Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Original Question:

 My Karyotype is 45,XY,rob(14,22) (q10,q10). My wife's is normal.

We have been married for 2 years, two times of miscarriage (at the 7th week and 4th week).Please advise us what the reproductive risk to have a normal child is.

  I’ve heard that translocation relating to chromosome 22 will impact to blood cancer – is that correct?

Answer:

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Original Question:

Answer:

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Original Question:

  4 biopsied blastocysts from two different IVF rounds revealed:

Answer:

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Answer:

Translocation t(17;22)(p11.2;q11.2).

Alternative segregation 2:2 may produce two types of unbalanced gametes:

1) der(17)t(17;22)(p11.2;q11.2) - deletion 17p11.2pter in association with excess 22q11.2qter. Such variant is almost incompatible with survival past 12 weeks.

2) der(22)t(17;22)(p11.2q11.2) - deletion 22q11.2qter in association with excess  17p11.2pter. Such embryo may survive until 12 weeks with a probability of 10-15%, but most likely could not survive till birth.

However when a translocation involves small acrocentric chromosomes we can expect 3:1 segregation. Such gamete will have an additional chromosome consisting of a piece of 22 (22pter-cen-q11.2) and a piece of 17 (p11.2pter). The embryo having such an imbalance will survive until birth. 

The total probability of an unbalanced fetus in the female carrier of such a translocation at 12 weeks is ~ 8-10%. In my opinion prenatal diagnosis is recommended.

There are a number of atypical features in your daughter. While terminal Xq deletions do cause skewed X inactivation, they are not to my knowledge associated with GH deficiency, hypoglycemia, or immunodeficiency. Skewing in and of itself is not that rare - a few percent of normal females have it - and is not usually clinically significant. However, your daughter could well have one or more defective genes on the normal, inactive X chromosome. If her father is normal, then the prediction would be that the X with the defective gene comes from the mother, who would be protected by her second X chromosome and random inactivation. If Dad carried the defective gene, he should have the same immunodeficiency. So an easy test would be to determine the parent of origin of the normal and deleted X chromosomes. This could be done by combined Chromosome Microarray and SNP analysis, offered by Baylor College of Medicine and other clinical genetic testing labs.

It is just becoming possible to look at all the genes on the X chromosome clinically. However, it is not yet routine, does not have perfect accuracy, and is expensive. If you want to pursue this I would recommend contacting a researcher interested in X-linked immunodeficiency, for example Jennifer Puck. She will probably want more documentation of the clinical nature of the immunodeficiency before embarking on laborious studies.

Sincerely,

Andrew R. Zinn, M.D., Ph.D.
Professor of Internal Medicine
University of Texas Southwestern Medical School

The condition Multiple Endocrine Neoplasia (MEN) is known to be caused by a gene mutation on chromosome 11. There are literally thousands of genes on chromosome 11, and the gene that causes MEN is just one of them. Without more information, Im afraid this is all I can add.

Amy Curry
Certified Genetic Counselor

The reason why you are having trouble finding information about a deletion of chromosome 13p is that, this chromosome change, by itself, would be unlikely to contribute to problems in a child. Certain chromosomes have very short "p" arms (the short ends of the chromosome as it is lined up in a picture) that consist of repetitive sequences of DNA. Chromosome 13 is one of these kinds of chromosomes. That is why someone can have a rearrangement of, say, chromosomes 13 and 14 in which the short arms of both the 13 and the 14 have been "lost" and the long arms of both chromosomes fuse and make a single large chromosome. This kind of chromosome rearrangement is called a 13;14 Robertsonian translocation. It is our current belief that individuals with a balanced form of this translocation, in the absence of other abnormalities, do not tend to have medical problems but do have an increased chance of having children who inherit an unbalanced chromosome combination.

There are other studies that the laboratory that studied your child's chromosomes can do that may help to clarify these results. Perhaps these have already been done. One is to study both parents' chromosomes. It may be that this unusual looking chromosome 13 is present in one of you and, therefore, is unlikely to be the cause of any problems in your child if both of you are healthy.

Another approach is to use a technique called FISH (fluorescence in situ
hybridization) in which a specific region of the DNA is examined by the use of "DNA probes". This allows specific areas of the chromosome to be studied in greater detail. There are DNA probes available for all of the ends of the chromosomes (telomeres). This is referred to as a telomere analysis.

When a cytogenetic laboratory performs a chromosome study they typically issue a karyotype report. On that report, there should be some interpretation of what the lab director actually saw when the study was done. A certified medical geneticist/genetic counselor can help families understand this kind of information and give you their impression about whether or not the chromosome change is causing a problem or if it is just a variation in chromosome structure.


Related Note:

It is, of course, impossible to interpret this kind of information without knowing the actual karyotype (e.g. 46,XX, etc.) and what other studies may or may not have been done. In my mind, the best solution is for the parents to get a copy of the karyotype report and consult with someone trained to explain it in person.

Myra Roche, Certified Genetic Counselor

In the literature there are reports of about ~225 persons with deletion 15q13.3 [including 9 who had deletions on both chromosomes 15]. Not a single one of these patients also had ectodermal dysplasia. To the best of my knowledge, this area does not contain genes responsible for ectodermal dysplasia. Most likely, both these conditions are unrelated.

Iosif Lurie, M.D.
Medical Geneticist
CDO Medical Advisor

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Answer:

The triple screen is a screening test done during pregnancy that measures three different substances in a pregnant woman's blood, including alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), and unconjugated estriol (uE3). These substances are made either by a developing baby or the placenta and circulate in a woman's blood during pregnancy. The amount of these substances changes throughout pregnancy, and therefore, accurate dating of a pregnancy is very important for reliable interpretation of the test results. 

The triple screen is a screening test for two chromosome problems (Down syndrome and trisomy 18) and open birth defects. Approximately 60% of cases of Down syndrome and trisomy 18 can be detected by a triple screen. In addition, the AFP value alone is used to screen for open birth defects, such as spina bifida. Approximately 85% of babies with spina bifida can be identified in this way. Since the triple screen is a screen and not a diagnostic test, a result indicating an increased risk for a chromosome problem or open birth defect does not mean that a problem exists, but rather that the pregnancy is placed into a higher risk group. It is also important to remember that a result indicating no increased risk does not mean with certainty that a baby is unaffected with one of these conditions. Consequently, further diagnostic testing such as amniocentesis is offered following a triple screen result that indicates an increased risk for one of these conditions. 

Specifically for your situation, it sounds like there may be an increased risk for trisomy 18. Trisomy 18 is an event that occurs by chance and there is nothing done to cause it or anything that can be done to prevent it. Typically, ultrasound abnormalties would be present, however, ultrasound is only a screening test like the triple screen is, and cannot be considered diagnostic. The amniocentesis, however, will give a definite yes or no answer as to whether the baby has trisomy 18 or any other numerical or structural chromosome abnormality. 

Amy Curry CDO Medical Advisor 
Certified Genetic Counselor 

It sounds like your friend had a blood test called AFP-3 (triple screen) or AFP-4 (quadruple screen). Some doctors use the triple, some use the quad; they are essentially the same test with about the same degree of accuracy. This blood test is a screening test. That means that it DOES NOT diagnose anything; rather, it gives a risk estimate. This blood test will give a risk figure for basically 3 kinds of birth defects: open spine defects, Down Syndrome and a rare chromosome disorder called Trisomy 18. The test is only accurate if the laboratory has the correct information regarding the due date. For instance, if your friend was more than 2 or 3 weeks off in her due date, then the test would be inaccurately read. However, if the test is analyzed correctly, it will provide an estimate of the likelihood that the baby would have one of these conditions. It sounds like her test came back with an increased risk for Trisomy 18. Trisomy 18 means that there are three number 18 chromosomes instead of just two. All our chromosomes come in pairs and are numbered. There are 23 pairs of chromosomes or 46 chromosomes total. If a baby had three of #18, there would be a total of 47. However, Trisomy 18 is quite rare. Most fetuses will have visible abnormalities that can be seen with a good ultrasound. If the ultrasound is normal, then most likely the baby does not have Trisomy 18. In general, the chance that the baby would actually have Trisomy 18 when the blood test is abnormal is about 1 chance in 100, or 1%. The chance for a normal baby would then be 99%. I would have to look at her actual test result to be more specific, but that is what it sounds like from your description. Amniocentesis is the only way to actually count the chromosomes and be sure. The doctor advised her appropriately. She should be reassured that the risk is fairly low of a real problem, especially since the scan looked normal. All of this information should have been completely explained in the genetic counseling before the amniocentesis. There are also numerous pamphlets and brochures about all of this. You can look at one from a lab I often use at the following website: http://www.genzymegenetics.com/clinicalinfo/afp3.htm 

I hope this provides your friend with some reassurance. I am certain this has been very distressing, but in most cases everything is fine. 

Donna Wallerstein 
Certified Genetic Counselor 
CDO Medical Advisor

Cantu syndrome is a very rare condition that involves, among other problems, growth and developmental delay and overgrowth of hair. It is presumed to be caused by an abnormality in a gene, but I do not believe the gene has been identified.

I found one report about a boy thought to have Cantu syndrome who was found to have a deletion at 1p36. I don't think this means that the two conditions are one and the same. Other patients with Cantu syndrome do not have the deletion. It may be a case of mis-diagnosis, or perhaps some cases of Cantu syndrome are caused by the deletion, and some are not. It is not clear at this time.

There is a good summary of 1p36 deletion (although it is quite technical) at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607872

Karen Heller
Certified Genetic Counselor
CDO Medical Advisor

Patients/families are encouraged to contact Dr. Lisa Shaffer's Laboratory Manager, Caron, at glotzbach@wsu.edu

We always begin discussions of such questions with a review of the
notion that evry child with chromosomal deltion syndrome is unique. The
breakpoints are different and there is great variability. We can never
draw iron clad conclusions from the literature.

Having said that, there are some commonalities that are reported. Many
individuals have a small head circumference. There often is a small
chin called micrognathia. Some have had cleft of the palate. Some have
had heart defects. Developmental disabilities are common in children
with this chromosomal variation. Low muscle tone (hypotonia) is also
seen. Within this is a great spectrum. Overall functioning and outcome
is difficult to predict. Only through ongoing developmental assessment
can anyone try to make predictions about the future. Clearly, careful
medical evaluation and developmental services are appropriate for your
child's care.

Dr. Robert Wallerstein
Medical Geneticist

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Answer:

PCR - polymerase chain reaction – is a method allowing the multiplication of a tested area of DNA.  Relative quantitative means that the results of the tested sample are compared with a standard (usually a healthy person). This method is primarily used in cancer cytogenetics when an investigator wants to determine the percentage of leukemic cells in a patient's blood or to see how production of the tested gene has changed in the process of treatment. In constitutional cytogenetics it may be used to confirm results of microarray.

From a clinical point of view, I would like to know the position of breakpoints of this duplication. In the literature, there are articles describing two families where dup 1q21.3 was associated with epilepsy, but in the first family (Muhle et al.) the duplication was from 152.646 to 152.838 MBA, and in another Saudi family (Nasser et al.) from 150.814 till 150.873.  There are also three sporadic cases of dup 1q21.3 associated with multiple malformations (no other details) - 1, tetralogy of Fallot - 1 andosterior ureteral valves - 1. I do not know why this patient was tested, but if the duplication overlaps with duplication in Muhle family or in Nasser family it may be considered as a risk factor for epilepsy.

If a parent has one child affected by Downs Syndrome - is there an increased risk of having a second child affected by this same disorder?

Answered by: Donna F. Wallerstein, MS
Certified Genetic Counselor

Straightforward Down Syndrome (Trisomy 21), in which there are three #21 chromosomes that are separate and distinct from each other, is not inherited.  It is an accident of nature and recurrence risk is generally quoted as 1% plus the mothers age-related risk.  For example, a 35 year old mother who already had a child with Down Syndrome would have a 1% plus 1 in 400 or 1.25% recurrence risk.  Families who have had one child with a chromosome abnormality are offered prenatal diagnosis (such as amniocentesis) in subsequent pregnancies because of this recurrence risk.

Some families have a translocation in which one #21 chromosome is attached to another chromosome.  In this situation, a parent with a balanced translocation (no genetic material missing or extra) is at increased risk to have a child with Down Syndrome.  Recurrence risk would depend on the exact translocation and whether it was the mother or father who was the carrier. 

There have been exceedingly rare reports of families who have recurrence of straightforward trisomies, although it is not usually the same one.  I personally have had several patients who have miscarried more that one trisomic fetus, but not the same chromosome was involved in each case.  It is theorized that some individuals are at increased risk for recurrent trisomy due to some mechanical error in cell division when the egg or sperm are formed.  This has not been proven or well studied.

If a parent has one child affected by Downs Syndrome - is there an increased risk of having a second child affected by this same disorder?

Answered by: Donna F. Wallerstein, MS
Certified Genetic Counselor

Straightforward Down Syndrome (Trisomy 21), in which there are three #21 chromosomes that are separate and distinct from each other, is not inherited.  It is an accident of nature and recurrence risk is generally quoted as 1% plus the mother's age-related risk.  For example, a 35 year old mother who already had a child with Down Syndrome would have a 1% plus 1 in 400 or 1.25% recurrence risk.  Families who have had one child with a chromosome abnormality are offered prenatal diagnosis (such as amniocentesis) in subsequent pregnancies because of this recurrence risk.

Some families have a translocation in which one #21 chromosome is attached to another chromosome.  In this situation, a parent with a balanced translocation (no genetic material missing or extra) is at increased risk to have a child with Down Syndrome.  Recurrence risk would depend on the exact translocation and whether it was the mother or father who was the carrier. 

There have been exceedingly rare reports of families who have recurrence of straightforward trisomies, although it is not usually the same one.  I personally have had several patients who have miscarried more that one trisomic fetus, but not the same chromosome was involved in each case.  It is theorized that some individuals are at increased risk for recurrent trisomy due to some mechanical error in cell division when the egg or sperm are formed.  This has not been proven or well studied.

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Answer:

Velocardiofacial syndrome and DiGeorge syndrome are synonyms. DiGeorge Syndrome is typically used when a patient has a heart defect and immunological problems, but it is arbitrary.  There is a more rare "distal" 22q11.2 deletion, when patients have deletions in the area between 22 and 23.5 Mb.

It is hard to predict what medical challenges may be in the future for children with chromosome changes. Every child grows and develops differently whether they have a chromosome change or not. We know that children with chromosome changes will most likely be delayed in their milestones and need special medical attention. In addition, it is difficult to know how your child will progress as her chromosome change has not been seen in other many other children. It is important to follow the development of your child closely and let her show us what she can and cannot do. When there is not much information in the medical literature, we need to take a systems approach and evaluate a child system by system to assess their status and then move forward. As we have said before, each child with a chromosome variation is unique on a molecular level and also clinically so it is very important to individualize.
Robert Wallerstein MD
Medical Geneticist

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Answer:

The most likely forms of unbalance, caused by t(2;12)(q21.1;q15) are der(2)t(2;12)(q21.1;q15) [deletion of the segment 2q21.1qter (~112 Mb) and excess for the segment 12q15qter (~60 Mb)] or der(12)(t(2;12)(q21.1;q15) [deletion for 12q15qter + excess for the segment 2q21.1qter]. In both cases the unbalance is too big to be compatible with life and any embryos with these types of unbalances will die in utero.

Even if we assume a segregation of 3:1 we can expect excess 12pter-q15 (~72 Mb) with excess 2q21.1qter (~112 Mb) or excess 2pter-q21.1 (~130 Mb) with excess 12q15qter. These variants are also 100% lethal.

A segregation of 1:3 will produce even more severe damage.

Therefore, all the possible variants of unbalance due to this translocation are incompatible with life, and if a pregnancy progresses until 12 weeks it means that the fetus has either a normal karyotype or is a balanced carrier.

1. The male who has a balanced Robertsonian translocation 45,XY,der(13;13)(q10;q10) may form only 2 types of sperm cells: sperm cells with two chromosomes 13 and sperm cells without chromosome 13. If the normal egg-cell will be fertilized by a sperm with 2 chromosome 13 it will cause trisomy 13 in an embryo (which may result in a miscarriage or in a baby with Patau syndrome). If the normal egg-cell will be fertilized by a sperm without chromosome 13 an embryo will have monosomy 13 (this pregnancy will result in embryonic death at very early stages, most likely even before pregnancy will be recognized). Therefore theoretically male with such translocation has no ways being a father of a normal baby. I do not think that a traditional assisted reproduction can help. Assisted reproduction for males having translocations allows to select normal sperm cells for fertilization. But if the person does not have normal sperm cells, there is no opportunity to do it.

The homologous t(13;13) are very rare. In my practice I had only one family who came to us after a birth of a child with Patau's syndrome. After diagnosing t(13;13) we told them about 100% risk. They did not trust us, continued to try and eventually had two more babies with Patau's syndrome.

Theoretically, there is one way of "rescue". If a sperm with 2 chromosomes 13 will fertilize an egg-cell without chromosome 13 (or if a sperm without chromosome 13 will fertilize an egg-cell with 2 chromosomes 13) the chromosomal complement of the fetus will be normal. I doubt, however, that it can be done artificially. Try to contact Reproductive Genetics Institute in Chicago: sometimes these guys are successful in previously unimaginable situations. Most likely their answer will be negative, but who knows...

2. The homologous Robertsonian translocations cannot be inherited. Your siblings cannot carry this translocation.

3. The general health prognosis for the carrier of t(13;13) is the same as for any other person: there is no specific risk associated with this condition.

Iosif Lurie, M.D., Ph.D.
CDO genetic consultant

The literature emphasizes mostly fertility issues. Symptoms include small testes, gynecomastia (breast enlargement) and sterility, similar to 47,XXY Klinefelter syndrome, but without the tall stature usually seen in that condition. As with all chromosomal conditions, the phenotype varies. Sometimes there is ambiguous genitalia or mild penis abnormalities, and high resolution ultrasound is helpful. Andrew Zinn MD Medical Geneticist

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Answer:

The formula dup(8)(q24.1q24.3) shows that (most likely) it was a "standard" cytogenetic examination. We do not know the exact breakpoints and the size of the duplicated segment, but it is obvious that at least 20-25 Mb of DNA are duplicated.

Isolated duplications of 8q24 are very rare. After removing all cases with associated imbalances, all cases with mosaicism and all cases with small (less than 2 Mb) duplications I could find only a dozen reports which may be relevant to the issue (the list is below).

There is no syndrome associated with duplications 8q24.1q24.3, but all patients with large duplications in this area had multiple defects, including ACC (agenesis of the corpus callosum), ASD (atrial septal defect), DH (diaphragmatic hernia), CLP (cleft lip and palate), CP (cleft palate) and many others. All children showed a delay in psychomotor development. Most of these cases were reported not in special articles, but in abstracts of different meetings or were mentioned in the large group of abnormal results upon examination of some special group of patients. 

In any case it is necessary to perform a cytogenetic examination of both parents to exclude a balanced translocation or inversion in one of them.

Isolated Duplications:

Approximately 50% or more of miscarriages are due to chromosomal abnormalities, and the main chromosomal abnormality that causes miscarriages is trisomy. Trisomy 7 is common in first trimester miscarriages. This is something that just occurred randomly by chance; either the egg or sperm that made this pregnancy was made with an extra chromosome 7, and when conception occurred, there were three number 7 chromosomes instead of the normal two. There has only been one report of trisomy 7 in the literature, and this may not have even been a "true" result. (Sometimes trisomy 7 can arise in a cell culture when the cells are growing so that they can be
analyzed, and not really be present in all the cells of the fetus).

Once a couple has had two unexplained miscarriages, chromosomes on the parents can be drawn in order to see if one of them carries a balanced chromosome rearrangement that does not cause them any health problems, but can predispose them to having pregnancies with unbalanced chromosomes. Since we know the cause of your most recent miscarriage to be a trisomy, this would not be recommended unless you had another miscarriage.

Amy Curry Certified Genetic Counselor

The "+7" refers to an extra chromosome number 7 in all of the cells of the fetus. Normally we have two copies of each of our chromosomes, and this means that the fetus had three copies of chromosome 7, which can also be called "trisomy 7". This is incompatible with life because it is too much genetic information, and this is why a miscarriage occurred. Unfortunately, of all recognized pregnancies, about 10-15% or more end in miscarriage, mostly in the first trimester. As you know, fetal tissue can be analyzed to see if there is a chromosome abnormality. Around 50% of these fetuses will have a chromosome abnormality; it is very common. Of all chromosomal abnormalities in miscarriages, trisomies (what happened in your pregnancy) are the most common. The vast majority of chromosomally abnormal miscarriages occur to chromosomally normal parents, and the chromosome abnormality happened as a sporadic event in the making of the sperm or egg.

Amy Curry, Certified Genetic Counselor
CDO Medical Advisor

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Answer:

It means that the heterochromatic segments on the long arm of chromosome 9 are unusually long. It is a normal variant and does not have any significance. 25-30 years ago this variant was considered a reason (or a risk factor) for recurrent miscarriages.

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

"Standard" cytogenetic examination (when chromosomes are analyzed under microscope) cannot detect all small rearrangements. That is why if a "standard" examination shows some unusual abnormal results, more precise molecular techniques should be applied.  If my understanding of your report is correct, it was found that your daughter-in-law has a translocation of part of chromosome 20 onto another chromosome and there is no loss or gain of chromosomal material.  However (if neither your son nor his wife are the carriers of a balanced translocation), the presence of two translocations (at least four breakpoints) in the fetus is highly unusual and a detailed ultrasound monitoring of the fetus is necessary.

Your specific question is whether or not anencephaly is related to Trisomy 18. The answer is that it is impossible to be certain, but anencephaly is only very rarely seen in association with Trisomy 18 and may certainly be coincidental. In addition, there is no information in your email to suggest that the fetus with anencephaly had Trisomy 18 or any of its associated features (such as clenched hands with overlapping fingers, cardiac defects, etc). Given this scenario, the most likely explanation would be that the two conditions were unrelated, but it would not be possible to rule out entirely a very unusual recurrence of Trisomy 18, with the first case having anencephaly. But there is no basis on which to draw that conclusion.

It is true that supplementation with high doses of folic acid (to be determined by a physician) are recommended following a pregnancy with anencephaly or other neural tube closure defects, and should commence well before a subsequent pregnancy.

Thomas Morgan
Medical Advisor
Medical Geneticist

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

2) Your daughter may have another condition (e.g., mitochondrial disease) which is unrelated to her chromosome deletion. 

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

In some types of leukemias, chromosomal abnormalities occur in abnormal blood cells. It is most likely that if other tissues (for example, skin cells) are tested, your karyotype will be normal.  CLL ( Chronic lymphocytic leukemia ) are not congenital (present from birth), but occur when cells are being transformed. Cytogenetic examination of people having CLL is used to determine the prognosis of disease and possible treatments. These abnormalities do not constitute chromosomal disorders. Your oncologist or hematologist will better explain the significance of the deletion that was found in your cells.

Best of luck to you. I hope this was helpful. 

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Answer:

Autism is a disturbance of social interaction that can be associated with learning disabilities. We usuually refer to this as autistic spectrum disorder because it is just as the name implies a wide spectrum with much variability. PDD refers to pervasive developmental disorder. This is a category that is essentially (to oversimplifly) mild autism.
Now, I believe that you are correct is saying that autism has a genetic basis. This basis is very diffuse and not well understood. In the medical literature, there are many different chromosome variations reported in children with autism. In my practice, we evaluate many children with autistic spectrum disorder and find some chromosomal variation. The issue is that the variation are not consistent. We find anomalies of different chromosomes and not in all children. We believe that there are other single genes involved that are not yet characterized.
So, having said that, autism is a description of a developmental profile. This has many causes. There are many genetic syndromes assocuated with a similar profile. There are many different diagnoses of the medical condition. Autistic spectrum disorder is a descriptiono f that profile. We use that as a diagnosis to decide what services will benefit a child educationally. It is a very mixed bag. A child with autistic spectrum disorder may or may not have another diagnosis explaining the cause for the developmental disturbance. They are not mutually exclusive.
I don't think that if a child had a genetic diagnosis that a diagnosis of autisnm is less likely to be made. It is just that the chromosomal diagnosis is more specific to the at child and implies developmental issues associated with it so a given practitioner may be more likely to use that diagnosis with the child in terms of services or categorization, but autism may still be present or not as the developmental profile of the patient.
Many children with developmental delay show autistic features. This refers as mentioned above to a disturbance in their social interaction. Learning and social interaction are closely linked so variation in one often affects the other. It is probably not possible to separate the two as to which is a primary and a secondary issue. I work closely with the Institute for Child Development at my hospital and we see many children with a variety of delays and autistic features. It is a wide spectrum of traits and variation that we do not yet fully understand on a medical or genetic basis. Hopefully, there is new information all the time, but a long way to go to understand these conditions.
Donna Wallerstein, Certified Genetic Counselor
Dr. Robert Wallerstein, Medical Geneticist

The type of chromosome rearrangement that your wife has is called a balanced reciprocal translocation. Balanced reciprocal translocations are thought to occur at a rate of approximately 1 in 500 individuals in the general population. Balanced reciprocal translocations happen when breaks occur in two or more different chromosomes and the resulting chromosomal fragments swap places. No chromosomal material has been lost or gained and so the vast majority of carriers of a balanced reciprocal translocation do not have any symptoms. When a person who carries a balanced translocation has children, there is a possibility that the baby will not inherit the complete set of information. Carriers are at risk of producing offspring with part of one chromosome missing (only one copy instead of two) and part of the other chromosome extra (three copies instead of two). These translocations are called unbalanced translocations and may lead to miscarriage or the birth of children with symptoms including mental retardation and birth defects because this extra and missing chromosomal material may contain hundreds to thousands of genes important for the growth and development of a baby. It is possible that your previous miscarriages had an unbalanced
translocation.

It is important to realize that your wife's chromosomal material is all present; it is just arranged differently. Because there is no extra or missing chromosomal material, your wife should not have any health problems related to the rearrangement. When a person with a balanced translocation reproduces, there is a chance that he or she will make an egg or sperm that does not have the correct amount of genetic material. When the eggs or sperm of a person with a balanced translocation are made, the chromosome material does not necessarily divide evenly. Half of the eggs will be made with the correct amount of chromosome material (A and B below), while the other half will have an unbalanced amount (C and D below). The four possibilities for a mating between a person with a balanced translocation for example between 1 and 2 and a person with normal chromosomes are as follows:

A) Normal chromosomes
B) Balanced translocation carrier
C) Missing part of chromosome 1, extra part of chromosome 2
D) Extra part of chromosome 1, missing part of chromosome 2

Possibilities A and B above would result in an individual with the normal amount of chromosomal material, while possibilities C and D would not. For possibility C and D, because there is an abnormal amount of chromosomal material, the fetus would not develop normally and the pregnancy will often end in miscarriage. If the pregnancy did not end in miscarriage, the baby would most likely be born with physical birth defects and mental retardation.

Theoretically, it would be expected that the four possibilities listed above would occur in equal proportions, meaning that a baby with an unbalanced amount of chromosomal material would be conceived 50% of the time. However, the actual observed chance for an individual who is a balanced translocation carrier to have a baby with unbalanced chromosomal material is less than 50%. One possible reason for this is that many fetuses with unbalanced chromosomes will miscarry early in pregnancy. However, there is a good chance that you will conceive a pregnancy with the normal amount of chromosomal material.

Amy Curry
Certified Genetic Counselor

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Editor’s note: Vanishing twin syndrome was first recognized in 1945. This occurs when a twin or multiple disappears in the uterus during pregnancy as a result of a miscarriage of one twin or multiple. The fetal tissue is absorbed by the other twin, multiple, placenta or the mother. This gives the appearance of a “vanishing twin.”

Answer:

If twins have two separate placentas, live cells from twin A cannot reach twin B.  If twins share the same placenta, blood cells from the affected twin can enter the vessels from the healthy twin. Although these blood cells may live for some time they cannot change the genetic code of the healthy twin. It is like a woman who receives a blood transfusion from a male donor – she will not obtain any genetic characteristics of her donor. 

The issue of increased cancer risk in children with chromosomal variations is not clear. There are many genes associated with the process of cancer development. Cancer occurs as a loss of control of cell growth. Most cancer occurs as an acquired process. This means that a person is not born with the genetic change to create loss of cell growth control, but through time-the normal aging process, changes or mutations occur in the genetic material. We think about this as a 2 step or 2 hit process. One change happens in a cell and then it takes a second change to put the cancer into motion. If a person is born with a chromosomal variation then he or she may have the first hit already and therefore be at increased risk by virtue of the fact that it will only take one more hit to cause the cancer to begin developing. This scheme was developed in regard to retinoblastoma, a cancer affecting the eye. Anyone can bet retinoblastoma. Children with a deletion of chromosome 13 in the right region, are at increased risk for developing the tumor because they only need one more hit.

Typically, we see the increased cancer risk in certain regions with certain known genes. It is usually associated in individuals with a deletion of that region. There are tumor suppressor genes that stop tumors from developing. The loss of these genes causes a loss of tumor suppression and can give some risk to increase tumor beginnings. In people with extra chromosomal material, this increased risk is less common as typically, there is no loss of function.

In following children with chromosomal rearrangements, data is new and evolving. In years past, many children with chromosomal variations did not survive early childhood. It may not be known how chromosomal variations affect much older people. There are no good natural history studies on many chromosomal variations. These are questions waiting to be answered.

There are certain regions with a specific cancer risk. In our practice, we had one child with a chromosomal variation and a cancer. We know that there is a relationship, but the question is what to do with that information. If a specific risk is known form a site, then surveillance is appropriate. For example, if a child has a deletion of a known cancer gene, then testing for that specific cancer at periodic intervals makes sense. If there are just non-specific cancer genes in a region, it is hard to know what to do if anything about that. There is no substitute for having a good pediatrician and investigating anything in the way of symptoms that is unusual. The cancer risk conferred by chromosomal variations in general is probably small outside of a few isolated cases. That may not be such a specific answer, but that is how I think about it.

I think that it is important for parents to discuss with their genetics professionals if there is any known cancer risk associated with their chromosomal variation to see if any increased surveillance is needed. Things such as imaging studies might be suggested. For most, there really is not increased risk. Hopefully, addressing this issue with the genetics professionals will allay any fears.

Donna Wallerstein
Certified Genetic Counselor

Robert Wallerstein M.D.
Medical Geneticist

It is often very difficult to predict the effects of a chromosome deletion because some deletions are very rare. In addition, even for those rare deletions that appear to be exactly the same, there might be very subtle differences that could cause differences in the clinical effects of the deletion. While there might not be much information about this particular deletion, it is recommended that the family be referred to a genetic counselor so they can better understand the significance of the deletion.

Michael Graf
CDO Medical Advisor
Certified Genetic Counselor

Unfortunately we do not know what causes chromosomal deletions. We think that something happens during the process of formation of the egg or the sperm or during the process of fertilization, although the egg and the sperm would probably look "healthy". There is no evidence to suggest there is some sort of environmental cause such as infections or other exposures. And, when the parents' chromosomes are normal, the chance of the deletion occurring again in another child is extremely small (less than 1%). So we assume that the mechanisms in the cell for duplicating and dividing up the chromosomes is imperfect; sometimes whole chromosomes or pieces of chromosomes can "get lost". We consider this to be a random, accidental sort of thing. I apologize that this explanation is probably not very satisfactory. However, our understanding of this matter is quite limited.

Karen Heller, Certified Genetic Counselor

ADDENDUM: For the most common microdeletions, there are genomic hotspots-the architecture of the genome makes these regions more prone for deletions.

Shashikant Kulkarni Director, Clinical & Molecular Cytogenetics, Laboratory & Genomic Medicine

Cerebral palsy is just a description, sort of like saying that someone
sneezed. You don't know why they sneezed - could be allergies, pepper,
catching a cold.... - lots of reasons. Same with CP; it just describes
what the therapist is seeing, some spasticity or perhaps one side is
more hypertonic than the other. Any time a child has a chromosome
problem, any
constellation of problems is possible. We do tend to attribute every
symptom to the chromosome finding, whether it is related or not. In
general, I tend to think of CP as more a "birth accident" kind of thing
because lots of kids who lose oxygen at or near the time of birth have
CP.
Certainly kids with chromosome problems can also appear to have CP or CP
like findings because again, CP is just a descriptive phase and not a
diagnosis on its own. Hope that helps,


Donna Wallerstein, MS
Certified Genetic Counselor

1) Just because the geneticist couldn't figure it out the first time, doesn't mean s/he won't figure it out a year or so later, when your child has grown and changed a bit, or when the doctor has learned something new. So go back for a follow-up visit.

2) Consider consulting another geneticist, even if you have to travel - to find one, go to "acmg.net" and use the "find a geneticist" function. Doctors expect you to seek 2nd opinions, especially when it's a tough case.

3) Ask the geneticist to review the chromosome report: how long ago was it done and which lab performed it? Perhaps it should be repeated? Perhaps there is a "FISH" test that can be added?

4) Ask the geneticist about chromosomal micro-array testing or "CGH" - this is a newly-developed test (still somewhat controversial and not widely available) that can detect very tiny chromosomal imbalances that may not be detected by a routine chromosome analysis.

5) Have you consulted a pediatric endocrinologist (hormone doctor)? Some of the things you describe (like hirsutism and excess growth) could be related to hormonal problems.

6) I would make periodic appointments with a geneticist, but in the meantime, if no diagnosis is available, just focus on the problems at hand and deal with each of them as best you can. For example, make sure she is receiving good care for her seizures; make sure she is receiving appropriate school services; etc. Although it is preferable to know what the diagnosis is, in the end, you still have to deal with each of her problems in just the same way as you would any other child with that same problem. And even if you learned that she had a particular rare diagnosis and you found 1 or 2 other children with the same thing, I assure you, each of them would have somewhat different problems - no two children are alike. Good luck to you and your daughter!

Karen Heller
Certified Genetic Counselor

Pericentric inversion of one chromosome 9 [inv(9)(p12q13)] is considered a polymorphic variation and is one of the most common forms of autosomal inversion diagnosed prenatally and postnatally. We come across this variation quite frequently and regard this as nothing but a polymorphism. With the knowledge we have today, we can be confident that this variation is clinically benign. We continue to learn more about these and other variations and their possible effects if any. I agree with the genetic counsellor that there is no need for the parents to be tested for this variant.
Shashikant Kulkarni
Director of Clinical and Molecular Cytogenetics
CDO Medical Advisor

We have had similar situations where a chromosomal rearramgenet has been
re-evaluated later with a change of breakpoints. Clearly, if you are trying
to find a near exact match in terms of comparison cytogenetically, this is
frustrating. As you say cytogenetics is somewhat subjective. The bands on
the chromosomes are numbered and it is very systematic in how the bands are
described. However, when there is a deletion or rearrangemnt, it may be
difficult to determine the exact bands involved. For example, the same dark
band can appear to be very different when the light band nearby is deleted.

The advent of FISH as well as other molecular techniques has made excellent
adjuncts available to the cytogeneticist. These are often used to help
analyze a particular deltion to describe it more accurately. Please keep in
mind that these techniques improve the resolution, but even deletions that
are apparently the same may be different on a molecular level. The gene
mapping technique is not done on a routine clinical basis, but more for
researchers trying to understand a particular region. This is very labor
intensive even more so than routine chromosomal analysis. Genes are still
below the level of resolution of cytogenetics. One band difference implies
a difference of hundreds of genes. We know that a single gene can make a
world of difference in an individual's development. So even with the same
cytogentic karyotype, there may be differences. This a large part of the
challenge of individuals with chromosome rearranegments. There is so much
variability. We can draw commonalities, but each individual is unique.

Robert Wallerstein
Medical Geneticist

Chromosomal Microarray Analysis (CMA) is a new molecular cytogenetic test designed to detect losses or gains representing deletions or duplications for a wide array of clinically significant regions of the human genome. The test will detect the great majority of the defined microdeletion and microduplication syndromes. However, CMA will not always detect balanced translocations, inversions, low level mosaicism or genomic imbalances.

Therefore if a routine karyotyping was not performed prior to or concurrently with CMA, it is recommended. In addition, gene mutations, uniparental disomy, imprinting defects, epigenetic mutations or small genomic imbalances such as intragenic deletions or duplications will not be detected by microarray.

A chromosomal translocation such as this clearly must have occurred at a specific moment in time, during the division of a specific cell, most likely a sex-specific cell that was responsible for producing either egg cells (in the maternal ovaries) or sperm cells (in the paternal testes).

"Mosaicism" or "gonadal mosaicism" are terms that refer to the theoretical risk that some variable percentage of maternal egg cells or paternal sperm cells contain the same translocation that was observed in a child born to that couple.

Unfortunately, we are unable to tell parents what percentage of their egg or sperm cells contains the translocation, and so geneticists must provide rough estimates, ranging from less than 1% to a few percent probability of recurrence, averaged across many couples. Any particular couple may have a much higher or much lower probability, however, depending on the percentage of abnormal egg or sperm cells.

Dr. Thomas Morgan
Medical Geneticist

There are several possible outcomes for a pregnancy: 1) Totally normal chromosomes 2) Balanced translocation - just like the mother - expected to be healthy, but with possible future reproductive problems 3) Unbalanced translocation - this could involve deletion or duplication of chromosome 21, deletion or duplication of 16p (short arm), or deletion or duplication of 16q (long arm). Most of these would result in a miscarriage, but a duplication of chromosome 21 ("trisomy 21") would result in a child with Down syndrome, and duplication of 16p, I think, can result in a live-born baby with very severe abnormalities.

Figuring out the chance of each of these outcomes is very complex and would require analysis of this family's history. In almost all situations, though, if the pregnancy continues all the way to term (and does not miscarry), the chance would be very high that the chromosomes would be either 1) or 2) and the baby would be healthy.

CVS or amniocentesis could determine the baby's exact chromosome make-up during a pregnancy. If IVF is done, it may also be possible to perform PGD (pre-implantation genetic diagnosis) to select only embryos that are either 1) or 2). This would have to be discussed up front with an IVF specialist. It is quite costly, and I am not aware of any sources of funding for this.

Karen Heller
Certified Genetic Counselor
CDO Medical Advisor

It is very hard to say what the exact effects of this duplication would be because in XX individuals (females), one X chromosome undergoes inactivation. Some females are completely protected from any adverse consequences of X duplications by inactivation; others may show all of the effects associated with trisomy for a large region of one chromosome. A very general statement is that cells do not grow or perform their specialized functions as well when there is an imbalance of genetic material, and brain cells are particularly susceptible to impairement by chromosome abnormalities because their function is so complex and specialized.

Andrew Zinn, M.D.
Medical Geneticist

There is no risk for recombination in male inversion carrier as males have only one X, it does not have the opportunity to recombine to generate a duplication/deletion.

Female inversion carrier - if the baby is a boy a miscarriage could result if the inverted X recombined with the normal X because this would result in a large X chromosome deletion and duplication that is not viable.
If the baby is a girl, there is a possibly of live birth of a child with physical and/or developmental abnormalities.
Dr. Andrew Zinn
Medical Geneticist

Answer: This does occur on occasion (probably rare) and can result in the same apparent chromosome abnormality having different effects in different relatives.
Dr. Andrew Zinn
Medical Geneticist
CDO Medical Advisor

Was FISH done to characterize this deletion?

It can be “assumed with near certainty” that there is usually no concern of abnormality, if the deletion is similar (thoroughly characterized by FISH in both the fetus and the carrier parent). As always there are very very rare exceptions when “similar” looking deletions are complex and differ at molecular level. So it is impossible to be 100% confident even if the deletion is found to be familial.

Shashikant Kulkarni
Director of Clinical and Molecular Cytogenetics
Assistant Professor of Pediatrics
Genetics & Genomic Medicine

Compiled by Penny Richards, turley2@earthlink.net

INTRODUCTION:
Though they may seem a minor concern next to heart surgeries and developmental delays, teeth are so important for eating, breathing, speaking, symmetrical facial structure, etc., that it's worth at least trying to stay on top of your child's oral health. In this FAQ, you'll get the distilled advice of the CDO parents on many subject concerning dental/oral health and hygiene.

Disclaimer: The following advice is culled from parent-to-parent postings on the CDO listserv. It should not be understood as a substitute for medical or nutritional advice from trained personnel.

TOPIC GUIDE:
BASIC ORAL CARE
BABY TEETH
DIET, FEEDING, AND ORAL HEALTH
DENTISTS
DENTAL SURGERY


BASIC ORAL CARE
Q. Why does my child have such weak teeth? Is it part of the chromosome disorder?

A. It's hard to say, but it is common for kids with chromosome disorders to have dental problems. There are many factors that contribute: there may be a basic congenital weakness in the structure of the teeth (for example, an insufficient quantity of enamel to protect them)just as there are congenital structural differences in other body parts. This can be worsened by environmental factorsour kids are often exposed to more powerful medications than other children, drink from bottles longer, consume sugary supplements for the extra calories, and have problems with oral defensiveness and self-care skills that make effective brushing a challenge. If breathing or feeding are also difficult for your child, the adjustments made to accomplish those necessary tasks (breathing through the mouth, for example) may further exacerbate decay in the mouth.

Q. How do I brush my son's teeth? He's very reluctant to let us into his mouth for any reason, and is not willing or able to brush his own teeth.

A. Many parents report success using electric toothbrushes (there are many models now available). There are several benefits cited: more efficient brushing, more consistent oral stimulation, and some kids like the buzzing sound and vibration involved. Ask your dentist or therapist if this is a good option for your child. Also, some dentists will provide you with a "bite block"a firm, foam tool that is inserted between the child's front teeth to keep the reluctant mouth open as gently as possibly. (This is also a useful item when administering some medications orally.) If your child must be restrained for toothbrushing, and you don't have two adults available, try wrapping his body in a large towel (to keep his arms from interfering).


BABY TEETH
Q. Will my newborn with a chromosome disorder get her first set of teeth later, just as she's growing more slowly than a typical child?

A. Not necessarily. Some families report delays in the eruption of baby teeth; others say they came right on schedule. Same with losing the baby teethsometimes it happens around age 6, as is typical, but sometimes it's delayed by as much as a few years. In addition, you may find that the order of erupting and falling out is not typicalmaybe a side tooth will come in first, or one or more teeth seem to be missing and never erupt.
Occasionally a child will have fused teeth, or other anomalies. Dental xrays can determine the state and number of the unerupted teeth, if this is troubling you or the doctors.

Q. My kindergartner has his first loose toothbut he can't talk, and I'm worried he'll swallow it when it falls out, without telling me. Isn't this dangerous?

A. Surprisingly, it's not usually dangerous to swallow a baby tooththey're made of pretty soft material and stomach acid is very effective in dissolving the sharp edges (same goes for small coins, they say). But if your child has swallowing or digestive problems, it might be worth mentioning this question to your pediatrician and dentist. Some dentists will let you to bring the child in when a tooth is very loose, and they'll pull it quickly, to save you from worrying "when?".


DIET, FEEDING, AND ORAL HEALTH
Q. How do I balance my child's need for extra calories with her risk for cavities?

A. Discuss your concerns with doctors, nutritionists, and dentistssometimes, the experts only see "their" part of the picture. If a medical professional recommends, for example, adding chocolate syrup to a baby's bottles for extra calories, that might not be in the child's best dental interestsask directly, is this worth the cavities it might cause?
Many of our children use dietary supplements like Pediasure or Ensurethese can be very sugary. Some parents dilute the supplement with milk or baby formula to minimize the harm. Remember also that there are many ways to increase calorie intake that don't involve sugarfoods higher in fat being the most obvious. A nutritionist can help you with ideas there.

Q. My child does not take nutrition or hydration orally. Are her teeth still at risk?

A. It is common to assume that such children will have fewer dental problems, but the fact is they just have slightly different oral health issues. The teeth still exist in a warm moist environment conducive to decay, and still need regular brushing to be kept clean. The gums are still prone to swelling in response to some medicationsbe sure to check often for bleeding or puffiness.


DENTISTS
Q. How do I find a dentist for my very young and/or very medically complicated child?

A. Ask your pediatrician for a referral to a dentist willing to see special needs children and VERY young children, and while you're at it, find out whether your insurance will cover such a visit (some won't cover dental appointments for under-2s). Alternatively, you can talk to other parents of special needs kids, or ask your child's case coordinator. Some teachers and therapists (especially those who deal with oral-motor issues) may also have leads for you. And occasionally parent support groups will invite a dentist to come speakthat might be another way to find someone for your child.


DENTAL SURGERY
Q. My child's dentist wants to do a few crowns and fillingsin the hospital! Is this common?

A. It is very common (and prudent) for dentists to prefer working under general anesthesia when there are likely to be serious risks with in-office sedation techniques. If your dentist is concerned about heart or breathing being interrupted, or suspects that your child may not respond typically to nitrous oxide or chloral hydrate, they will probably feel safer doing the necessary work in a hospital with an anesthesiologist and other supports available.

Q. Is this surgery going to be a logistical nightmare?

A. Scheduling a day surgery for dental work in hospital can be a HASSLE, but if you juggle the authorizations right, you can get the OR time and anesthesia covered by your health insurance, and the dental work covered by your dental insurance (assuming you have that). You may also take this opportunity to schedule a second procedure best done under general anesthesiasome parents have arranged for blood draws and hearing tests in conjunction with dental surgeries, for example. That might make the financial bite easier to justify. (Answered from the American perspective that assumes private insurance as a normparents in countries with national health coverage have a different system to negotiate. Additionally, some families may qualify for special public or charitable funding to deal with necessary dental workthese programs vary from state to state and country to countryask your caseworker if you're wondering what your options are.)


Q. Won't she look funny with a mouth full of silvery crowns?

A. People, especially other children, may notice your child's dental work.
Like all noticeable differences, it may prompt questions from curious strangersyou'll learn to answer these in your own way, just as you probably already answer other questions about your child's visible differences. And remember, the appearance of crowns may be unusual, but it's better than the appearance of a mouth full of decay. If the crowns will be very visible, ask your dentist if they can use a material that looks more "tooth-colored."

Q. Any other tips to prepare for this surgery?

A. Be sure to discuss ALL physical differences with the dentist AND the anesthesiologist before the surgeryeven if it doesn't seem relevant to dental surgery, mention it anyway just to be safe. Be sure to discuss antibiotic prophylaxis with the dentist before hand if your child has a heart defect. Expect to discuss the worst case scenarios with the doctor and anesthesiologist right before the surgery. They will tell you that there are no guarantees; that sometimes with our kids there are complications no one could foresee; that they may call off the surgery suddenly, if the anesthesiologist can't establish an airway. In short, plan as you would for any surgery, and don't assume this is "just minor"especially the first time, you'll probably experience much the same anxiety and fear as any parent before ANY surgery on her child.


A FINAL WORD:

Don't blame yourself for a child's disappointing oral health. Your hard work can minimize her need for intervention, but it probably can't be eliminated entirely. Even typical kids get cavities, right? Do your best to follow dentists' recommendations, and don't put off checkups or surgeries.

The karyotype indicates that the Y chromosome material has replaced a small piece of the short arm of the X. Since the SRY gene was absent, the baby will definitely be a girl. She may have short stature that can be treated with growth hormone and could have some issues with ovarian function. Both of these problems are managed by a pediatric endocrinologist, and I recommend the parents seek a referral to an endocrinologist after the girl is born.

SHOX gene is most likely deleted. That's why I mentioned short stature as a possible outcome. There is a chance of the wrist problem, known as Madelung deformity. In our experience, it is uncommon and usually mild with this particular type of SHOX deletion. There is nothing to do but watch and wait - if it occurs (often around the time of puberty) and is symptomatic, surgical correction is an option. Same goes for short stature - wait and see.

Andrew Zinn, M.D.
Medical Geneticist

Sugar (i.e. diabetes) and liver issues would definitely not be a cause of the chromosome 1p36 deletion. If the question was whether the 1p36 deletion could cause sugar or liver issues, these issues are not the most common health problems described with 1p36 deletion. However, chromosome deletions have been associated with a large array of health problems and these health problems can vary from individual to individual, even with the same apparent deletion. In addition, these issues, especially sugar issues (diabetes) are very common in people without a chromosome abnormality so it may be difficult to determine whether they are related to the 1p36 deletion. I would recommend speaking to a geneticist and/or a genetic counselor to learn more about these medical conditions and to help determine whether they might be associated with the 1p36 condition.

Michael Graf Certified Genetic Counselor
CDO Medical Advisor

WHS is diagnosed by clinical evaluation of characteristic dysmorphic features and by performing cytogenetics and FISH studies. Some of the patient have a cytogenetically visible deletion (identified by classical cytogenetics) with varying breakpoints on the short arm of chromosome 4 at 4p16.3, others have a cryptic deletion requiring FISH (fluorescent in situ hybridization) to make the diagnosis. Hope this helps.
Shashikant Kulkarni
Director of Clinical & Molecular Cytogenetics
CDO Medical Advisor

Yes, the risk of whole chromosome disorders like trisomy 21 (Down syndrome) rises with increasing age of the eggs.
Andrew Zinn MD
Medical Geneticist

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Full Question:

I have Turner’s Syndrome mosaic (6%) with a healthy 4 year old son who was conceived naturally. Since trying for a second child, I have had an ectopic pregnancy, a missed miscarriage, and a D&E at 16 weeks due to the baby having triple x syndrome.  My question is, since I have mosaic Turner’s Syndrome and am now 4 years older since my son’s birth, is it worth it to continue trying naturally? Does my child have a higher risk of having Turner's?  Also, since i've failed my IVF cycle does this mean that conceiving a chromosomally normal child is a stretch? I would love to believe that natural selection is better and that maybe the meds just didn't work for me but i really don't know.  Any insight would be helpful, thanks in advance.

Answer:

You have 6% of 45,X (Turner’s Syndrome) cells in your blood, but we do not know the ratio between 45,X and 46,XX cells in your ovaries. However, only 46,XX cells may produce egg-cells suitable for fertilization. Women with a 45,X/46,XX karyotype may have difficulties conceiving, but their risk of having a 45,X child is the same as for 46,XX women. 

There is almost always a centromere. IDIC is short for isodicentric and centric implies that there is a centromere. In rare cases there is no classic centromere, but something else then becomes a neocentromere.
Andrew Zinn MD
Medical Geneticist
CDO Medical Advisor

Answered by Robert Wallerstein M.D. 

Echogenic bowel is an ultrasound finding with increased signal in the intestines. It is a normal variant that has a small association with Down syndrome, cystic fibrosis and some infections. It overall is usually a normal variant of pregnancy, but some testing is often advised due to the associations mentioned above.

With standard G-banding one may be able to see relatively large structural chromosome changes by examining the entire genome in one test.

With FISH one could examine individual loci (regions of interest) at a higher resolution (that means smaller changes ? deletions or duplications that are not visible by G-banding), but can only examine few loci at a time. Additionally one needs to have a prior knowledge based on the clinical presentation of the patient, as for which region should a FISH test be performed.

In contrast to this, an array is the best available method to perform several FISH tests, spanning the entire genome (if this is whole genome) or targeted region of the genome (targeted to regions which are known to cause a genetic disorder) at a higher resolution, more sensitive, and specific than a FISH test. However, an array will not detect balanced rearrangements in the genome. For the balanced rearrangements one needs to still do standard G-banding (Karyotyping).

Vaidehi Jobanputra, Ph.D.
Assistant Professor
Columbia University Medical Center

FISH is a very specific procedure where DNA probes are used to detect whether or not a specific piece of DNA on a chromosome is present or not. With our current technology, you can only FISH for one deletion at a time. Geneticists will start out with a deletion that is most likely based on clinical features, and then move on to those that may be less likely but that the patient could still fit into. Unfortunately, this is the best way we have with the present technology. The only exception is subtelomere FISH, which is a test that can look at the tops and bottoms of all the chromosomes in one test. You can ask your doctor if he has ordered this test or if he thinks it is worthwhile to perform based on your child's features. Amy Curry CDO Medical Advisor

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Answer:

The SRY is a gene located on the short arm of Y-chromosome. This gene is necessary to produce the development of testicles. If this gene is mutated or missing the person will have basic female genitalia.

There are several reports in the literature of XXY patients who also had deletions of the SRY gene (or mutations of this gene). But as far as I know all of these patients had a female phenotype. Your correspondence indicates that you identify as a male and that makes a deletion of the SRY gene doubtful. Furthermore, a reliable genetic diagnosis requires specific laboratory examination.

CDO¹s library contains several articles discussing 47XXY, the SRY gene and individuals with abnormal SRY.  For more information on any library
article, please contact info@chromodisorder.org

In children with chromosome issues, there can be many forms of hearing loss. As you likely know, there are 2 main forms of hearing loss: conductive ( mechanical deafnes) and sensorineural (nerve deafness). Children with chromosome isses can have either one. The deletion or duplication of chromosomal material can cause differences in the shape of the ear inner and outer and predispose to hearing loss. The chromosome issue can also predispose to differences in the nerves of the ear causing hearing loss.
This is not necessarily a part of each chromosomal disorder, but chromosome problems do create increased risk for hearing loss. Therefore, it is our clinical practice to recommend hearing screening as a part of the management of children with chromosomal problems. This recommendation should be broadened to all children with developmental issues as hearing loss can be a major cause of speech delay and is treatable if detected. Any concern about hearing should be discussed the child's health care provider and appropriate testing arranged.
Extreme sensitivity to sound is a part of sensory overload where a child has difficulty screening out multiple stimuli from the environment. When you are in a noisy room, you have to focus on a small number of sounds or you will get overwhelmed and loose the ability to function in that setting. For many of us, this is a skill that we take for granted. Many children with chromosomal or other developmental issues have difficulty with focus and discriminating between sounds and get easily overwhelmed. This is a different mechanism from the hearing loss, but is also associated with chromosomal issues, but is common with other developmental conditions as well.
Robert Wallerstein MD
Medical Geneticist
CDO Medical Advisor

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Answer:

This situation relates to the earlier question as it is a scenario where the microarray technology can be helpful to look for a microdeletion not initially detected. I will say that in clinical practice, we have seen many children where we feel very likley that there is a chromosome problem and all testing is normal. This may represent a single gene issue not detectable on chromosome analysis. This situation is one where the clinical skill ofthe geneticist is important in assessing whether a known genetic syndrome is present or other possibilities. It is a common scenario.
Robert Wallerstein MD
Medical Geneticist

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Answer:

The clinical significance of small proximal duplications of chromosome 1q21.1 is not very clear.  Yes, several patients with such duplications were found among patients with epilepsy, autism or psychomotor retardation. But it does not mean that dup 1q21.1 was RESPONSIBLE for all these abnormalities.

But what happens in real practice?  Scientist A studies patients with (for example) autism. Assume that he studied 200 kids and found two having this duplication. Scientist B studies patients with epilepsy and finds one with dup 1q21.1.  Scientist C examined 150 patients with heart defects and reported two with dup 1q21.1.  Assume that genetic counselor has a consultation with a woman whose prenatal test showed this duplication in the apparently normal fetus. This counselor checks the medical literature and finds that there are 5 reports on this duplication, and in 3 cases the patients had some mental issues.  What can he/she recommend? Of course, it is an oversimplification, but you can see my point.

There is another kind of study reported in the literature when representatives of a large laboratory analyze all persons with any give abnormality found in their center. They may report 10 or 15 patients with dup 1q21.1 (or any other microduplication), and all (or vast majority) of these persons had some mental or physical problems. But these problems were an indication for cytogenetic examination, and the discovery of any microduplication does not guarantee its etiological significance.  I do not want to say that dup 1q21.1 is harmless in all cases, I just want to say that we do not have any real information to make a conclusion about its significance.

If we could find a large number (200-300) of newborns with dup 1q21.1 (or any other microduplication) and follow these children for 10-15 years we could then see how many will eventually experience symptoms or deficits and how many will remain healthy.

In my opinion the cytogenetic examination of both parents is a prerequisite for any decision about a pregnancy in all cases where a microduplication 1q21.1 (proximal or distal) is found in a fetus. And if one of the healthy parents is a carrier we have a very good chances to believe that the baby will be healthy. 

Attached is the article by Rosenfeld et al. – the largest publication on proximal dup 1q21.1. There are many other single cases, but in all these cases the authors report results of a cytogenetic examination in the specific groups of patients.  One studies heart defects and reports this duplication among persons with heart defects. Another studies schizophrenia and reports several patients with dup 1q21.1 in his study group. So, these results are inconclusive regarding the real significance of dup 1q21.1.

Even in families with much larger duplications of 1q21.1 the clinical manifestations in different members of the family may be very different.

Just today I read another article where a son of a woman with another microduplication (16p11) had some abnormalities. He had the same microduplication as his healthy mother.  But his doctors decided to examine his genome. They found mutations in another gene, which was really responsible for child’s disorder. Without these tests this child would be considered as having his disease due to duplication. 

Until now we do not have any real information about the significance of proximal dup 1q21.1, but in my opinion the transmission of this duplication from the healthy parent to the fetus should not be considered as an absolute indication for termination.

Best wishes

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Answer:

If a patient has isolated Pierre Robin sequence and there are no other

similarly affected persons in his/her family, the risk for siblings of the

patient is less than 1%. Risk for the offspring of the affected person

(for the children of your daughter) is approximately 2-3%, because we

cannot exclude a new dominant mutation.

Inversions are considered to be benign polymorphisms in most cases. The inversion you describe is paracentric inversion meaning that it does not involve the centromere and involves the long arm of chromosome 2. These inversions in MOST cases are considered to be harmless and will not cause any abnormality in the individual. But each inversion is unique based on the breakpoints and a risk for any abnormality in the individual carrying the inversion will depend on many factors mainly: 1) if the inversion which is apparently balanced by classical cytogenetics is really balanced, there are several examples in literature indicating that these so called balanced rearrangements are in small proportion of cases are in fact unbalanced; 2) If any of the breakpoints disrupt a gene of important function. The way to figure these two scenarios are as follows: 1) To see if the inversion is really balanced, one can investigate copy number changes by microarray CGH analysis (offered by Baylor and a company called Signature genomics which will cost approximately $1000; call them to check the recent cost);
2) to check if the breakpoints disrupt a gene is an academic question at this point, there are several experts working on this purely for research with the aim that one day this information will help in better understanding to these chromosomal rearrangements. These researchers are interested in dissecting out the gene disruption causing the ABNORMALITY in the individual carrying the chromosomal abnormality.
One such group is at Harvard medical school called as DGAP (developmental genome anatomy project), of which I was an active researcher till June of last year.
Of note is that the individual carrying a paracentric inversion may have difficulties in having kids due to unbalanced gametes formed.
Shashikant Kulkarni
Director of Clinical and Molecular Cytogenetics

This is a normal variant, well-known in the population, particularly among individuals of Ashkenazi (Eastern European) Jewish ancestry. It is very unlikely that this would be associated with any increased risk of miscarriage. We would read this as a normal result. 

Donna Wallerstein, MS 
Certified Genetic Counselor 

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Yes, this deletion is compatible with life.  There are several reports of patients having deletions of a similar size in 5q15q23. Children may have agenesis of the corpus callosum, cleft palate, and kidney defects (horseshoe kidney). Hearing defects were found in several patients with this deletion.  Moreover, this area includes the APC gene - absence of this gene causes multiple colorectal polyposis and malignant tumors of the colon.

Slow growth is seen in 100% of 5p-. There does not appear to be a relationship between 5p- and premature closure of the sutures, or craniosynostosis. I could only find one report of the two conditions co-occurring, and it was in the setting of a complex chromosomal rearrangement that included trisomy 13q as well as 5p-. It would be useful to know what types of investigations were done to determine the nature of the chromosome abnormality, and consider doing FISH studies to verify that it is a simple deletion of 5p.

Dr. Andrew Zinn
Medical Geneticist
CDO Medical Advisor

I looked at the literature. There are some reports of linkage based studies which suggest a possibility of a locus involved in cholesterol metabolism. But these studies have not been replicated and a definitive answer is lacking. So at this point, it is not known whether aberrations of this genomic region would be responsible to affect cholesterol levels.

Shashikant Kulkarni
Director of Clinical and Molecular Cytogenetics
Assistant Professor of Pediatrics
Genetics & Genomic Medicine
Department of Pediatrics

Yes, Isochromosome has one centromere with 2 short or long arms attached. Isodicentric has two centromeres and a short segment in between, in addition to the long and short arms.
Andrew Zinn Medical Geneticist
CDO Medical Advisor

The question that you raise is an important one that does not have a
clear answer. The life expectancy for people with chromsomal deletion
syndromes is usually related to the manifestations of the chromsomal
condition. As your genetciist said that the shortened life span is
related to clefts and poor nutrition. The basic answer is that the
chromosomal deletion can cause other medical issues such as a cleft or
a heart defect. A heart defect can be life threatening. If a person has
a serious heart condtion, this can shorten his or her life. This can be
related to the chromosomal issue and in that sense the chromosomal
condition can shorten the lifespan. Since chromosomal variation are so
different in the physical ways in which they manifest, this is a wide
open question.

Another issue in the answer to your question relates to the care of
individuals with developmental disabilities. Many years ago surgery was
not routinely offered to individuals with chromosomal syndromes to
repair certain anatomic defects. These individuals suffered from the
effects of physical differences caused by their chromosomal variations.
The medical issues of a heart defect not repaired or a cleft not
repaired are significant. I care for an adult woman who has a cleft
that was not repaired. She has speech and respiratory issues that would
have been prevented of the cleft was repaired in infancy. The consensus
in the medical community has changed and quality of life issues are an
important issue to consider in making decisions about care. So
individuals today who have the same chromosomal condition, but who
receive more aggressive medical care may have better long term
outcomes.

This also speaks to the information that is available about different
chromosomal issues. The natural history studies of different
chromosomal conditions were often done many years ago and are not
tracking those people who had increased medical care. The old studies
may not apply to children treated in the 21st century with improved
techniques. Also, chromosomal condition are not common so collecting a
large series of individuals is not easy. It takes a large number of
patients to get enough information to make generalizations about a
condition. These numbers are just not always available.

So, there are many questions unanswered. It continues to remain
important to chart each child's course as an individual looking at his
or her issues as a unique condition.
Robert Wallerstein MD
Medical Geneticist

Marijuana use is not known to affect the chromosomes of a baby. However, some studies suggest that marijuana use can decrease the likelihood of a couple becoming pregnant (perhaps due to decreased sperm count) and some studies suggest marijuana use during pregnancy can cause slower growth of the unborn baby and/or increased miscarriages. Other studies have not confirmed these findings. While there are limited long-terms studies of children who have been exposed to marijuana during pregnancy, some of these studies suggest that these children may have subtle differences in their ability to pay attention while other studies have not found this to be true. Although marijuana use has not definitively been linked with any specific birth abnormality or learning disability, it is suggested that parents should refrain from marijuana use during pregnancy and around children to minimize any potential risks. If an exposure has occurred, your physician and/or genetic counselor can more accurately describe any potential risks.

Michael Graf
Certified Genetic Counselor

The maternal serum screening tests keep evolving. These days there are various combinations of blood levels for HCG, PAPP-A, estriol, AFP and may include an ultrasound measurement called NT (nuchal translucency). The screen produces a number that represents the chance that the baby has Down syndrome. If the chance is elevated, the woman is usually offered an amnio. When the baby has a different chromosome problem, it may just be coincidence that the screen was positive or it may be that the levels were a little off because of the problem in the baby. At any rate, the final chromosome analysis will determine if the baby has an extra chromosome 21 or not.
Karen Heller
Certified Genetic Counselor

There is not a lot of data yet on microarray analysis of balanced translocations. The available literature suggests that a significant proportion (~40%) of fetuses with translocations and ultrasound abnormalities will turn out to have a deletion or addition by microarray analysis, but that very few fetuses with translocations and normal ultrasounds will have deletions or additions detectable by microarray. So most likely the microarray will not show anything, but there are a variety of different arrays being offered clinically and the likelihood of finding an abnormality could vary depending on exactly which array is used. If the array is normal, that is further reassurance that the outcome will most likely be good. If the array does show an abnormality, the prognostic value would depend on exactly what genes are duplicated or deleted. If the translocation happens to disrupt a critical gene, there may be a deleterious effect, even if there is no associated deletion or duplication detectable by microarray analysis.
Andrew Zinn MD
Medical Geneticist

Microarray testing is a new technology that looks for subtle chromosome rearrangements not detectable on routine chromosome analysis. It is very useful for diagnosis of chromsome problems. It is not specific to any one area. It is a good survey of the entire genome. In a child with a previously diagnosed deletion, the microarray is unlikely to add more information. The knowledge of the terminal deletion may be adequate for clinical management. In this situation, it would be more helpful to contact researchers who are characterizing that specific region in question to see if they can use specific probes to better characterize the deletion.
Robert Wallerstein MD
Medical Geneticist
CDO Medical Advisor

Miscarriages are common (~25% of all recognized pregnancies end in miscarriage). Far more likely to have been coincidental than related to your daughter's specific chromosomal diagnosis. There is no evidence that you and your wife are at increased risk for conceiving children with chromosomal abnormalities, compared with other couples your age.

Thomas Morgan MD
Medical Geneticist

Most of the time, paracentric inversions are not thought to cause any problems. However, they are difficult to see and interpret (in the lab), and there are some examples (including chromosome 18) where they have been reported to be associated with reproductive problems. In your case, I think it would be important to have a genetics physician or genetic counselor meet with you to review the lab report together with your history, and try to determine whether this inversion could be causing a problem, including if there is a chance to have a child with severe problems as a result. Check with your doctor for a referral, or go to nsgc.org.
Karen Heller
Certified Genetic Counselor

This karyotype means that some of the cells analyzed had the usual number of chromosomes whereas some cells had one chromosome 18 replaced by a ring chromosome 18. A ring chromosome is a chromosome where the two ends of the chromosome join, creating an apparent circle or ring. The "dn" means de novo, which means that the ring chromosome was not inherited from either of the parents.

It is very difficult to predict with much certainty about whether and how much a person might be affected with such a karyotype. In general, individuals with a ring chromosome 18 can be missing some genetic material from chromosome 18 which could cause developmental delay and/or physical abnormalities depending on what genetic material is missing.

What makes it even more difficult to determine the affects of this finding is that only some of the cells that were analyzed have the ring, while the other cells had two normal chromosomes 18 (referred to as mosaicism). The existence and extent of development or physical problems also depends on which cells have the ring and which do not. For example, if the cells in the brain have two normal chromosomes 18, then it is less likely there will be development delay. Unfortunately, it is not possible determine which cells in the body have the ring chromosome and which do not making it impossible to predict the effects. Speaking with a genetic counselor and/or geneticist could help explain this further.

Michael Graf, Certified Genetic Counselor
CDO Medical Advisor

Mosaicism in an amniocentesis can be very confusing. If the level II ultrasound is completely normal, then the risk of an affected child is reduced, but not eliminated. Also, the number of cells counted is important. The more cells counted, the more likely to be accurate. Mosaicism found in an amniocentesis does not necessarily represent the level present in the child (for example the child could have 6% mosaicism in the skin and 50% in the brain, there is no way to ever know that for certain.) In that regard, testing the fetal blood is not always helpful. You may find no cells with the deletion in the blood, but that doesnt help us decide whether the amnio results are accurate. The mosaicism may also be confined to the placenta and not representative of the fetus at all. As you can see, there are many caveats when thinking about mosaicism from the amniocentesis. 

Dr. Robert Wallerstein & Donna Wallerstein

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

The report shows the fetus has uniparental disomy 5 (both copies of chromosome 5 are from the same parent), but there are no other abnormalities. Uniparental disomy may produce clinical abnormalities only if the affected chromosome has a recessive gene, causing the disorder in a homozygous condition. Most likely, the probability of such a situation is less than 5%, but there is no way to actually predict the result.  I know of only 2 reports of UPD5 in persons with clinical abnormalities. One of these patients (Numata et al., 2014) had some skin disorders, because she was homozygous for one of the genes responsible for this condition. Another patient (Seal et al., 2006) with partial UPD5 had schizophrenia, but nobody knows whether this disorder was caused by UPD5 or if it was just random association. 

Medical Report Cited Above:

“In normal conditions the fetus receives one chromosome 5 from the mother and another from the father. Analysis showed that your fetus has both his chromosomes 5 from the same parent. This analysis could not tell whether these chromosomes are maternal or paternal. It is a isodisomy for the whole chromosome 5.

All human chromosomes carry hundreds genes, many of these genes are related to human disorders. Basically all genes causing disorders may be subdivided into 2 groups. 1) Dominant genes cause disorder even when one gene is affected but the homologous gene on the other chromosome is normal. Because (we presume) you and your husband do not have any genetic disorders we think that neither of you has any disorder-related dominant genes. 2) Recessive genes cause disorder only if the child (fetus) has the same abnormal genes on both chromosomes (in your case on both chromosomes 5). The condition when both genes are the same calls homozygozity. Because your fetus has two identical chromosomes 5 he is homozygous for all genes located on this chromosome. We do not know however if you or his father have any mutated (abnormal) genes on this chromosome. But if the inherited chromosome 5 has any mutated recessive genes the fetus may have a disorder, caused by this mutation.

There are no indications that persons with UPD have additional risk beside expression of recessive genes.

Analysis further showed that the fetus does not have deletions or duplications of any chromosomes, including chromosome 5.

Each chromosome consists of several areas, and each area includes several specific genes. When we know that, for example, an individual has a deletion of 5p13.3p15.3 we know which genes are lost and what can be expected in that case. It is like if we know that a certain bookcase in the library contains books about the Civil War but we know that this bookcase was destroyed during a flood.  We know now which books were lost."

Editor's Note:

Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or of part of a chromosome, from one parent and no copies from the other parent.  UPD can be the result of heterodisomy, in which a pair of non-identical chromosomes are inherited from one parent or isodisomy, in which a single chromosome from one parent is duplicated.

UPD can occur as a random event during the formation of egg or sperm cells or may happen in early fetal development. It can also occur during trisomic rescue.

Trisomic rescue (also known as trisomy rescue or trisomy zygote rescue) is a genetic phenomenon in which a fertilized ovum containing three copies of a chromosome loses one of these chromosomes to form a normal, diploid chromosome complement. If both of the retained chromosomes came from the same parent, then uniparental disomy results.

A ring chromosome occurs when a piece is lost from each end of a chromosome, and the broken ends attach to each other, forming a ring shape. This produces problems in a child because of the loss of chromosomal material at both ends of the chromosomes. Typical problems include small size, small head, poor muscle tone, developmental delay in younger children and mental retardation in older children. There are also usually alterations in appearance, and there can be major birth defects such as heart or kidney abnormalities.

When a chromosome analysis reveals a mosaic pattern with some of the cells being normal (as in this case), we can hope that the presence of normal cells in the body will make the condition less severe than usual. However, this cannot be predicted, and every case is unique. It would be important for this baby to be evaluated by a good pediatrician and, hopefully, by a clinical geneticist, to evaluate for the presence of any current problems or birth defects, and to monitor for any future problems. Getting enrolled in an infant stimulation (early childhood intervention) program will provide him with assistance in his development and will enable a gradual estimate of how he is likely to do learning-wise. It is impossible to make predictions at 3 months of age!

Karen Heller
Certified Genetic Counselor
CDO Medica Advisor

The chromosome results show that there is one normal chromosome 22 and one chromosome 22 that is a “ring.” A ring chromosome just means that the two ends of the chromosomes “stuck together,” likely during the formation of the sperm or egg. There is nothing a parent does to cause this to happen. When a ring is formed, there can be extra or missing pieces of the chromosome. In this case, it doesn’t appear that the laboratory found any extra pieces of chromosome 22, but it is possible that either or both ends of the chromosome may be missing. While additional laboratory studies would be necessary to confirm whether there is missing genetic material, even with that additional information, it would be difficult to suggest what type of physical or medical problems might be associated with any missing genetic material. Missing genetic material often leads to various physical and/or medical problems, but it is often very difficult, if not impossible, to know what types of problems are associated with a particular chromosome deletion, especially for more rare deletions such as those found associated with ring(22). While there are other known individuals with a ring chromosome 22, each may have slightly different missing (or extra) pieces of genetic material, so it will be difficult to make comparisons to other children.

Also, please note that if you do any research about ring(22) chromosomes, there are two general types of ring(22). One ring is found in addition to two other normal chromosomes 22. Those chromosome results would show 47 chromosomes and would have a karyotype of 47,XY+r(22) or 47,XX,+r(22). Those individuals can sometimes have overlapping symptoms to each other due to the extra ring chromosome. However, that chromosome abnormality does not show much overlap with individuals with 46,XY,r(22) or 46,XX,r(22), where one of the chromosomes 22 was replaced with the ring chromosome, which is the case for your son.

The ring chromosome is very likely the cause of the physical, developmental and medical problems in your child. However, it would be impossible to know that for sure. That is true even if additional laboratory studies were performed to confirm whether there is extra or missing genetic material. Unfortunately, it is often very difficult to obtain detailed information about what to expect with relatively rare chromosomal abnormalities, such as ring chromosome 22. I would highly recommend meeting with a geneticist and/or a genetic counselor to try and learn more about this chromosome abnormality.

Michael D. Graf, MS, CGC, MBA
CDO Medical Advisor

In the vast majority of cases, paracentric inversions are not felt to cause any problems. In fact, they are generally discovered quite incidentally. It is very unlikely, though not impossible, that someone who carries a paracentric inversion is at increased risk for having a child with a chromosomal abnormality. It may be that the inversion is not even related to the history of miscarriages. It would be useful to consult with a geneticist or genetic counselor to review your family history and try to decide if this inversion is likely to be causing any problems. Also be sure to check with your doctor for other possible causes of miscarriage.

The use of IVF (in vitro fertilization) with PGD (preimplantation genetic diagnosis) should not be necessary in this situation. Perhaps prenatal diagnosis by amniocentesis or CVS (chorionic villus sampling) could be considered during a pregnancy, if there is some concern for a problem.

The inversion described is called a paracentric inversion because the inversion is totally contained within one arm of a chromosome - in this case, the long arm of chromosome 10. (A pericentric inversion is one that occurs with breaks on opposite arms of the chromosome, and the inverted segment includes the centromere.)

Karen Heller
Certified Genetic Counselor

If the inversion is truly identical in the mother and the child, it should not be causing the child's problems.
Either the problems in the child are caused by something else, and the chromosome finding is coincidental; or else there is a tiny imbalance (extra or missing chromosomal material) in the child that is not present in the parent.
We would not expect there to be any pattern with males versus females, since this does not involve the X or Y chromosomes.

Karen Heller
Certified Genetic Counselor

A satellite was observed on the short arm of chromosome #14 in all 29 spreads, this is a normal polymorphic variant. Such normal polymorphic variants however, may contribute to instability of chromosomes during meiosis with a tendency towards an increased risk of aneuploidy.

The region of chromosome 14 that we call the "satellite" is larger than usual. In general, we do not expect this to have any effect - it should not cause infertility or pregnancy loss. Just in case it is affecting the chromosomes (which is unlikely) you may want to consider the following: 1) if you have another pregnancy, consider testing the baby's chromosomes during pregnancy (amniocentesis) 2) if you have another miscarriage, ask the doctor to order a chromosome test on the tissue Because this finding is probably not significant, you should check with your doctor about other possible causes of the infertility and pregnancy loss.

KAREN HELLER
CERTIFIED GENETIC COUNSELOR

Mosaic means that not all the cells in someone’s body have the exact same genetic material. For example, if someone has a chromosome deletion and is mosaic we think that not all of the cells in that person’s body have the deletion. In other words, some of the cells would not have the chromosome deletion. Mosaicism is hard to establish clinically because our body has so many cells. For example, if a blood test shows mosaicism with some cells having the chromosome deletion while other cells are “normal”, it is hard to know if other organs of the body would have this cellular makeup. Mosicaism is often an explanation of why some people have less serious medical problems w! ith a chromosome deletion. They may not have as many problems because they have some cells with the correct amount of genetic material. How mosicaism occurs is shortly after conception when the cells are going through mitosis a mistake occurs. All new cells after this mistake will have the deletion but as it occurred after conception there are still normal cells from before the mistake.
It is hard to completely rule out if your daughter may be mosiac for her deletion. Even if her chromosome results from looking at the cells in her blood show no cells without the deletion; we cannot know if the cells in her liver or heart or brain all have the deletion or if they are mosiac. In the big picture it doesn’t effect your daughter's medical care. It may hypothetically help us understand why she can do some things but not others but it doesn’t change with how we take care of her.
Robert Wallerstein, MD
Medical Geneticist

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

This formula means that this patient (or fetus) is a female with a deletion of the short arm of chromosome 5 from the area p14.1 to the telomere.  This represents a large deletion, and ~25 Mb of DNA is missing.  An examination was performed using In Situ Hybridization technique.  The symbol "ish" is an abbreviation of the first letters of this technique.  When a sample is examined using this technique, the lab uses specific probes that (normally) have to be joined with some specific areas of the studied chromosome.  If this hybridization does not occur, it means that the segment of the chromosome that has to carry this gene or this clone is missing.  In this particular case, there was no hybridization within subtelomeric clone C84c11/T3, within gene FLJ25076 and within CTNN2 gene (catenin).  The symbol "-" indicates there was no hybridization within these areas.  Of course, a deletion from 5p14.1 to the telomere presumes that many other genes are also missing, but this technique uses hybridization with only several selected areas of the chromosome.  Clinical information about patients with such deletions may be obtained on websites about "cat cry" or "cri du chat" syndrome.

Many questions that we receive are about prenatal diagnosis of chromosomal disorders. WE thought that this time we would summarize some general information about prenatal diagnosis. WE hope that it is helpful.

Chorionic villus sampling and amniocentesis are the two most common methods of prenatal diagnosis. Both techniques can be used for a variety of kinds of genetic testing as well as other types of testing, but are most commonly used to detect chromosome abnormalities/variations. What both tests have in common is highly accurate chromosome karyotyping of a fetus.

Instructions for patients having prenatal diagnosis can vary widely from facility to facility. Some prefer that the patient come with a full bladder (drink three 12 ounce glasses of water one hour prior to the test); others prefer an empty bladder. All patients must have a blood type done before testing. Some facilities also require an antibody test and a gonorrhea/chlamydia test, as well as a dating ultrasound. Different facilities will have different requirements about pre-procedure preparation.

CVS is typically done at about 9-11 weeks of pregnancy, but can be done earlier for special circumstances or slightly later. True CVS can only be done until about 12 weeks of pregnancy, beyond that point it is called placental biopsy because the fingerlike villi are no longer present. There are two techniques for CVS: transabdominal and transvaginal. Transabdominal is similar to amniocentesis: the doctor uses a thin needle to penetrate the abdominal wall and the placenta. A tiny amount of tissue is extracted through the needle. The cells in this early placental tissue divide quite rapidly, making a quick chromosome analysis possible. The transvaginal technique is done by passing a small catheter (essentially a thin plastic tube) through the vagina and cervix. The doctor guides the catheter to the placenta where a small amount of tissue is extracted. Both the transvaginal and transabdominal techniques require ultrasound guidance and skill. Both techniques take about 10 minutes to perform and usually no anesthetic is administered. Both techniques are considered minimally uncomfortable, although tolerance varies from person to person, as with any medical procedure. Once the tissue is obtained, the patient is permitted to go home and post-procedure instructions are to take it easy for about 1-2 days, no intercourse and no tub baths (showers are fine), no heavy lifting or exercising. Some patients will experience menstrual-type cramps lasting from a few hours to a day or two and possibly some bleeding or staining. Excessive bleeding, cramping, foul-smelling discharge or fever should be brought to the attention of the patient's primary obstetrician.

Test results from either procedure can vary from a few days to about 2 weeks, although most results seem to come in about one week. More complicated genetic analysis (for sickle cell anemia, thalassemia, or rare
disorders) can take anywhere from one month to six weeks.

CVS has a risk of miscarriage that is generally quoted as greater than that of amniocentesis, usually from about 1 in 100 to about 1 in 200. Some practioners feel that if the background risk of miscarriage in the first trimester is adjusted for, risk from CVS is comparable to that of amniocentesis.

CVS is generally performed in a hospital or specially designated facility and is almost always done by a perinatologist. A perinatologist is a doctor who has completed a four-year residency in obstetrics and gynecology and then another three-year fellowship in perinatology. The perinatologist is a high-risk pregnancy specialist and usually will perform numerous procedures in any given week, month or year. Because the skill of the practioner is directly related to the success of the procedure, it is always helpful to ask "How many of these do you do per month?" and "How long have you been in practice?"

CVS has one other well-publicized risk: the risk that the procedure can cause limb abnormalities. Numerous studies have documented an increase in limb defects (missing arms, legs, fingers or toes) in babies born after CVS. Most of these defects occurred in children whose mothers had had CVS very early, before 9 weeks of pregnancy. This is still a risk in later CVS, but much reduced. Overall, the risk of limb abnormalities is less than the risk of miscarriage associated with the procedure.

Amniocentesis is simply removal of a small amount of fluid from the amniotic sac. It is done usually between 15 and 20 weeks of pregnancy, with most women having the procedure around 16-18 weeks. Amniocentesis is also done with ultrasound guidance - a thin needle is inserted through the abdomen into the sac and about 20-30 cc's of fluid is withdrawn. The whole procedure takes only a few minutes. Some physicians will give an injection of lidocaine to "numb" the abdomen; however, most practioners do not give a local anesthetic.

Many obstetricians as well as perinatologists perform amniocentesis. It can be done in a private office, hospital or other outpatient facility. Although skill is important in performing amniocentesis, it is generally considered a less complicated procedure than CVS. Test results for routine chromosome analysis usually take about 10-14 days. Again, more complicated genetic testing may take quite a bit longer. Following amniocentesis, instructions usually include taking it easy for about 24 hours, with no heavy lifting or exercising. Any signs of fever, leaking amniotic fluid vaginally, foul-smelling discharge or excessive cramps or bleeding should be reported to the primary obstetrician. Many women will experience mild menstrual-type cramps that may last for a few hours or a day or two.

Many risk figures for miscarriage following amniocentesis have been published. In general, the risk of miscarriage is between 1 in 200 and 1 in 400. Some practioners will have significantly lower rates of miscarriage than those; others may have higher rates. Again, it is wise to ask how many procedures per week or month the doctor does and how long he or she has been practicing. Reputable practioners will have some method for following outcomes and should have at least a rough idea of the number of miscarriages in their patient population. Any practioner who says he has "never" had a patient miscarry following amniocentesis is probably not keeping track of outcomes. Some pregnancies will naturally miscarry in the second trimester, with or without amniocentesis, so it stands to reason that those patients who have had amniocentesis are not immune to the natural background risk.

Both amniocentesis and CVS have had numerous cases in which every ailment under the sun is blamed on the procedure. No major studies have identified significant risks or risk trends, other than miscarriage for both procedures and increase in limb abnormalities following CVS. These appear to be the primary risks for the two procedures.

Women who have Rh negative blood type must have an injection of Rhogam immediately following the procedure.

Although both amniocentesis and CVS are good tools for identifying chromosome abnormalities and variations, routine testing will not identify every possible variation. Specialized testing for very small deletions or additional material is not routinely done. If a family knows that they are at risk for a child with a microdeletion, then specialized testing may be able to be done using fluorescent in situ hybridization (FISH) for the specific chromosome region. This generally results in additional cost, as well. Standard CVS or amniocentesis will usually cost between $1000 and $3000, depending on the region of the country that a person lives, where the test is done (hospital will usually cost more than a private office) and other factors.

No prenatal test can guarantee a normal, healthy child. About 3-5% of newborns have some type of birth defect. Prenatal testing can provide reassurance about specific concerns, but cannot rule out every type of problem.

So why would a woman choose CVS over amniocentesis or vice-versa? The primary motivating factors appear to be timing and risk perception. Many women prefer CVS because it is done earlier in pregnancy and results don't take quite as long. Others prefer the "tried and true" reputation of amniocentesis and the arguably lower risk for miscarriage and other complications. Each family must make their own decision regarding which, if any, prenatal diagnosis is right for them.

Robert Wallerstein M.D. Medical Geneticist
Donna Wallerstein
Certified Genetic Counselor

The literature on this subject of maternal age and the probably of translocations remains unsettled. There is a well documented increased risk for Down Syndrome (trisomy 21) and certain other trisomies caused by failure of chromosomes to separate in the final stages of egg cell production. This process is not related to translocations.

Increase in translocations due to paternal age? Maybe, but not a dramatic increase. The incidence of translocations is still quite rare. The literature on this subject again remains unsettled.

Thomas Morgan, MB
Medical Geneticist

In theory, the risk would be 50% because the mother would either pass on her ring 21 or her normal 21. Reality is less than 50% for a variety of reasons, however. The best thing to do is to do a chromosome analysis on the baby; ring 21 is very easy to diagnose with a simple chromosome analysis from a small blood sample. Developmental concerns from a ring chromosome can vary quite widely depending on how much genetic material is lost in the formation of the ring. Some individuals with ring chromosomes have mild symptoms. How severely affected is the mother? We would expect the child to have similar signs and symptoms if she inherited the ring 21.
Donna Wallerstein, MS
Certified Genetic Counselor

Assuming complete viability of unbalanced forms, then the theoretical risk to a balanced carrier of having a child with an unbalanced karyotype would be 50%. There would also be a 25% chance that the child would have normal chromosomes, and a 25% chance of the child being a balanced translocation carrier, just like the parent.

However, the practical range of risks for a live-born child with an unbalanced karyotype, as noted below, is from 0-30%, not 50%, due to reduced viability leading to miscarriage. Attempts to further refine an individual carrier's probability are hazardous, amounting to little more than guesswork, because sufficient data on pregnancy outcomes do not exist for most balanced translocations. As Dr. Wallerstein noted, the risk is slightly higher if the mother is the carrer, as compared to the father. Parents of one live-born child with an unbalanced translocation should assume that the risk may be at the higher end of the practical range. It is also important to keep in mind that the "probability" that any particular child will have an unbalanced translocation is either zero or one when we cite "risk figures" we're taking the average, or counting up all the ones and dividing by the number of pregnancies. All couples at risk should seek professional counseling from a clinical geneticist or genetic counselor.
Thomas Morgan, MD

This section written by Dr. Haag:

The Robertsonian translocation of 13;14 is the most common of the Robertsonian translocations.  It is estimated that about 1/1,300 people carry this translocation. The major risks for pregnancy outcome with this translocation are 
1) a pregnancy that goes to term with trisomy 13; this risk is considered to be low, less than 1% and more likely less than 0.5%.

2) a second, and even more rare outcome is having both copies of chromosome 14 from the father by a complex mechanism of starting out as a trisomy 14 and loosing the maternal 14.  There are only a few reported cases of this and the condition is associated with unusual features and developmental delay.

3) I could find no satisfying statistic related to the miscarriage rate from an abnormal karyotype when a parent carries the t(13;14), however an unbalanced karyotype found at 2nd trimester by amniocentesis is reported to be about 1.4%  (ref:  Gardner and Sutherland, p120) when the male carries the t(13;14).  We must assume that this is higher for first trimester losses that do not get studied.  Again, I have not found a figure related to this since most first trimester losses do not get studied until a couple has had 2 and sometimes 3 or more consecutive losses. It has also been proposed, but in no way proven, that the miscarriage rate is higher when the fetus has the balanced t(13;14).  The reasons are not clear, but related to the structure of the translocation.

The odds are still in the couples favor to have a good pregnancy outcome.

Further description of the possible pregnancy outcomes when one carries a Robertsonian translocation:

Written by  - Donna F. Wallerstein, MS, Certified Genetic Counselor

To really understand the odds, you have to keep in mind that there are 6 possible combinations of chromosomes in sperm (father is the translocation carrier):

1.  The sperm cell contains the translocated chromosome only.  This is balanced, with no missing or extra material.
2.  The sperm has his normal 13 and normal 14 - no translocation 
3.  The sperm contains translocated chromosome AND regular 13 - too much 13 material
4.  The sperm contains translocated chromosome AND regular 14 - too much 14
5.  The sperm contains only the usual 13; the 14 is missing
6.  The sperm contains only the usual 14; the 13 is missing.

If the first two sperm fertilize an egg, the resulting embryo should be genetically normal and we would not expect miscarriage.  Keep in mind that some 20% of all pregnancies miscarry for various reasons.

If sperm #3 fertilizes the egg, the fetus will have trisomy 13; the vast majority of these pregnancies miscarry (90%+)

If sperm #4 fertilizes the egg, the fetus will have trisomy 14; again, most if not all of these would miscarry.  I am not aware of any cases of liveborn children with a complete trisomy 14, but I did not do an extensive literature search.

If sperm #5 or #6 fertilizes the egg, we would expect all of those embryos to be miscarried; monosomy (only one) of 13 or 14 is essentially "incompatible with life" - the embryo would not develop.

If you look at the various combinations, only 2 of the 6 would be expected to develop normally.  So a doctors estimation of 30% chance  for a normal conception can be explained by looking at these possibilities.  How it actually works out in real life is somewhat different.  Some of the unbalanced conceptions would be lost before you knew you were pregnant (unrecognized
pregnancy), particularly the ones with only one of a particular chromosome. When a man is the balanced translocation carrier, the odds are usually better. Perhaps the genetically unbalanced sperm are not as strong or viable, making it easier for  the balanced sperm to get to the egg first.  Couples with this very common balanced translocation usually do have normal, healthy children. Translocations can be passed for generations in a family before someone discovers they have it.

It is true that genetically unbalanced embryos usually do miscarry.  Most of these miscarriages do occur in the first trimester and that is true for all miscarriages, regardless of the cause.  I would say the chance of having a live born baby  with a chromosome abnormality is in the range of 2-3%.  I  could not find strong numbers for how many pregnancies really do miscarry in couples where the male partner is a balanced translocation carrier, but the literature suggests a higher than background (ie greater than 20%) rate of miscarriage.  Other conception possibilities do exist:  exploring the option of pre-implantation diagnosis in which an embryo is conceived using in vitro fertilization and then genetically studied before it is implanted in the mothers uterus.  In this way, only genetically balanced embryos would be implanted.  Your genetic counselor could give you more detailed information about this option, or seek the opinion of a reproductive endocrinologist.  Several centers around the country have good experience with pre-implantation diagnosis.

"Robertsonian translocation" is a descriptive term which tells us that the chromosome rearrangement involves certain chromosomes - specifically, chromosomes 13, 14, 15, 21 or 22. No genetic material of consequence is lost in this rearrangement; therefore, they are said to be balanced translocations. In this specific case, the translocation involves one copy of a chromosome 14 and one copy of a chromosome 15. There is also one free copy of chromosome 14 and one free copy of chromosome 15. Therefore, all of the information that is needed for normal growth and development is present; it is simply arranged differently in all cells. The actual karyotype is described in technical terms as:

45,XY,rob(14;15)

When the sperm cells of a person with a translocation are made there are several possible ways for the chromosomes from the original cells to divide into the individual sperm cells. Specifically, the resulting sperm cells can contain:
1) One free copy of chromosome 14 and one free copy of chromosome 15.
2) The translocation chromosome which contains one copy of chromosome
14 and one copy of chromosome 15.
3) The translocation chromosome plus one free copy of chromosome 14.
4) One free copy of chromosome 14.
5) The translocation chromosome plus one free copy of chromosome 15.
6) One free copy of chromosome 15.

If either option 1 or 2 above are the sperm utilized for fertilization then the resulting child would have the normal amount of chromosomal material. However, if any of the unbalanced sperm cells are utilized for fertilization, the result may be a child (or a fetus) with an unbalanced karyotype. There are several possible outcomes in this case:
1) Fertilization of an egg with a sperm containing the translocation
chromosome plus one free copy of chromosome 14 would result in a conceptus with trisomy 14, which is not compatible with life.
2) Fertilization of an egg with a sperm containing only one free copy
of chromosome 14 would result in monosomy 15, which is not compatible with life.
3) Fertilization of an egg with a sperm containing the translocation
chromosome plus one free copy of chromosome 15 would result in trisomy 15, which is also not compatible with life
4) Fertilization of an egg with a sperm containing only one free copy
of chromosome 15 would result in monosomy 14, again not compatible with life.

Another phenomenon which is important to consider in this situation is uniparental disomy (UPD). UPD occurs when a person inherits both copies of one chromosome from one parent and no copies of that chromosome from the other parent. Due to this chromosome rearrangement, there is the possibility to make sperm cells which contain both copies of either chromosome 14 or chromosome 15. Should fertilization of the egg take place with either of these two sperm types the result would be an embryo with either trisomy 14 or trisomy 15. However, our cells are quite adept at recognizing when there is too much genetic information inside of them. Therefore they may undergo a process called "trisomy rescue" by which they attempt to discard the additional chromosome. The cells can't determine which chromosome came from which parent so it is possible that the maternal chromosome 14 or 15 would be the chromosome removed from the cell leaving both copies of the paternal chromosome 14 or 15. In this instance, the result would be paternal UPD for chromosome 14 or paternal UPD for chromosome 15.

Paternal UPD 14 includes, but is not limited to, intrauterine growth retardation, congenital heart disease, mental retardation and/or developmental delay, musculoskeletal problems, and abnormal physical characteristics. Long term survival for these children is dependent on their specific medical problems but they are likely to have a normal life span. Paternal UPD 15 results in a condition called Angelman syndrome.


Therefore, the major concerns for a male who carries a 14;15 Robertsonian translocation are:
1) Having a baby with Paternal UPD 14.
2) Having a baby with Paternal UPD 15 and thus Angelman syndrome.
3) Recurrent miscarriage.

An article published in the journal Prenatal Diagnosis (2002, volume 22:
p.649-651) summarized the published data and found that after a fetus was diagnosed with a balanced Robertsonian translocation prenatally, there was a risk of 0.65% for UPD. It is very possible for a person who carries a balanced 14;15 Robertsonian translocation to have normal, healthy children.


If an individual carries this balanced translocation there is an increased risk to have a child with a chromosome abnormality, diagnostic prenatal tests such as chorionic villus sampling (CVS) or amniocentesis are available to you. Either of these tests can be used to look at the fetal chromosomes to determine whether or not a baby has inherited a balanced chromosome complement as well as for UPD studies. There is a risk that a woman will miscarry following either CVS (approximately 1%) or amniocentesis (approximately 0.5%).

Amy Curry Certified Genetic Counselor

This email underscores the key interpretive principle in clinical genetics: genetic diagnoses often do not predict a child's developmental or medical outcome. Duplications are often even more unpredictable than deletions. The other children that this parent viewed in the medical book may have had different duplications (or only superficially similar ones). I believe, in a case like this, that what is already known about the child clearly trumps the chromosomal diagnosis, which simply gives an explanation, at the molecular level, for what developmental issues he has had.

Thomas Morgan
Medical Geneticist
CDO Medical Advisor

Sturge Weber Syndrome is not caused by any consistent chromosome abnormality. For the most part, it is not well understood what causes this conditon. A few research studies have shown that when affected tissues from a patient are compared with nonaffected tissues, the affected tissues had a chromosome abnormality while nonaffected tissue from the same patient did not have that chromosome abnormality. However, in the patients analyzed, it was not even the same chromosomes that were involved. Therefore, there is no known exact underlying cause. However, research is always being done, and more may be learned in the near future.

Amy Curry
Certified Genetic Counselor

The girl has a balanced X-autosome translocation involving the short arms of the X and chromosome 19. She also has an intact X chromosome and an intact chromosome 19. In XX females, one of the two X chromosomes is chosen at random in each cell of the early embryo and undergoes inactivation in order to balance the level of X chromosome gene activity between XX females and XY males. In most females with a balanced translocation, the intact X is inactivated in 100% of cells; otherwise there will be too much activity of some of the X chromosome genes and too little activity of some of the autosome genes involved in the translocation.
The most common clinical consequence of a balanced X-autosome translocation is premature ovarian failure. However, some females have other abnormalities. There are several possible explanations:
1. The other abnormalities are coincidental and are due to some other cause.
2. The translocation disrupted critical gene(s) on the X and/or the autosome.
3. The translocation is not truly balanced. There is a piece of the X or chromosome 19 missing or duplicated, but this is too small to see under the light microscope. There is a test called CGH that might be able to detect whether the translocation is not truly balanced.
In this particular case, I favor explanations #2 or #3. There are a number of researchers interested in studying translocations such as this one. Here in the U.S. there is one at Harvard called the Developmental Genome Anatomy Project, http://www.bwhpathology.org/dgap/
There is also a consortium of autism researchers who might be interested in studying this particular case. www.naar.org/news/pdfs/agp1a.pdf
Dr. Andrew Zinn MD
Medical Geneticist

Compiled by Penny L. Richards, turley2@earthlink.net

INTRODUCTION: 
Many parents of children with disabilities are asked to speak to children in schools, camps, teams, scout troops, and other structured settings for interaction with typical peers.  This is an excellent opportunity to educate your child's friends and potential friends about rare chromosome disorders, but....it takes some preparation. Children need to have the concepts explained differently than most adults require. This FAQ is a series of lesson ideas for children of various age groups. (Throughout the text of this FAQ, words in "ALL CAPS" may be considered "vocabulary words," to be written on a board or sheet of newsprint if appropriate.)

About the author: Penny L. Richards is mother to Jake Turley, a seven-year-old with a 7q deletion. She has a PhD in education and is a certified social studies teacher, as well as a longtime church educator. 

TOPIC HEADINGS
1. ASSESSING CURRENT KNOWLEDGE
2. EVERYONE IS UNIQUE
3. VISUAL AIDS
4. QUESTIONS & ANSWERS
5. CHECKING FOR UNDERSTANDING

1.ASSESSING CURRENT KNOWLEDGE
If the group you are speaking to already knows your child, ask them what they know about him/her. "What have you noticed about Jessie since you met her?" The children may be shy at first about saying anythingthey may have been told *not* to point out what makes your child different. That's okaylet them say anything they feel comfortable saying, even if it's a little off-topic: "Jessie wears cute pink shoes," for example. The point is just to get them thinking, and for you to get a sense of their comfort level and current knowledge. It is also possible that you will hear explanations the children learned from their parentsand these may or may not be true (some parents may themselves lack accurate information). Be careful not to dismiss any ideas the children offer as "silly," or "wrong"the children are here to learn from you, and will listen more carefully if you respect them. (Example: "My mother says Jessie's head was hurt when she was born, and that's why she can't talk." "No, Jessie didn't ever hurt her head, but I understand why some people might say that.")

If the children you are speaking to have never met your child, you can have a similar conversation, but on the general subject of developmental disability. In this case, the starting question is, "Do you know someone who is disabled? What does that word mean? What can you tell me about people with disabilities?" Write the phrase "PEOPLE WITH DISABILITIES" on the board if you have onethis will help concentrate their thoughts.

2.EVERYONE IS UNIQUE
After getting a sense of the current knowledge the children have, introduce the idea of being UNIQUE. Every child is unique, tell them. They can each tell you how they are unique: "I'm unique because my name is unique," or "I'm unique because no one else has the same parents as me." Explain that ONE of the ways your child is unique has to do with her CHROMOSOMES. If the group of children is very young, under age 8 or so, you can skip the following explanationthey're usually not too interested in the science talk. (You can just say, "chromosomes are tiny squiggles in your body that tell it what to do.") But older kids are often familiar with the picture of a double helix, and may have heard of genes, so they'll be okay with the following explanation.

Chromosomes, you explain, hold the instructions in every cell of our bodies, instructions called GENES that tell the cells what to do. They're very very tiny, so doctors have to use special microscopes and cameras to see them. A picture of your chromosomes looks like 23 pairs of squiggles (if you have a picture of this, show it). Boys usually have a picture that can be described as 46 XY; girls have a picture that can be described as 46 XX. These numbers and letters together are called a KARYOTYPE, in case you're interested in the exact name of things. Now what do you think is unique about Jessie's karyotype? (Take a few guesses, then write it on the board under the 46 XY, 46 XX already there.) See, it's much more complicated. Some of the genes are missing (or "there are some extra genes," or "some of the genes are in a different place than they should be," depending on your child's disorder). Jessie is unique because every cell is missing some instructions (or has too many instructions, or has instructions that are out of order). No one else in the whole world is missing the exact same instructions as Jessie, but there are many other people in the world who also have unique chromosomes. (You can tell them about CDO if you like, at this point.)

3.VISUAL AIDS
You may want to bring in photos or even video of your child to share with the children. Some ideas include baby photos (so they can see that there have been big changes in her life, even if the noticeable changes seem tiny to their peers), photos of their adaptive equipment (so you can show them "how Jessie is learning to walk," or "how Jessie sits up to eat at home"), or photos of your child in recreational settings ("See, here's Jessie riding her tricycle in the holiday parade" or "Here's Jessie swimming"). 

4.QUESTIONS & ANSWERS
Let the children ask questions after you've given your short explanation of chromosomes. Some typical kid questions and answers you may find handy: 

"How can Jessie be six or seven years old and still not walk or talk?"  Respond by asking if they know any other children their age who cannot walkyes, they will say, there's a boy at school who uses a wheelchair, or a girl who has crutches because she broke her leg. So, you say, not everyone your age can walk all the time. Do they know a child their age who cannot talk? Oh, yes, one will say, my cousin has autism, and she doesn't say too many words; or there's a boy at my school who has a hearing aid and sometimes when he talks I can't understand him. So, you say, sometimes seven year olds can't talk very well, either. 

"How can Jessie be eight years old? She's smaller than my three-year-old brother!" Explain that your child doesn't grow as quickly as other children, because her body doesn't know how to use food to make bones, and muscles, and fat, the way it should. But she does grow. And she really is the age you say!

"Why does Jessie have [x]?"(X may be a g-tube, a trach, metal teeth, AFOs, whatever) Explain that your child needs some extra help with some things other bodies can do alone. Remind them that lots of people use extra helphow many of their parents wear glasses? How many of their friends have braces? Have any of them ever used crutches, or a sling to support a broken arm?  Surprise them with an unusual fact: "Jessie's AFOs are specially made just for hershe got to pick out the straps and trim to match her favorite colors," or "Jessie's g-tube means she NEVER has to taste yucky medicineswe put them into her stomach with the tube, so she doesn't have to swallow them." Tell them that they should not be afraid of the extra things on your child's bodythey're not hurting your child, and they won't do anything strange. (Kids may think any visible tube will squirt at them, or that the body part inside an orthotic is oozing or swollenchildren have active imaginations, and many will imagine horrible things if no one tells them differently).

Some quick Q&A examples...
"Does Jessie go to school? "Sure she doesand she takes the bus too.

"How does she do her homework if she can't write? "Well, Jessie's homework is different from yours, but he still has to do it.

"Will Jessie ever talk? "We don't know, but her best chance comes from having friends like you, who talk to her anyway.  

"Can I help push Jessie's stroller sometimes? "Yes, if you always ask for permission first, and you promise to be very careful. She's not a toy, remember.

5.CHECKING FOR UNDERSTANDING
Before you finish your presentation, ask the children to tell you what they learned this is your chance to correct any misunderstandings they may still have. Reassure them that they can't "catch" a chromosome disorder from your child; that if they weren't born with a chromosome disorder, they won't ever "get" one. Remind them that the word you want to hear them use when they talk about your child's condition is [x] (this will vary from family to familyI prefer that they say Jake is "disabled," or "has a disability," but you may have another word that you prefer to hear). Acknowledge that they may hear people use other words, but you don't like those as well. If it's a concern, you may also want to say something like, "Now I know you will all agree that it would be very mean to make fun of Jessie's speech/movements/behaviors/appearance because now you understand that she's doing her very best, but her body works differently than yours, that's all. And that goes for other people with disabilities too, right?"  Finally, tell them that you're glad they're going to be part of your child's life, and you know they'll all have more fun together, now that everyone understands more about her condition and her different needs.

Example: del(9)(p22.1.)This is how a terminal deletion (any thing north of this band is deleted) is written - If this was an interstitial deletion (meaning involving only the band mentioned) it would have been written as del(9)(p22.1p22.1). Shashikant Kulkarni Director of Clinical and Molecular Cytogenetics Assistant Professor of Pediatrics Genetics & Genomic Medicine Department of Pediatrics CDO Medical Advisor

Since lactase dehydrogenase is a recessive condition, there would have to be a second genetic change on her other chromosome that is not involved with the deletion in order to be affected. This is an uncommon situation. Having said that, uncommon situations occur. My thinking would be to look into the symptoms of lactase dehydrogenase deficiency-diahrrea etc, and if these are present then look into testing.
Robert Wallerstein, MD
Medical Geneticist

Answered by Robert Wallerstein M.D.

Tetraploid is a condition where there is an entire extra set of chromosomes-92 in total. Tetraploid is usually an artifact of culture meaning that it is something observed in the laboratory and not in a person due to the way in which the testing is performed. This can be seen in some cells or in all cells. It is commonly seen in some cells in an amniotic fluid specimen and thought to be a normal variant. When seen in all cells, it has more concern as it is linked to miscarriage. If an ultrasound of the pregnancy is done at the same time and found to be normal, it is likely an artifact or some normal cells from the membranes of the pregnancy which can have tetraploid with no consequence. We do see tetraploid in some miscarriage tissue specimens so it is probably linked to pregnancy loss in some cases. 

One way to determine if the correct interpretation is normal variation after an amniocentesis is to obtain a fetal blood sample from a procedure called PUBS- percutaneous umbilical blood sampling. This is a technique where a specialist inserts a needle into the umbilical cord and removes a small amount of blood. This is usually a safe procedure in the hands of a skilled perinatologist (high risk obstetrician), but does have some risk. The chance of miscarriage after a PUBS procedure is quoted as 2 to 5%. This fetal blood sample is a way to look directly at the chromosomes of the fetus. 

The placenta and membranes of a pregnancy arise from the same genetic material, but are not under as tight control as the fetus so there are variations in chromosome number that can be isolated to the placenta and membranes without affecting the fetus. This is usually the case with tetraploid. If the ultrasound looks normal and there are no other issues, it usually has a normal outcome. There have been a few cases of people with mental retardation who have a tetraploid cell line. Some cells tetraploid, others normal. So there are some risks, but again most times normal outcome is the rule.

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Answer:

Both variants of this unbalanced translocation are too large to produce a viable fetus that is compatible with life. Therefore, there is a more than 50% chance that any further pregnancy will result in a miscarriage.  I think that almost all embryos with an imbalance caused by this translocation will die before 10 weeks. Therefore, if the mother is 12 weeks and there are no ultrasound abnormalities of the fetus, it is a very good sign. But, I can't guarantee that survival until 12 or even 14 weeks is not possible.

*Editor’s Note: Chromosome translocations are each very unique. Some unbalanced translocations are compatible with life.  For specific information on any translocation please submit an ASK THE DOCTOR inquiry or email info@chromodisorder.org for assistance. 

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Answer:

Sexual ambiguity may be found in many types of gonadal dysgenesis (sort of 45,X/46,XY; 46,XX/46,XY, numerous structural abnormalities involving Y) and in several autosomal abnormalities (del 9p24, del 13q32 etc.) but patients with 47,XXX do not fall into this category.

I checked a database of chromosome variants that have been previously reported in (presumably) normal individuals. There is one report of a variation at the same location. Although details about this "normal" variant and the person carrying it are not available, it does suggest that the duplication by itself may not cause this patient's problems. However, it could be a contributing factor. There is not yet a comparable database of chromosomal variants in diseased individuals. This leaves us with the frustrating status of "variant of unknown significance." This is a common problem with chromosomal microarray analysis.

Dr. Andrew Zinn
Medical Geneticist
CDO Medical Advisor

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Basically only 3% of human DNA contains genes.  The other 97% contain remnants of old genes, regulatory regions, so-called parasitic DNA, etc. Deletions or duplications of the regions which do not include genes are considered as having no clinical significance.  Most likely, the segments of chromosome 7 deleted and the segment of chromosome 3 duplicated in your daughter’s DNA  do not contain any genes.   It is possible that she inherited these harmless variants from you or from her father.

Some ring (22) chromosomes are “supernumerary” meaning that the ring is found in addition to a normal set of 46 chromosomes. Those individuals can have symptoms similar to Cat Eye Syndrome because there is an extra piece of chromosome 22.

Michael Graf MS, CGC, MBA
CDO Medical Advisor

This is a very difficult question to answer as it is very individualized. There are some children with chromosomal disorders that don’t survive past the neonatal period. There are others that survive to senior citizen age. In general children with a variety of severe disabilities are surviving longer. The issues involved are better care for children with disabilities and a more aggressive approach. As an example: years ago, open heart surgery would not be offered to a child with Down syndrome due to its limited availability and quality of life issues. Now, the thinking has so radically changed that it is standard of care to offer surgery for Down syndrome individuals if needed. This has had a dramatic impact on the survival for these individuals. The average age of survival for these individuals previously was mid 30’s now it is 65.



The change in medical care to offer the full range of treatments and supports to individuals with developmental disabilities has changed this outlook.



Now, to be more specific about your question, children with chromosomal disorders can often have swallowing difficulties. This can create a situation where there is aspiration of food or saliva into the lungs and creates chronic pneumonias. This is a major health issue. Congenital heart disease is a problem. Kidney disease can be a problem. If a child has significant problems with a major organ system, his or her survival may be compromised. It really is not possible to give any estimate as it is so variable. In our practice, we have patients who are newborns essentially age 0 all the way to 67years.



Our suggestion is to look at long term survival and plan for such so that a child’s needs may be met as needed. If anyone gives you an estimate, it is just a guess as none of us knows exactly what the future holds. Serious issues can shorten life and we can hazard a guess, but that is all that it is. IN general children who are severely affected by chromosomal disorders who survive past the newborn period are surviving to their 20’s. Please heed our caution that an individual situation can vary widely.

Robert Wallerstein M.D.
Medical Geneticist

The standard cost is about $500.00 per person. If you have insurance it should be covered.
Andrew Zinn MD
Medical Geneticist

Answered by Iosif Lurie MD, Medical Geneticist

Chromosome Disorder Outreach provides information on chromosome abnormalities, which cause developmental and/or medical symptoms, and which are present from birth. Our focus is solely on congenital disorders. 

Many cancer cells also have changes in their number of chromosomes. But these changes are not inherited; they occur in somatic cells (cells other than eggs or sperm) during the formation or progression of a cancerous tumor.

There are multiple conditions (including myelodysplastic syndromes (MDS)) where patients have acquired chromosomal abnormalities occurring due to changes in previously normal cells. These conditions are not congenital chromosomal disorders but rather acquired changes due to a disease process.  The excellent cancer specialists at Anderson Medical Center are much better able to answer the questions you posed in your inquiry.  Our best to you.

Answered by Dr. Iosif Lurie

The general risk of any abnormalities (even with normal chromosomes) is ~2.5-3%. Add the risk related to a de novo X-autosomal translocation (~3%), and you will have a risk of ~5.5-6%.  

Considering that the phenotype of a ring chromosome can be so variable, I would think pediatricians would want to know whether a ring exists in this child with a family history of ring(21), even without apparent symptoms. It might take a discussion with the physician, and it definitely might require an explanatory letter to an insurance company (either proactively or if the initial claim is denied). The insurer may still (arguably appropriately) deny the claim since child is not showing symptoms. The physician may be more open to ordering chromosome to ensure the child doesn’t have a ring to ease the parent’s anxiety and to know whether the child should be monitored more closely, but also because it may be important for the child to be tested as they reach child bearing age because ring chromosomes can cause problems during meiosis. Michael D. Graf, MS, MBA Director, Business and Program Development Certified Genetic Counselor

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Chromosomal examinations are able to detect an excess or absence of any chromosomal segments, but they cannot detect mutations in one gene. There are several thousand genetic disorders, caused by mutations of one gene, and detection of any of these disorders requires specific analysis of these genes. So, basically if a physician suspects that a patient has Marfan syndrome he/she must order a test to detect Marfan syndrome. Likewise, if there is suspicion of Tay-Sachs disease, the specific tests have to confirm/reject this diagnosis. 

The same is true for neurofibromatosis I: most cases of this disease are caused by mutations in NF1 gene, and only a special test for this disease can confirm the diagnosis. Cytogenetic (i.e. chromosomal) examination is not a relevant test for a diagnosis of neurofibromatosis I, and testing for neurofibromatosis is not an obligatory part of a genetic examination of any patient. This test is performed only when there is a clinical suspicion for this diagnosis.

Editor's Note:  

Neurofibromatosis 1 (NF1): also known as von Recklinghausen NF or Peripheral NF. Occurring in 1:3,000 births, web characterized by multiple cafe-au-lait spots and neurofibromas on or under the skin. Enlargement and deformation of bones and curvature of the spine (scoliosis) may also occur. Occasionally, tumors may develop in the brain, on cranial nerves, or on the spinal cord. About 50% of people with NF also have learning disabilities.  NF1 is located on chromosome 17. 

Fortunately this type of deletion usually does not have major clinical consequences in girls, since one X chromosome is inactivated in all females, and when one chromosome is abnormal, it is the one that is generally inactive. If there is a problem, it most often involves fertility, but the severity is highly variable. However, I would want to know if the chromosome study was done for routine prenatal diagnosis or because of specific medical problems.

Andrew Zinn MD
Medical Geneticist

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

Answer:

Boys with similar small duplications of chromosome Xq26.2 show almost identical abnormalities with the Croatian child. Moreover, this boy has only two duplicated genes OR13H1 and FIRRE. Therefore, the critical region may be narrowed to these two genes. We do not know whether this boy has periventricular heterotopias or not, but it does not change the situation. Absence of abnormalities in his mother may be explained by inactivation of the X-chromosome carrying duplication.

In about 10% of cases of low sperm count, or absence of sperm with no other known cause, there may be a visible deletion of the Y chromosome that can be observed in the mans metaphase cells under the microscope. These studies are called chromosome analysis or karyotyping (cytogenetics is also used to term these studies). It required a sample of about 10mls or less of whole blood submitted to a cytogenetics laboratory.

Research studies of the genes in the region of the Y that can be deleted in infertile males, have shown that there are a handful of genes that are necessary for normal sperm production. Sometimes there can be mutations in these genes which are not visible under the microscope, so specialized techniques are used to study the DNA from the patient, focusing on the Y chromosome genes that are known to be involved in sperm production. About 2% of healthy males are infertile because of low sperm production. No one knows at this point how many of these males have the mutation in the genes on the Y, however it is assumed that a proportion of these men will have
mutations if they are tested. Therefore, DNA testing for the Y chromosome
mutations involved in sperm production is a common recommendation. This also requires about 10ml of whole blood sent to a specialized DNA laboratory that does these tests.

Because males with these mutations are typically normal and healthy, with their only symptom being infertility, there is no increased risk for birth defects in a child, should this individual be able to conceive using his own sperm. His daughters will not, of course, get his Y chromosome, so they are not at risk for anything other than the background risks that are counseled for in this couple. If the man has a visible deletion on his Y chromosome, or very small mutation on his Y discovered through genetic testing, this would account for his low sperm count, and his sons can expect to have the same condition, since they would get their Y from him.

With a sperm count of 1 million, specialized reproductive techniques available at certain centers may be able to use his sperm for IVF.

Mary Haag
CDO Medical Advisor

The Y chromosme carries only a few genes. They are involved with male
sexual characteristics and fertility. The q arm is mostly heterochromatin-
genetic filler that is not active. Deletions of the Yp arm can affect
fertility depending on where the deletion is located. Molecular studies for
some of the infertility areas can be helpful to understand where the
deletion is located and what is involved. this usually is involved in
fertility issues. The specific scenario of why the chromosome study was
initially performed could be helpful in understanding the situation.

Robert Wallerstein CDO Medical Advisor
Medical Geneticist