Q. What can be determined by a Level 2 Ultrasound?
A. *Cleft palates are generally observed by looking at the tooth buds and noticing if there is a break in the horseshoe-like appearance. Cleft lips can be seen as a break in the skin.

*Agenesis of the corpus callosum is a very difficult call prenatally. One of our top radiologists the other day said that he believes he has as many false positives as he has false negatives on prenatal ultrasound.

*Hypertelorism is observed by expecting to see an equal ratio of the left eye, the space between, and the right eye. If this is not in equal thirds the radiologist may suspect hypertelorism. There are also standard measurements for a given fetal age.

*When looking for it, it is possible to identify hypospadias prenatally

Q. What is gonadal mosaicism?
A. Well, to get us on the same page remember that a dominant condition is caused when one copy of a gene (from our mother or father) has a mutation that causes the condition. Usually dominant conditions are passed down from affected person to affected person in a family. Sometimes, when a baby develops, a new mutation occurs which causes the condition. In this case the baby has a risk (50%) to have affected children, but no one else in the family carries a gene mutation.
You might imagine that a new mutation can occur virtually anywhere in the body and that the number of cells with the mutation varies depending on the stage of development when the mutation occurred. Some people may have met someone who is said to be mosaic for Down Syndrome, meaning that only a portion of the cells in their body have the extra chromosome 21. Sometimes people who are mosaic for Down Syndrome seem to be more mildly affected than people who have the extra chromosome in all the cells of their body because of the normal activity of cells in their body with the usual 46 chromosome compliment.
Our gonads are our reproductive organs (a woman's ovaries, a man's testes). If you imagine a new mutation occurred in the gene for G/BBB syndrome in some of the cells that will become eggs or some of the cells that become sperm, you might imagine that the person would not be affected, but would be at risk to have multiple affected children. In other words, rather than a new mutation occurring in the developing child, the new mutation occurred in the egg or sperm cells of the parent. Thus each time a child is conceived there is a chance (related to the number of gonadal cells with a mutation) that the child will be affected. When a geneticist looks at a family like this it is a puzzle because the geneticist would have thought either the mother or father would have signs and symptoms of the dominant condition for there to be more than one affected child. Gonadal mosaicism has been shown to explain this puzzle in other conditions.

It's so difficult to be patient with the researchers when your family plans are on hold. I can only hope that we will take great strides forward very soon, and have a test available for G/BBB that detects nearly all affected persons. Thank goodness we have people like Drs. Muenke and Ballabio who are interested and actively pursuing this.

Q. How often do mutations cause Opitz G/BBB syndrome?

A. There are a couple of concepts here that come into play. I think that you have a good handle on them, I'll just provide the vocabulary.

First, there is the idea of fitness. This is the idea that if a condition is so severe that the affected person does not have children, there must be new mutations in the world for the condition to be perpetuated. If, on the other hand, someone can have the condition and have children at the normal rate, the rate of new mutations does not need to be high. This can be represented mathematically. The person who is completely unable to have offspring has a fitness of 0 and the person who has offspring completely as usual has a fitness of 1. You might imagine the G/BBB syndrome has a fitness somewhere in between. We know of some affected people who will probably have offspring at the usual rate, and there are other affected people who probably will not become parents.

An X-linked condition with a fitness of 0 (such as Duchenne Muscular Dystrophy) has a new mutation rate equal to 1/3. Given this, the very highest the new mutation rate could be for X-linked Opitz syndrome is 1/3 or 33% of the time. To use another example, classic hemophilia has a fitness of 0.7 and a new mutation rate of 15%.

Okay, for you math-buffs out there Haldane's rule is: m = s x u divided by 2u + v'
where s is selective disadvantage, v is the mutation rate in males, and u is the mutation rate in females. m is the proportion of all patients with an X-linked recessive disease who have a new mutation.

Clinically, someone who is an expert in G/BBB syndrome like Dr. Opitz can make educated guesses that someone in the family tree (talking about X-linked inheritance now) appears to have been a carrier or affected. It is possible, for example, that a maternal uncle was affected or even the maternal grandfather, although frequently the condition is expected to have gone silently from female to female in the family. Female carriers of X-linked Opitz syndrome may have very subtle signs such as hypertelorism (widely spaced eyes).

Another concept in genetics that I should touch upon is the idea of variable expressivity. Imagine several people in a family have the mutation that causes G/BBB syndrome. However, one person has serious medical issues, another has only slightly annoying medical concerns, and a third person never even noticed that he/she was different (although a medical geneticist with a critical eye could pick him/her out).

If we were to go one step futher and say that some people with the gene mutation clinically have G/BBB syndrome, and other people in the family have the gene mutation but clinically have no signs or symptoms of the condition, this would be called reduced penetrance. With reduced penetrance it is an all-or-none (not shades of grey)phenomenon. For example, we are collecting samples on families with spontaneous pneumothoracies. In this condition women with the gene mutation will have a pneumothorax in their lifetime about 20% of the time, while men with the gene mutation will have a pneumothorax 50% of the time.

The reason I bring up these ideas is that we clearly see that G/BBB syndrome seems to "skip generations." Now if we were to sift back through information you may have on your relatives and ancestors we may find subtle signs (very mild expression of the condition) and we may even consider that the condition entirely skipped somone (reduced penetrance). So now when we are asked, "how often is there a new mutation with dominantly inherited G/BBB syndrome?" we have a very difficult question before us. While it may appear to come out of nowhere (i.e. a new mutation) we cannot be entirely confident that this is the case. When pressed, Dr. Opitz honestly replied that no one knows the answer; he could not venture a guess.

I believe that we will be able to re-evaluate the situation once we know the gene mutations that kids with G/BBB syndrome carry and can trace it back through the family. We have to wait for the empiric answer to come from a study of the genes, rather than our clinical impressions.

I hope this helps.

Thank you Alexis. You help us understand!