My second email to Dr. Hall

Dear Dr. Hall,

Thank you very much for your reply.

I believe that you are referring to the study reported in Klopocki et al, 2007 (AJHG 80, 232)? Both you and Dr. Mundlos are co-authors on that paper. I came across the paper many months ago and gave a copy to Emma's geneticist, Dr. Yano, at USC Women and Children's Hospital. This is exciting research and it would be wonderful if Emma could somehow contribute to this! I will definitely get in touch with Dr. Mundlos.

Unfortunately I don't know the answer to your question about chromosome studies. I suspect that Emma has not had any genetic studies done to date, as her doctors at USC have been quite satisfied with the diagnosis of TAR Syndrome, knowing that (at least, until Klopocki et al) there was no known genetic test that would confirm this diagnosis.

I think it's very important now that they test her to confirm or rule out the microdeletion on the 1q21.1 chromosome reported in your study, given the partial radius bone discovered by Dr. Paley.

Also, I should let you know that, after Dr. Paley told us about his surprise finding in Emma's left arm, I sent out an electronic plea to the Yahoo TAR Support Group for anyone with a diagnosis of TAR Syndrome who may have a partial radius on one or both sides to email me and let me know.

I received two positive responses:

a) The first was from the mother of a girl who has an abnormally low IQ. This girl was born with TWO partial radii! But her orthopedic surgeon removed them, saying that the bone fragments might become infected if left in place!? This girl is a teenager/young adult, and her mother reports that she has never been tested to see if her low IQ might be due to an intracranial bleed or to some other cause.

b) The second was from a young woman who reported that one of her friends with TAR Syndrome has a partial radius bone. She says her friend is a young married female who has a child with the diagnosis of TAR Syndrome as well.

Could this possibly be phenotypic variation?

I will keep in touch with you and let you know what happens after I contact the research group in Germany. I have a website that I recently created for Emma which is not yet public (it's still a work in progress)...here is the URL, if you'd like to "meet" Emma:

http://planetemmaclarissa.blogspot.com/

You can see that Emma is very special in many ways. :-)

Thanks again,
JoAnn

Dr. Hall's reply, received 25 April

Dear Mrs. ***,

It does sound like Emma is a puzzle and as you point out, microcephaly, developmental delay and cerebral palsy may well be related to the drugs and alcohol during pregnancy. However, Emma may be one of the keys to the whole TAR situation!

Last year after almost 40 years of research, the cause of TAR was partially found. What was found was that all TAR patients have a small microdeletion on one of their chromosomes, but they also have some other factor that is not well understood yet. The research group in Germany who found the microdeletion are still trying to sort out exactly what is going on. I would suggest strongly that you get in contact with them since first of all I think they will do the testing for you for free and second of all it may be that Emma could be the key to what they are trying to work out.

Has Emma had chromosome studies done? There is a new technique in which it is possible to look for very small chromosome deletions, too small to see with a microscope, called CGH, (comparative genomic hybridization). I would also suggest that CGH be done to see if she has a very small deletion in the area of TAR or if she has some other chromosomal problem that could explain her other findings. In fact the presence of a small radius bone is fascinating and I am unaware of anyone else with that. However, it is also possible that the drugs and alcohol somehow allowed her to make that part of the bone that other TAR patients don't have. That's why I think it is particularly important that the studies be done on her.

The other potential answer is that there was a change in the genetic information in that part of her arm (a mutation with mosaicism). Thus, after the studies are done in Germany, it may be particularly worthwhile to take tissue at the time of surgery and look at the DNA from the cells in that tissue and see if they are somehow different from the DNA in her other cells. That is called DNA subtraction and again the group in Germany would probably be able to do that. I know Dr. Paley well. He is great and I'm sure would collaborate.

It is also possible that Emma has a bigger deletion than most of the TAR children and that could explain the problem. What we know from other families is that one or the other parents (who are perfectly normal), carry the deletion, and that the children inherit some other factor as yet unknown from the other parent that leads to thrombocytopenia and absent radius. That is why I say Emma may be the answer to the whole situation.

I'm pleased you felt you could write to me. Let me know what the folks in Germany say when you write to them. Feel free to attach my letter and your letter is a wonderful summary that should help them understand that Emma is a very special case.

Sincerely,
Judith Hall

My first email to Dr. Hall, sent 20 April

Dear Dr. Hall,

I'm writing to you about my 22-month-old adopted daughter, Emma, who happens to also be my biological granddaughter. I wish to ask your opinion of Emma's current diagnosis of TAR Syndrome, as you are the person who originally defined and named that syndrome. I was given your email address by someone I know through the Yahoo TAR Support Group. Please pardon my verbose email, but I feel that, since I am asking for your opinion on a previously established diagnosis, it is important that I give you as complete a picture of Emma's medical issues as humanly possible.

First I should inform you that my daughter Karen, Emma's biological mother, was homeless throughout her pregnancy with Emma, and has a long history of mental illness and drug and alcohol abuse. However, Emma did not test positive for drugs in her system at birth.

Emma has MULTIPLE diagnoses, the chief of them being TAR Syndrome. The others include (but are not limited to): microcephaly, Failure to Thrive, global developmental delays, GERD, asthma, eczema, and a soft-tissue anomaly, namely a retrocardiac mass (~3mm in diameter) which seems to be a cyst attached to her esophagus. She also exhibits renal abnormalities (duplicate collection system in one kidney, anomalous bladder structure) which may be associated with TAR Syndrome.

I should mention the fact that Emma has never had the severe problems with thrombocytopenia experienced by many children I know about from the TAR Support site. Emma has had exactly *three* transfusions in her life, all before she was 1 month old. By the time she was 6 months old, her platelet counts were occasionally spiking up to the 200-400 range (normal)! She does sometimes experience platelet counts as low as 20-60 during viral infections, and she was quite anemic for the first year of life.

Her developmental pediatrician and her regular pediatrician agree that it is highly likely that Emma also has spastic diplegia, albeit a mild manifestation of this type of cerebral palsy. This diagnosis has not yet been formally established. The pediatric neurologist at Los Angeles County USC Women and Children's Hospital refuses to see her until she is at least two years old (her 2nd birthday will be 7 June 2008). Around her birthday in June, she will be scheduled for an MRI of her head to be done in preparation for the pediatric neurology consult regarding the possible CP.

Emma currently can sit up for very short periods of time if we first position her properly on the floor. She cannot crawl or stand or walk. She is very weak in her trunk and even her head control is not what it should be for a child almost 2 years of age. She has been known to be very stiff in her hips and lower limbs, but not consistently.

I realize that Emma's microcephaly, global developmental delays and CP (or CP-like symptoms) may all be the direct result of Karen's drug or alcohol use during her pregnancy. We will never know for sure.

There is some lingering question about the possibility of craniosynostosis. A CT scan was inconclusive. A consulting neurosurgeon, Mark Krieger of CHLA, says that he seriously doubts that any of the sutures have closed. The only possibility that he sees is bilateral lambdoidal synostosis, but apparently some of the experts even doubt that this type of craniosynostosis exists, therefore it isn't possible. Our experience has been such that we believe, with Emma, all things are possible! :-)

The morphology of her head, after wearing an orthotic helmet for many months to correct positional plagiocephaly, is at least suggestive of craniosynostosis (at least in my humble opinion as a layperson). During the period that Emma wore her helmet, the back of her head slowly "rounded out" from the base of the skull up to the lambdoidal suture line, but remains flat above that line....which seems odd if craniosynostosis is not present.

Emma has been seen by numerous doctors at various clinics at LAC+USC WCH since birth, specifically hematology, urology, orthopedics, general pediatrics, neurosurgery, ophthalmology, developmental pediatrics, and nutrition. She is also supposed to be seen in the near future by a general pediatric surgeon about the cyst in her chest.

The latest development in Emma's saga occurred last Thursday, and it is the main reason I decided to send this email to you. Last Thursday was Emma's first visit to Dr. Dror Paley of the Rubin Institute, Sinai Hospital in Baltimore. Dr. Paley told us about Emma's astonishing x-ray results: she has a partial radius bone in her left arm! This remnant is NOT near the elbow, but instead is in the wrist area....and it has its own growth plate! Dr. Paley says that this opens up other options for the surgery on her left arm that he doesn't have with the right arm, which is missing the radius entirely. No one has ever bothered to tell us this before, if they even
noticed it.

My first thought upon returning home to California was to check your review on the following website: http://www.ivh.se/TAR/info/review.htm. Sure enough, my vague memory was correct. You state, "The consistent feature of TAR is absence of the radius but presence of the thumb. One hundred per cent (or as close as you can get to a hundred per cent) of individuals with TAR have bilateral absence of the radius. For practical purposes the diagnosis shouldn't be considered unless there is complete absence of the radius bilaterally."

So, now for the $64,000 question: does Dr. Paley's new finding regarding Emma having a partial left radius mean that she does NOT have TAR Syndrome?

If she does not have TAR, what on Earth does she have?? I found many many other syndromes in online searches (including the very rare Baller-Gerold, speaking of craniosynostosis), but none of them seem to fit Emma as well as TAR Syndrome. But, of course, I bow to your judgment in this matter.

I'm very interested in your opinion, and hope that you have the time and inclination to share it with me. Also I'm very grateful for your patience if you have bothered to read this far! :-)

Thanks in advance for your help in this matter,
Sincerely,
JoAnn