heard about Downs syndrome, which results from an extra copy of chromosome 21, and occurs in approximately 1 out of 1000 live births, or one of several other chromosomal variations which are even less common, occurring in as few as 1 out of 10,000 births.

Ironically, although far less well known – probably because they are the least severe and have little or no dysmorphism – the most common chromosomal variations in full-term births occur on the X and/or Y chromosomes. For instance, with respect to the X chromosome, Turner syndrome refers to females who are born with only 45 chromosomes. 

Girls who are born with an extra X chromosome are referred to as Triple X or Trisomy X. Boys, who are born with an extra X  chromosome are 47,XXY and at risk for developing Klinefelter syndrome. And boys, who are born with an extra Y chromosome are referred to as 47,XYY.  In addition, there are a number of other X and/or Y conditions including up to 49 chromosomes.  These include 48,XXXX, 48XXXY, 48XXYY and 48XYYY; and although increasingly rare, also 49XXXXX, 49XXXXY, 49XXXYY, 49XXYYY and 49XYYY.

So many X’s and Y’s… Aren’t they all simply variations of Klinefelter syndrome…? 

No, they are not.  Although each of the variations in the number of X and/or Y chromosomes are obviously related to some degree, it is incorrect for example to characterize 48XXYY as being a variant of Klinefelter syndrome per se. As noted in the sections specifically discussing 47XXY and Klinefelter syndrome, 47XXY males are at a heightened risk of developing Klinefelter syndrome - which is the name attributed to a particular combination of signs and symptoms.  It has been shown that 48XXYY males are at a heightened risk of developing a different - and in many ways a more severe - set of signs and symptoms, some of which overlap with Klinefelter syndrome and others that are quite distinct and/or different. 

Accordingly, although it is true that XXYY is a variation of XXY, XYY, XXXY, XYYY and other X and Y chromosome aneuploidies, it is preferable to view 48XXYY as not being a variant of Klinefelter syndrome.  In fact, by grouping 48XXYY along with Klinefelter syndrome in much of the early literature concerning X and Y chromosome aneuploidies, medical researchers and scientists have inadvertently made it more challenging for families and individuals with XXYY to seek and receive the appropriate levels of treatment and support.

Professionals who rely on literature that does not explicitly distinguish between the signs and symptoms of Klinefelter syndrome and those signs and symptoms typically occurring with “XXYY syndrome” often contend that a patient’s complaints are not related to the extra chromosomes because such symptoms are not reported to be part of Klinefelter syndrome. As a consequence, such providers tend to refer patients for numerous additional, often unnecessary, evaluations and defer commencing appropriate care. This can lead to added costs both for testing and treatment regimes that end in disappointment.

By comparison, when professionals understand that XXYY syndrome has its own distinct set of signs and symptoms – a number of which are totally discrepant from Klinefelter syndrome - this confusion can be minimized and a holistic treatment can be pursued that is targeted and appropriate to the condition.  For example, contrast the usefulness of a doctor saying: “Oh yes, that [sign or symptom] has been found to be present in boys who are 48XXYY and here is what we do about addressing it…” with the practitioner who instead says “This is not a Klinefelter syndrome thing, and therefore this patient needs to undergo additional testing and you may want to consider family therapy to deal with some of these behaviors….” 

The preferred approach recognizes that the biology of 48XXYY is constitutionally different from individuals who have Klinefelter syndrome (be they 47XXY or not), and avoids parents and providers of 48XXYY boys setting unrealistic goals and expectations, postponing more intense early intervention services on a “wait and see” basis as may be more common with 47XXY and/or 47XYY, and/or being told that harmful environmental influences such as poor parenting may be the reason for aberrant behaviors that are uncommon in boys who are 47XXY.

Where can I turn for condition-specific information and support for 48 XXYY?

Although we anticipate that a number of the features, interactive tools and materials available through AXYS’s website may also be of assistance, AXYS strongly encourages families and individuals dealing with 48XXYY, or this pre-natal diagnosis, to contact the XXYY Project, whose mission is “to build the capacity of parents and service providers to assist XXYY males in leading purposeful, productive lives.”  

Where can I turn for condition-specific information and support for other conditions involving two or more extra X and/or Y chromosomes?

We are unaware of other organizations or groups who provide support for these conditions. Accordingly, in the meantime families and individuals dealing with one of these conditions, or a pre-natal diagnosis of one of them, are welcome to use the features, interactive tools and materials available through AXYS’s website and to call us for additional information and we will endeavor to place you in touch with other families in our database who are addressing the same or the most similar condition. 

Please call AXYS’s offices at (888) 999-9428 or contact us either to get help locating resources or to let us know that you have an organization that you would like for us to consider adding to this section.


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