The Genetics Front:

There have been a few chromosomal arrangements found in a subset of women with MRKH (Ledig et al., 2011; Nik-Zainal et al., 2011), and a few genes have aberrant function in adult uterine remnants (Rall et al., 2011).

These are intriguing, but not causative findings.  The chromosomal rearrangements simply say that there is possibly a mutation in a gene near this breakpoint that could be implicated (not necessarily causative) in MRKH (Ledig et al., 2011; Nik-Zainal et al., 2011).  However, we have no idea where the breakpoint is. If we think of chromosomes as interstates, then what we know is that a pothole somewhere in a 500 mile span on I-95 near Jacksonville, Florida caused the wheel to fall off on 5 or 10 cars. However, we are presuming that it is the pothole that caused the wheel to fall off. There is always the possibility that the reason the wheel fell of is because the lug nuts are loose or something else happened. It could also be that the reason the wheel fell off is that because these 5-10 cars hit the pothole, but also had loose lug nuts. Other cars that hit the pothole, but had tight lug nuts fared just fine.

Just as there are many towns and cities within any 500 mile section of I-95, there are many genes located in the same region of these chromosomes, so finding the particular pothole or pothole plus loose lugnut combination is very, very difficult.

As for the second scenario---

One or two papers showed that a subset of women with MRKH (about 5 or 10) had genes with abnormal function in uterine remnants (Rall et al., 2011). This sounds really promising, as a few of these genes are known to be important in development of the uterus. However, this data needs to be interpreted with caution. In order to determine the genes that are causal to MRKH, it is necessary to look while the uterus is forming, not at later time points. Uterine remnants from adults give the closest approximation of what could have gone wrong, but do not really tell us what went wrong during embryogenesis.  

For example, you come home from work and find out that the paper towels you left on the counter are scattered throughout the house and that the stack of papers you left on the table has crashed to the floor. Since your dog was at home, you conclude that your dog did both of these things. This is a reasonable conclusion, but does not take all of the potential scenarios into consideration. For example, you also left the window open, and it was really windy during the day. It is also possible that the wind blew the stack of papers off of the table. However, in order to determine what happened, you decide to hide a video camera in the kitchen. After watching the footage, you determine your neighbor came in during the day to borrow a cup of sugar and her two-year old made a mess in your house! So, what I am trying to say is that even though several genes have abnormal function in uterine remnants from women with MRKH does not mean that defects in these genes caused MRKH. They provide important clues, and are the best guess given what we know, but since we have not examined the function of these genes during embryogenesis in a fetus that has MRKH, it is impossible to determine if misregulation of these genes or other genes occurred in the patients examined.  

Here are the references for the 3 articles I summarized:

Ledig, Susanne, Cordula Schippert, Reiner Strick, Matthias W Beckmann, Patricia G Oppelt, and Peter Wieacker. 2011. “Recurrent Aberrations Identified by Array-CGH in Patients with Mayer-Rokitansky-Küster-Hauser Syndrome.” Fertility and Sterility 95 (5) (April): 1589–1594. doi:10.1016/j.fertnstert.2010.07.1062.

Nik-Zainal, Serena, Reiner Strick, Mekayla Storer, Ni Huang, Roland Rad, Lionel Willatt, Tomas Fitzgerald, et al. 2011. “High Incidence of Recurrent Copy Number Variants in Patients with Isolated and Syndromic Müllerian Aplasia.” Journal of Medical Genetics 48 (3) (March): 197–204. doi:10.1136/jmg.2010.082412.

Rall, Katharina, Gianmaria Barresi, Michael Walter, Sven Poths, Karina Haebig, Karin Schaeferhoff, Birgitt Schoenfisch, et al. 2011. “A Combination of Transcriptome and Methylation Analyses Reveals Embryologically-Relevant Candidate Genes in MRKH Patients.” Orphanet Journal of Rare Diseases 6: 32. doi:10.1186/1750-1172-6-32.

Amy C. Lossie, PhD

Feb 7, 2013
From The Incubator, Hatching Conversations About Science 
On the Doctor-Patient Disconnect
By Michelle Lowes, MD 


http://incubator.rockefeller.edu/?p=177

What a refreshing read! Dr. Lowes wrote an insightful essay to start the conversation on how to improve doctor-patient relationships. The following excerpt from the article really sums up my thoughts about how to navigate the complex medical system. Those of us who know how to critically navigate the system have a huge advantage over those that do not have access to medical journals that are often hidden behind paywalls, to the tune of $35-50 per article. We also have been trained to critically evaluate these articles and can easily digest and interpret conflicting reports. Here is an excerpt from her essay:

"I've been thinking a lot lately about how patients navigate the medical world. There's a lot of information out there, but you have to find it, read it, and understand it all. I'm a doctor, and the first thing I would do is find a specialist who treats panosis (a made up disease). I'd go to PubMed and research the medical literature on panosis. I’d pull down reviews and recent studies and weigh my treatment options. I’d probably get a second opinion. I know what questions to ask and I can deal with the medical jargon. I would even ask to see the lab results and go over them myself and discuss with colleagues. I can work out the limitations of the tests, what being outside the range of normal means. But I doubt that my approach is what most people could or would do."

I encourage all of you to read this article and give her feedback, because it filled me with hope, hope that at least one physician understands and is working to make it easier for all of us to navigate the system. I hope she is training the next generation of physicians, and instilling a sense of patient-centered obligation to all of her trainees. 

Amy C. Lossie, PhD

March 23, 2013
My Take on the Heredity of MRKH:  A Geneticist Discusses MRKH


There is considerable debate about whether or not MRKH is caused by mutations in a specific gene or genes OR whether it is a sporadic event that is not caused by DNA mutations.

Dr. Laufer thinks it is not heritable because he has one patient who has an identical twin sister who does not have MRKH. This indicates that in this particular woman with MRKH, there was most likely NOT a mutation in her DNA. However, it is entirely possible that a new mutation arose in this individual after the twins separated from a single egg. This would be called a somatic, de novo mutation, and they are rare, but do occur. So, I do not completely agree with Dr. Laufer's argument, unless he has sequenced the entire genome of these two women and found that there are no differences in tissues that are closely related to the uterus (i.e. kidney).  I would not necessarily believe sequence data that came from blood, because a mutation could have occurred that only affects the mullerian tissues, and that would not be seen in blood.  The closest tissue type is the kidney.  I sincerely doubt Dr. Laufer could get ethical approval (called IRB for Institutional Review Board approval) to biopsy the kidney from the two sisters and perform these tests.

In contrast, there are at least 5 examples I know of where at least 2 family members (sometimes sisters, nieces, or cousins) that have MRKH. This implies that there IS a genetic component, and argues quite convincingly that MRKH is NOT caused by a single gene mutation (like cystic fibrosis), but is instead due to DNA mutations in multiple genes AND/OR other types of mutations that affect when genes are turned on or turned off. These can include DNA mutations in regulatory regions and epigenetic mutations (mutations that occur in the DNA punctuation). Epigenetic mutations are sometimes repaired during embryogenesis, but sometimes can happen during embryogenesis. So, it is very difficult to make a definitive answer. 

The reasons I say that MRKH is probably not caused by a dominant mutation in a single gene are that: 1. There is at least one example where an Aunt and niece both have MRKH. This implies that the sister of the Aunt is a carrier for at least some of the mutations. 2. Several women with MRKH have had daughters through IVF/surrogacy that do not have MRKH. 3. Several physicians (i.e. Dr. Joe Leigh Simpson) that study MRKH believe it is part of a spectrum disorder, with MRKH being on one end of the spectrum (i.e. more mutational events or sporadic defects during pregnancy) and bicornate uterus on the other. Some women with bicornate uterus can get pregnant, while others cannot. 

The best evidence for what can be expected comes from the MRKH community. Several women with MRKH have used IVF and surrogacy, and I have not heard of any examples of where their daughters had MRKH. However, I do not know the numbers of women who have done this, and therefore, do not know if the data would be statistically significant. Given the fact that I think mutations in many genes (maybe 5 or more) are necessary for MRKH, I would not expect that the daughters themselves would have MRKH, but could carry a subset of the mutations. I have weighed the pros and cons of this very carefully, and although I chose not to have children, it is not because I was afraid of having a daughter with MRKH, although my husband (film and video guy, not a geneticist) was quite concerned about that. 

At this point, I cannot say with certainty that MRKH is or is not caused by mistakes in the DNA that can be passed on to the next generation. I’ve tried to provide the group with information that they can use to make a more informed choice regarding having biological children. 
Amy C. Lossie, PhD

Lawrence C. Layman, M.D. Prof & Chief 
Section of Reproductive Endocrinology, Infertility, & Genetics Department of Ob/Gyn 
Developmental Neurobiology in IMMAG 
Neuroscience Program


Telephone:  (706) 721-3832, (706) 721-7591
Fax: (706) 721-6830, (706) 721-0340
Email:  llayman@georgiahealth.edu
Lab website: http://www.georgiahealth.edu/institutes/immag/Lawrence/index.htm


Dr. Lawrence C. Layman, M.D. is the Robert B. Greenblatt, M.D. Chair in Endocrinology and Section Chief of Reproductive Endocrinology, Infertility, & Genetics at Georgia Regents University. After completing medical school at the University of Cincinnati, he did a residency in Obstetrics & Gynecology at the University of Louisville and a fellowship in Reproductive Endocrine & Genetics at the Medical College of Georgia. He is board certified in four different medical specialties—Obstetrics & Gynecology; Reproductive Endocrinology & Infertility; Clinical Genetics; and Clinical Molecular Genetics.            


Dr. Layman is a physician-scientist who takes care of patients and has a special interest and expertise in the management of delayed puberty and reproductive tract anomalies such as Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. He has been funded by the NIH since 1997 for a grant entitled “Genetics of delayed puberty.” He has published more than 100 papers in peer-reviewed journals and reviews. His research efforts have focused on identifying genes in delayed puberty due to idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS), and he has characterized 4-5 new genes. He became interested in finding the cause(s) of MRKH during his clinical practice, where several patients with MRKH are currently under his care. He is conducting genetics studies and actively pursuing funding to identify mutations in genes that cause MRKH.

© 2012-2013. Beautiful You MRKH Foundation, Inc. All rights reserved. 

Talking about MRKH Research

Feb 7, 2013
From The Incubator, Hatching Conversations About Science 
On the Doctor-Patient Disconnect
By Michelle Lowes, MD 


http://incubator.rockefeller.edu/?p=177

What a refreshing read! Dr. Lowes wrote an insightful essay to start the conversation on how to improve doctor-patient relationships. The following excerpt from the article really sums up my thoughts about how to navigate the complex medical system. Those of us who know how to critically navigate the system have a huge advantage over those that do not have access to medical journals that are often hidden behind paywalls, to the tune of $35-50 per article. We also have been trained to critically evaluate these articles and can easily digest and interpret conflicting reports. Here is an excerpt from her essay:

"I've been thinking a lot lately about how patients navigate the medical world. There's a lot of information out there, but you have to find it, read it, and understand it all. I'm a doctor, and the first thing I would do is find a specialist who treats panosis (a made up disease). I'd go to PubMed and research the medical literature on panosis. I’d pull down reviews and recent studies and weigh my treatment options. I’d probably get a second opinion. I know what questions to ask and I can deal with the medical jargon. I would even ask to see the lab results and go over them myself and discuss with colleagues. I can work out the limitations of the tests, what being outside the range of normal means. But I doubt that my approach is what most people could or would do."

I encourage all of you to read this article and give her feedback, because it filled me with hope, hope that at least one physician understands and is working to make it easier for all of us to navigate the system. I hope she is training the next generation of physicians, and instilling a sense of patient-centered obligation to all of her trainees. 

Amy C. Lossie, PhD

Elisabeth Quint, M.D. 

Assistant Dean for Clinical Faculty
Professor of Obstetrics and Gynecology
4121 Med Sci I, SPC 5628
1301 Catherine St.
Ann Arbor, MI 48109-5628
Phone: (734) 763-0253
email: equint@umich.edu

Dr. Quint received her M.D. in 1985  from The University of Leiden Medical School in the Netherlands. She completed her residency in Obstetrics and Gynecology at the University of Michigan and joined the U of M faculty in 1991. She was appointed to the rank of Clinical Assistant Professor in Obstetrics and Gynecology in 1993, promoted to Clinical Associate Professor in 1999 and Clinical Professor in 2005. She has served as Assistant Dean for Clinical Faculty since 2004. 

Dr. Quint is a Board Member and Past President of the North American Society for Pediatric and Adolescent Gynecology, a member of the Adolescent Health Care Committee of the American College of Obstetrics and Gynecology and an examiner for the American Board of Obstetrics and Gynecology. She is an expert in pediatric and adult care of teens, women and families affected by MRKH. She has published extensively on different aspects of MRKH, including psychosocial effects and therapeutic innovations. She has actively fought for MRKH awareness throughout the medical community. 

Full Bloom Professional Memberships in Alphabetical Order

Marc R. Laufer, MD

For Teens: 
Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School
Chief of Gynecology, Boston Children's Hospital: www.childrenshospital.org\gynecology
Co-Director Center for Young Women's Health: www.youngwomenshealth.org
Phone: (617) 355-7648

For Adults:
Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School
Center for Infertility and Reproductive Surgery, Brigham & Women's Hospital
Phone: (617) 732-4222

Dr. Laufer is a Professor of Obstetrics, Gynecology, and Reproductive Biology at Harvard Medical School. Dr. Laufer came to Boston as an intern/resident in OB/GYN at Brigham & Women’s and Massachusetts General Hospital in 1986 after completing his undergraduate studies as a University Scholar and his medical degree, both at the University of Pennsylvania. After residency he then completed specialty training in fertility and pediatric and adolescent gynecology.  He has been the Chief of Gynecology at Children’s Hospital Boston since 1994 and is a gynecologic specialist in the Center for Infertility and Reproductive Surgery at Brigham and Women’s Hospital.

Dr. Laufer is widely recognized as one of the world’s leading experts in pediatric and adolescent gynecology, endometriosis, and structural anomalies of the reproductive tract.  He is a co-author of Emans, Laufer, & Goldstein’s Pediatric and Adolescent Gynecology now in its 6th Edition.  His areas of clinical expertise include adolescent and adult endometriosis, and surgical and non-surgical management of congenital anomalies of the reproductive tract. He is the Co-Director of the Center for Young Women’s Health [www.youngwomenshealth.org] which was established in 1997 and receives over 1 million visitors per month.  The educational website provides resources for girls and young women on hundreds of health topics.

Dr. Laufer is an expert in the diagnosis and management of MRKH.  He treats teens and adults from around the world in a multidisciplinary team approach at both Boston Children’s Hospital and Brigham and Women’s Hospital.  The team hosts an annual conference for teens and families with MRKH yearly in Boston.