25 Years of Medical Advances in Turner Syndrome
The medical treatment of TS changes with new research and insights and many important medical milestones have occurred since Dr. Turner first published his paper on Turner syndrome in 1938.
The following information was obtained from old TSSUS newsletters, literature, and the “Recommendations for Diagnosis and Treatment of Individuals with Turner Syndrome (1994, 2001 and 2007). Thanks to Natalie Bonfig for putting together this history timeline.
1938 Dr. Turner publishes “A Syndrome of Short Stature, webbed beck and infantilism,” a report describing seven girls who shared a number of features, including short stature. Dr. Turner helped pioneer the use of exogenous sex steroids as a treatment for ovarian failure, ushering in estrogen. Go to: http://www.turnersyndrome.org/files/what-ts/what-ts-177.pdffor more information.
1959 The first published report of a female with a 45,X karyotypeby Dr. Charles Ford and colleagues in Harwell, Oxfordshireand Guy's Hospitalin London.It was found in a 14-year-old girl with signs of Turner syndrome.Our own Donna Rice was one of the first to be diagnosed via the Karyotype in the Chicago area by Dr. Schwartz.
1978 Louise Brown, the first “test tube baby” is born.
I980’sThe first women with TS used donor eggs to have children.
1994 Dr. Radwanska calls using donor eggs for TS pregnancy a “standard practice.” Widely touted for a while, but it is now downplayed due to the cardiac risks for the mother. Every woman with TS who would like to undergo in-vitro fertilization needs to have a complete cardiac work-up.
1987 The National Institutes of Health (NIH) begins a study to determine the efficacy of growth hormone (GH) and low-dose estrogen therapy in girls with Turner syndrome.
1989 The issue of the FDA classifying growth hormone as an anabolic steroid was discussed in congress. Additionally the concern of the breast cancer risk with HRT began.
1994 The Turner Syndrome Society of the United States brought together 16 nationally recognized leaders in related, but multidisciplinary, research and clinical practice areas to create the first Recommendations for Diagnosis and Treatment of Individuals with Turner Syndrome.
1996 “Improved Final height in girls with Turner’s syndrome treated with growth hormone with growth hormone and oxandrolone in TS” http://jcem.endojournals.org/content/81/2/635.abstractStudy says that GH and Oxandrolone increase in significant growth acceleration. 1996 Journal Endocrine. However, early addition of estrogen decelerates the height velocity and reduces the gain in height.
1996 Dr. David Page discusses gene mapping. “While geneticists now believe that the explanation for the individual features of TS can be found on individual genes or sets of sets of genes, they are just beginning to identify those genes,” according to Dr. Page.
1997 The FDA approved Growth Hormone as standard care for individuals with TS
1997 Dr. Kirt Simmons reports that “growth hormone therapy tended to increase the growth of the lower jaw while having no significant impact on the growth of the upper jaw.” He further suggests that patients and orthodontists take this into consideration during orthodontia treatment.
1997 TSSUS Conference Speaker: Dr. Paul Saenger presented an overview of the growing database of study results which include the following findings:
- Average adult height gain of approximately 3 ½ inches.
- Average age at enrollment of GH treatment of approximately 10 years.
- Average duration of GH treatment of 3.7 years.
1998 A study by Bonamico et al in Italy has shown a significant correlation between TS and Celiac disease.
2000 TSSUS conference speakers: Drs. Ross and McCauley see a connection between cognition and estrogen replacement therapy (ERT). “They hypothesized that estrogen replacement therapy in girls with TS would improve memory, improve motor performance, and decrease the speed of processing necessary for some non-verbal tasks.
2000 The transdermal patch became the latest form of ERT.
2000 TSSUS conference speaker: Dr. Marsha Davenport recommendations for growth included:
- Begin GH as soon as growth failure is demonstrated.
- Begin oxandralone around the age of 11 years.
- If greater height is desired, delay estrogen therapy to 15 years old.
2000 The sequence of human DNA was completed.
2000 TSSUS conference speaker Dr. Zinn mentions that the “SHOX gene in TS which is involved in short stature and certain other TS skeletal abnormalities has been identified.” He also said, “We are narrowing on the gene on the X chromosome that makes TS girls susceptible to poor visual-spatial abilities and other learning disabilities.”
- Dr. Marsha Davenport begins The Toddler Study which was a “nationwide investigational trial to study the effects of growth hormone (GH) when started at a very young age
- Dr. Carolyn Bondy begins the Turner Syndrome National Institutes of Health (NIH) study of the “comprehensive characterization of clinical features of TS and identification of the specific genes linked to each feature. This study is designed to improve diagnosis and recognition of potential and existing medical problems, resulting in improved preventative and therapeutic medical care.”
- Recommendations for Diagnosis and Treatment of Individuals with Turner Syndrome include:
- “TS may be defined as the combination of characteristic physical features and complete or partial absence of the second sex chromosome, with or without cell line mosaicism.”
- Heart Issues: “Those with cardiac heart defects or aortic root dilation, regardless of age, require monitoring”
- Heart Issues: “Although the vast majority of TS patients with aortic root dilation have an underlying risk factor, a small vulnerable minority do not. In view of the limited information available in this regard, it is unclear whether more frequent echocardiography is warranted in patients without CHD.”
- Heart Issues: “Pregnancy, either spontaneous or assisted, requires careful monitoring.
- Hormone therapies: “Once a patient with TS has dropped below 5th percentile of the normal female growth chart, initiation of GH should be considered.Therapy may be started as early as 2 years of age, although there is presently only limited experience of treating children of this age.”
- Ovarian Function: “Estrogen therapy needs to be initiated and adjusted according to the needs and priorities of the individual with TS. Thus, if growth promotion is a priority, estrogen therapy should not be initiated before 12 years of age unless height has already been maximized. Estrogen therapy should ideally be started by 15 years of age.”
- Pediatrics to Adulthood: “Individuals with TS should transition from pediatric to adult healthcare supervision around the age of 18. The medical problems present in childhood should be monitored into adulthood.”
- Hearing Loss: Hearing loss in TS can be conductive or sensori-neural. The sensori-neural hearing loss affects 50-90% of patients and is progressive after 35 years of age.”
- Bone Density: “Bone mineral density is a problem with many adult women with TS. Osteoporosis therapy should be started if there is significant deterioration.”
2001 TSSUS conference, according to Dr. Rosen, not all individuals with Turner syndrome experiences NLD.
- Dr. Bondy presented some preliminary results of the TS NIH Study:
- Bone Density: “Findings thus far indicate that participants who have been treated with estrogen have near normal bone density and no increased risk of fractures when bone density is measured with a CT scan. Those participants who were not on estrogen for extended periods of time showed osteoporosis and increased wrist fracture on the CT scan. Therefore, preliminary findings suggest that ERT is very important for bone health.”
- Glucose Tolerance: “Oral glucose tolerance testing revealed that individuals with TS are at increased risk of developing Type 2 Diabetes.”
- Heart: MRA (Magnetic Resonance Angiogram) was used to investigate cardiac issues in participants with TS and allows the researcher to see more of the heart than other techniques.”
- Psychosocial Functioning: Evaluation of psychosocial functioning of participants with TS suggests that many individuals experience extreme shyness and social anxiety. These findings emphasize the importance of support for individuals with TS.”
2003 TSSUS Conference: Dr. Dean Mooney states that “virtually all girls and women with TS have NLD although the degree to which it affects them differs considerably”
2003 TSSUS Conference: Dr. Michael Silberbach and is colleagues introduce the “Healthy Heart Project” to answer the question “What is the danger of aortic root enlargement in TS individuals without any identifiable heart disease?”
2004 NIH TS Study findings: Published in the American Journal of Medicine (September 2003). “This study showed that individuals with TS who received adequate estrogen treatment did not have osteoporosis of the spine any more often than an age-match group of women with normal ovaries and karyotype. It also found that many women who are less than 4’ 10” tall are erroneously diagnosed as having osteoporosis because the common method used to measure bone mass density is not accurate in small women.”
2005 Dr. Silberbach launches the TS Aortic Dissection Registry which continues today. The project’s mission is to gather important information about those with TS who develop aortic dissections so that the clinical profile prior to a dissection might be more easily recognized.
2005 TSSUS Conference, Dr. Davenport presented some highlights from the Toddler Study:
- Girls who showed the largest growth responses were the ones who had the largest difference between their calculated “target” height percentile and their present height percentile. A girl’s “target” height is mid-point between both parents minus 2.5 inches.
- If children are introduced to GH early, then they may not need to withhold introduction of estrogen and conversely, they can benefit that much earlier from its protective effects on various body systems such as bone mineralization and the heart.
- Based on this study, GH should be introduced when the child develops growth failure.
2006 Summer Edition of TSS Connect. Dr. Bondy shares an update of the NIH study. NIH researchers advise that all individuals with TS would greatly benefit from an MR (Magnetic Resonance) imaging study of the heart.
2007 Expert’s Conference Edition of the TSS Connect, Dr. Bondy discusses some for the new guidelines and some of the important discussions around TS.
- “Recently it has become possible, using DNA amplification technology, to sequence DNA from very small amounts of human blood or cellular material. Newborns routinely have a heel-prick blood specimen to test for various congenital diseases, and several states are now considering screening for X-chromosome DNA sequences implicated in the Fragile X syndrome. This test may also detect cases of missing X or excess X chromosome material (Turner and Klinefelter syndromes, respectively)….However, the TS expert group concluded that under-diagnosis and delayed diagnosis of TS is a real problem, with the average age of diagnosis at present about 15 years, and approximately 50% of females with the syndrome never being diagnosed. Importantly, early detection of TS permits identification of cardiovascular system problems such as bicuspid aortic valve or hypertension that require treatment to prevent complications.”
- “Testing for Y chromosome material should be performed in any TS patient with a sex chromosomal fragment of unknown origin (i.e. X vs. Y)…The patient and/or her parents should be informed of the finding of Y-chromosome material with the utmost sensitivity regarding gender identity issues to minimize psychological harm…Gonadoblastomas may transform into malignant germ cell neoplasms, hence, the current recommendation is for laparoscopic, prophylactic gonadectomy.”
- “We suggest that cardiac echo is usually adequate for the asymptomatic newborn and young girl, but the threshold for getting an MR study should be very low if any concerns are aroused. Moreover, all girls should get a baseline MR cardiovascular study as soon as they are old enough to cooperate with the requirements for holding still. Also, the ECG may provide evidence for cryptic involvement of the right heart and pulmonary system, or electrophysiological abnormalities that result in prolongation of the cardiac repolarization time (QTc).”
- “When estrogen therapy is required to induce pubertal development, the form, dosing and timing should reflect the process of normal puberty. Delaying estrogen therapy until 15 years of age to optimize height potential, as previously recommended, seems unwarranted. This emphasis on stature tends to undervalue the psychosocial importance of age-appropriate pubertal maturation and may be deleterious to bone and other aspects of the child’s health. Furthermore, recent evidence suggests that some treatment regimens using estradiol that begin replacement at the age of 12 years permit a normal pace of puberty without interfering with the positive effect that GH has on final adult height.”
- “The transition from pediatric to adult health care should occur at the completion of growth and puberty during late-stage adolescence (usually by age 18). However, transition should be initiated as a staged process. Beginning at approximately age 12, the center of care should be shifted incrementally from the parent to the adolescent with TS. The health care focus also shifts from maximizing height to inducing feminization, counseling the adolescent with TS about the evolving impact of her condition into adulthood, and promoting the development of independent self-care behaviors.”
- “Before contemplating spontaneous or assisted pregnancy, individuals with TS need a complete medical evaluation. Particular attention should be paid to the cardiovascular system, and echocardiography, ECG and MRI need to be performed prior to any attempt at pregnancy. Women with cardiovascular issues (BAV, dilated aorta, history of coarctation), as described above, are best counseled against attempted pregnancy…A multidisciplinary team, including 2007high-risk pregnancy specialists, endocrinologists, and cardiologists, generally at a tertiary care facility, should follow all pregnancies.”
2006 TSSUS conference, Dr. Silberbach gives his Annual Report Card on the Healthy Heart Project.
- “It is clear that even for those under eighteen years of age; the incidence of high blood pressure in TS is significant.
- TS Individuals, whether that have a bicuspid aortic valve or not, have larger aortas that the aortas of 46, XX females. “The new guidelines for monitoring wellness in TS girls and women now clearly recommend that all those with TS should have regular check-ups to monitor the sizes of their aortas throughout their lives.”
2007 TSS Connect Conference Edition. Dr. Mooney states that “girls and women with NLD can potentially accomplish anything that a neurotypical population can, but they may follow a different, and longer, path.”
2007 TSS Connect Conference Edition. Dr. Davenport updated attendees on the Toddler study which include the following recommendations:
- All estrogens are not equal – there are different types of estrogen as well as different delivery methods (transdermal, oral or an intramuscular shot.) There are ongoing studies to determine if one delivery method secures better results than the others.
- Begin GH therapy as soon as growth failure (decrease in height percentiles occurs)
- Most effective daily dose of GH is .375/mg/kg/week, with the dose being adapted to individual IGF-1 levels
- Consider oxandrolone (.05mg/kg/day or less) for girls older than 9 with extreme short stature
- Consider estrogen at 12 years of age.
2007 TSS Connect Conference Edition. Dr. Loscalzo explains that “the X chromosome has been sequenced. It has approximately 900-1400 genes. When there are two chromosomes present, one copy is inactivated. However, there are some genes that are active on both X chromosomes and many of these genes are similar to gens on the Y chromosome. These genes are the ones that are probably important to the features of TS.”
2007 TSS ConnectConference Edition. John Miles, Caremark, spoke of the continuing difficulties in getting GH approved by insurance companies even though FDA approved GH therapy for Turner syndrome.
2007 Conference Edition. Dr. Judith Ross discusses the findings from an NIH study to determine the efficacy of growth hormone (GH) and low-dose estrogen therapy in girls with Turner syndrome. The study concluded that low-dose estrogen (1-3 micrograms per day) has no effect on advancing bone age and may accentuate the effect of GH on final adult height.
2007 Conference Edition. Dr. Samuel Levine says that “aside from short stature and infertility, hearing loss is perhaps one of the most common characteristics of TS and presents one of the most challenging life complications for women and girls with TS.”
2010 Conference, Dr. Mooney spoke about what individuals with NLD excel at and what is difficult for them. “Primary assets include auditory perception, simple motor skills and rote material. Primary deficits include visual perception, tactile perception complex psychomotor skills and novel material.”
- Fall Edition TSS Connect: Dr. Bondy provided some new updates to the NIH study
- “She mentioned that echocardiograms fail to visualize the aortic valve clearly in 30 percent of girls with TS. Everyone with TS should receive a cardiac MRI at least once, usually from pediatric to adult care and more if an anomaly is detected.”
- “Good news! The data are good and significantly higher than US average for education and good for employment; numbers for marriage lower than average, and for children way lower obviously.
- “Dr. Bondy emphasized the importance of starting and remaining on some sort of estrogen replacement therapy” to maintain strong bone density.
2011 Fall Edition TSS Connect. Dr. Silberbach’s Healthy Heart Presentation included:
- He encouraged everyone to sign up for the GenTAC study which is a National Registry of Genetically Triggered Thoracic Aneurysms and Cardiovascular conditions. .
- “Results from the Healthy Heart project suggest that in adults there is a slight increase in the aortic diameter in TS over time.
- Since many with TS have a bicuspid aortic valve,” there has been a noteworthy change in preventative care recommended for this condition: antibiotic prophylaxis (taking antibiotics as a precaution before dental work and some other procedures) is no longer in the guidelines published by the American Heart Association.”
2011 New England Journal of Medicine: Combination of 2 hormones dramatically increases height in girls with Turner syndrome. Study’s lead author, TSSUS Medical Advisory Board member Dr. Judith Ross says “the results will change the practice of treating girls with Turner syndrome.” Dr. Ross, M.D (http://www.jefferson.edu/peds/faculty_profile.cfm?key=jxr003) is professor of Pediatrics at Jefferson Medical College of Thomas Jefferson University. Providing very low doses of estrogen to girls with Turner syndrome as well as growth hormone, years before the onset of puberty, increases their height and offers a wealth of other benefits, says the report, published in the March 31st issue of The New England Journal of Medicine. http://www.nejm.org/doi/full/10.1056/NEJMoa1005669
2012 In women with Turner syndrome, the risk of death from aortic dissection or rupture during pregnancy may be 2%, and this risk persists during the postpartum period owing to pregnancy-related aortic changes. Turner syndrome is a relative contraindication for pregnancy; however, it is an absolute contraindication for pregnancy in a patient with a documented cardiac anomaly. This document replaces the 2008 document of the same name in the American Society for Reproductive Medicine. (Fertility and Sterility 2012 by American Society for Reproductive Medicine.)