Home » Rothmund-Thomson Syndrome: Looking for Answers
June 2003 – Baylor College of Medicine
By Ruth SoRelle, MPH
When Lisa L. Wang, MD, was a first-year pediatric oncology fellow, one of her patients was a boy with osteosarcoma, a form of bone cancer, who also had a rare genetic disorder called Rothmund-Thomson syndrome (RTS). As she got to know him better, she learned that a sister had the rare syndrome as well, and she also had osteosarcoma.
“We consulted with Dr. Sharon Plon, who directs the Cancer Genetics Clinic, about the disease and asked if his osteosarcoma was related to Rothmund-Thomson,” she said. “The answer at the time was, ‘Probably, since osteosarcoma had been described in RTS patients in the literature, but we don’t what the exact relationship is.’”
In the second year of her fellowship, Wang joined Plon’s laboratory. In addition to directing the Baylor Cancer Genetics Clinic, Plon, MD, PhD, an associate professor in the departments of pediatrics and molecular and human genetics, also directs the Baylor Neurofibromatosis Clinic. Wang decided to research Rothmund-Thomson syndrome as well as its link to osteosarcoma.
Rothmund-Thomson syndrome, first described in 1868, is an autosomal recessive disorder, which means that patients have received defective genes from both parents. Patients who have it have a red rash that begins in infancy and eventually covers much of their bodies. They are usually short with skeletal abnormalities that can include a lack of digits or malformed hands and feet. Many have cataracts that begin at a young age. However, it was the predisposition to cancer – particularly osteosarcoma – that interested Wang.
“What is the defect in Rothmund-Thomson? Why do they get osteosarcoma?” she asked. “If we could understand the development of cancer in these patients, it would help our understanding of the disease in other people as well.”
While the tools of molecular biology and the study of disease at the level of molecules were invaluable in her work, the Internet played an important role as well.
Dr. Sharon Plon, who served as Dr. Lisa Wang’s mentor in this search, agrees that the ability to let patients know of their interest in the disease via the Internet was invaluable.
“I doubt the study of this rare syndrome and others that are similar could be done without the availability of this tool,” she said. The Internet enabled not only physicians to find the team at Baylor and the Texas Children’s Cancer Center but also patients and their family members who were seeking information about the disease.
“We have built a large cohort of patients from whom we have collected clinical information and biological samples,” said Wang. Their database also includes many family members who are not affected by the disease.
Wang and Plon’s studies involve two groups of patients. One group is studied from afar, using written information and medical records that already exist. The other group comes to Texas Children’s Hospital in Houston for tests. While these patients are in the hospital, Richard Lewis, M.D., a Baylor professor of ophthalmology, evaluates their vision. Moise Levy, MD, an associate professor of dermatology, evaluates the characteristic rash and performs skin biopsies. Clinical tests and X-rays are obtained through the Baylor General Clinical Research Center at TCH and biologic samples are obtained for research laboratory experiments. From these studies, the team hopes to learn more about the natural history of the disease.
The study is supported by the National Institutes of Health and the Doris Duke Charitable Foundation. Eventually, Wang hopes to establish a formal registry of patients with this syndrome as well as a support group for them.
While Plon and Wang were collecting information about patients, Japanese researchers had identified defects in a gene called RECQL4 that appeared to be associated with Rothmund-Thomson syndrome, at least in some cases. Their report, published in Nature Genetics (Kitao, Saori, Akira Shimamoto1, Makoto Goto2, Robert W. Miller3, William A. Smithson4, Noralane M. Lindor4 & Yasuhiro Furuich, Nature Genetics 22( 1) 82-84) identified mutations in the gene as a cause of at least a subset of Rothmund-Thomson cases.
When Wang and Plon looked at the cases of Rothmund-Thomson syndrome with which they were involved, they found that two-thirds had mutations in RECQL4 that truncated its coding portion. In other words, the orders the gene gives for making a protein was cut off early and the resulting protein was predicted not to work.
Those patients, said Wang, had a higher risk of developing osteosarcoma.
The gene in question – RECQL4 – is involved in basic cell functions such as the translation of genes into proteins and DNA repair. Mutations that result in an inactive RECQL4 protein could lead to malignant change, she said.
In her study, chronicled in the Journal of the National Cancer Institute, Wang evaluated the DNA of 33 patients with Rothmund-Thomson syndrome. Of those, 23 had mutations in the RECQL4 gene that resulted in a shortened protein. The 11 patients who had osteosarcoma all had the shortened form of the RECQL4 protein.
Ten of the patients in her studies did not have the RECQL4 protein mutation that truncated the protein. That may mean that a mutation in a different gene is the source of their disease, said Wang. Osteosarcoma is not associated with these patients, she said.
By contrast, however, none of the patients with the mutation in the gene that she studied had cataracts beginning early in life. That could mean that a mutation in another gene is responsible for this problem.
Wang said her study of the syndrome is only beginning.
“One thing I want to study right now is whether these patients have a more or less aggressive form of osteosarcoma,” she said. “How do they respond to the toxicities of chemotherapy? Some people suspect that chromosomal instability is an important factor in treatment.”
Eventually, she hopes that using the knowledge of the gene mutation involved in the disease will result in a laboratory test for Rothmund-Thomson disease. With the knowledge that patients have the particular mutation associated with osteosarcoma, physicians can counsel families about the risks of cancer and also obtain a baseline set of X-rays that can be compared against new X-rays, should a bone abnormality become apparent.
“Among our patients, cataracts are not a prominent feature,” said Wang. “On the other hand, in the early descriptions of the syndrome, cancer was not mentioned at all. That indicates that there may be two different forms of the disease – one associated with cancer and some not. There may be another gene or mutation that is not associated with osteosarcoma.”
Wang has learned much about these patients and hopes to learn more.
“In the absence of cancer, their lifespan appears to be normal,” she said. “The rash, however, persists for life. As far as we can tell from our cohort, their intelligence is normal. There are many other unanswered questions regarding small stature, infertility, and the need for hormone supplementation.”
She thinks that the carrier rate (those people who have one mutated gene) is low, making the disease itself even more rare because it would be unusual for two people who carry the mutated gene to have a child.
“In addition to collecting clinical information, we will continue to do the lab work,” she said.
The normal protein made by the gene encodes what is known as a DNA helicase. DNA helicases are involved in critical operations of both DNA and RNA. Among these operations are replication, recombination, repair and transcription. Only five human DNA helicases are known. Two of the others are also associated with cancer syndromes, said Wang.
“If we understand the pathways through which the helicases act in this syndrome, we may be able to learn about the pathways of cancer in general,” she said.