Connecticut Children’s Emily L. Germain-Lee, MD Changing Lives through Research of Rare Disorders Posted on February 28, 2018 In honor of Rare Disease Day—which raises awareness of rare diseases and their impact on patients and families—we sat down with pediatric endocrinologist and researcher Emily L. Germain-Lee, MD to discuss her advances in the treatment and research of rare bone and endocrine disorders. Dr. Germain-Lee is the Chief of the Division of Pediatric Endocrinology & Diabetes at Connecticut Children’s and Professor of the Department of Pediatrics at the University of Connecticut School of Medicine. At Connecticut Children’s, she directs the Center for Rare Bone Disorders and the Albright Center, and co-directs the Osteogenesis Imperfecta Center. How did you come to specialize in Albright hereditary osteodystrophy (AHO) and other rare bone/endocrine disorders? Was there a single experience you can point to that motivated you? I am very lucky that my mentor from twenty years ago, Dr. Michael Levine, is one of the world’s experts in Albright hereditary osteodystrophy (AHO). I saw my very first patients with AHO with him at Johns Hopkins, and I was totally gripped by their stories and clinical presentations. All of them had literally looked for years to find a physician who knew how to diagnose and treat them or who had even heard of their condition. They were desperate in their searches, and I wanted to help not only by providing clinical care and spreading awareness for this devastating disorder but also by investigating the pathogenesis of this condition in the laboratory with the goal of finding potential treatments. This led to more and more patients with AHO traveling to see me, and because AHO involves many bony abnormalities as well as many hormonal problems, I started getting referrals for all types of rare bone and endocrine disorders. Why is this work important to you, and why should it be important to others? I felt that as an endocrinologist and as a laboratory investigator, I was in a position to try to make a difference in the lives of patients with rare bone and endocrine disorders. This was especially true for AHO, which encompasses so many aspects of bone development and endocrinology. As time progressed, I saw more and more patients with AHO and learned a great deal about the specific problems involved. I now follow the largest population of patients with this disorder worldwide, which provides me a unique opportunity to do in-depth clinical and laboratory investigations. There is still so much that needs to be done. In AHO, a defect in one gene causes innumerable problems such as abnormalities in bone formation, metabolism, growth, cognition, and behavior. From helping patients with AHO, as well as from studying the pathogenesis of the condition in my laboratory utilizing my genetically-engineered mouse model, I am learning more about the etiologies of the abnormalities. This could have implications for treatments for my patients and potentially shed light on more general disorders as well. I see the importance of studying rare bone disorders specifically, as the impact of the devastation of skeletal disease is often overlooked in the face of other organ systems deemed more life-threatening when affected, even though all aspects of daily life are compromised when the skeleton is. Therefore, patients with rare bone disorders often feel as though they do not have a voice. I want to help by being their voice. Overall, I think that studying any rare condition caused by a defect in fundamental cellular processes can lead to insights that have much broader implications for understanding the pathogenesis of many other disorders. Therefore, I think that studying rare conditions should be deemed important. Can you share a bit about some research initiatives you’re currently involved in? All of my research involves a bedside-to-bench approach through examination of both patients in clinic and mouse models in the laboratory. AHO has been a main focus of my research for many years. One of my current and long-standing research initiatives in AHO is to elucidate the basis for the development of subcutaneous ossifications (bone deposits under the skin), which are a source of pain and impairment in activities of daily living. We just published a 16-year investigation looking at the effect of various parameters such as gender, hormonal status, and severity of the mutation in humans with this disorder, and we are now focusing on a mouse model that I developed that recapitulates many aspects of AHO in order to understand the molecular and cellular basis for these ossifications. The goal is to find ways to prevent these ossifications from developing, as these can be very debilitating for patients. Another of my current projects, which is funded by a grant from the NIH, is to investigate cognitive and behavioral issues in AHO patients, a source of great morbidity. The ultimate goal is to improve overall functioning in these patients through early intervention. I am also evaluating parameters in my laboratory that may serve as biomarkers for a patient’s future cognitive and behavioral functioning with implications for treatment. In addition to AHO, I have a variety of research projects underway focused on osteogenesis imperfecta (OI), also known as “brittle bone disease.” As with AHO, I go from the bedside to the bench from clinical studies in patients to basic science studies focused on mouse models. With respect to OI, one of my projects is to test a new therapeutic approach in mice to improve both bone density and muscle mass. This project also relates to a larger overall collaborative project that I am carrying out with a group at Jackson Laboratory to understand the role of a specific signaling pathway in regulating bone and muscle in the context of aging since many rare bone diseases involve premature deterioration of both bone and muscle at an early age, even in childhood. Finally, I have a variety of other projects focused on other rare disorders, such as Sturge-Weber Syndrome, which I am carrying out in collaboration with my colleagues at Kennedy Krieger Institute in Baltimore. How have your treatment and research efforts inspired hope in families with children affected by these disorders? One of my main research efforts over the past 20 years has been on growth hormone treatment in AHO. I showed many years ago that AHO patients have growth hormone deficiency as a result of resistance to growth hormone releasing hormone, which normally acts to stimulate growth hormone production by the pituitary gland. This finding explained part of the basis for the severe short stature and obesity seen in AHO patients and immediately suggested a therapeutic approach to treat these patients. I conducted two R01 clinical trials sponsored by FDA Orphan Products Development in which I treated AHO patients with growth hormone, and although I am still in the process of finishing up the analysis of the final data from these trials, it is clear that growth hormone has many beneficial effects in these patients, which I believe has made a huge difference in their health and in the quality of their lives. Growth hormone is the first new treatment in AHO in 7 decades. By following large numbers of AHO patients for many years, I have also been able to identify clinical problems that can be addressed through early intervention. For example, I showed that many patients develop carpal tunnel syndrome, for which early recognition is important. They also have a range of cognitive and behavioral deficits, and I am currently conducting an NIH-funded study to understand more precisely these issues as previously described. Finally, I am conducting many basic science projects using a mouse model that I developed to try to understand better the underlying mechanisms involved in the pathogenesis of both AHO and OI, and the patients always are very excited to see that research efforts are ongoing to try to understand their conditions better and to develop new treatments. It must be an incredibly isolating experience for children affected by these rare bone/endocrine disorders. Are there any communities or gatherings you’re involved in that help children and families cope with and manage their conditions? Years ago I started the Albright Center, the first and only clinic worldwide focused on AHO, in order for the patients with this condition to have a place for diagnosis, management, treatment, and participation in research studies—this was moved to Connecticut Children’s when I moved to Hartford. I spearheaded a support and advocacy group for AHO many years ago; the parents now provide support to each other through Facebook, and many meet together on their own when in Connecticut to see me at the Albright Center. I helped to organize the first Rare Bone Disease Summit held at Johns Hopkins to bring together physicians and scientists working on rare bone disease in order to bring awareness to these conditions. I try to bring awareness to AHO specifically whenever I can, such as through an ABC Nightline show several years ago that was done on my Albright Center at Kennedy Krieger Institute. Since being at Connecticut Children’s, I started the Center for Rare Bone Disorders in order to have a place for patients with any rare bone disorder to be seen. The Albright Center and OI Center here at Connecticut Children’s lie under the overall umbrella of the Center for Rare Bone Disorders. I was invited this past September to give two talks at the International Meeting of Pediatric Endocrinology to large audiences of endocrinologists from around the world on the topic of AHO to bring awareness of how to make the diagnosis early and how to treat appropriately. I am also a member of the international expert consensus panel for AHO that met in France in March, 2017 in order to establish the first consensus guidelines for standard of care. In January of this year, I advocated at a meeting of the State of Connecticut General Assembly Task Force to Study Rare Disease regarding the need for more research funding and support for patients with rare bone diseases and rare diseases in general. I will be heading back to the Legislative Office on Rare Disease Day in order help advocate for AHO, OI, and other rare bone disorders. At the OI Center at Connecticut Children’s, we hold a 1-hour session at lunchtime during which the patients and families can provide support to each other and help each other with coping tactics. We just met last week. I am active in the OI Foundation and help with support and advocacy through them as well. As Vice President of the Human Growth Foundation for over 10 years, I have been able to advocate nationally and internationally for children with growth disorders, including those with rare bone diseases. Finally, I am a member of the Scientific Advisory Panel of the Rare Bone Disease Alliance, which works to educate physicians, expand research on rare bone disease, and assist rare bone disease patients and family members. What brought you to Connecticut Children’s? My husband and I wanted to move back to New England at some point in the future for personal reasons, although I had not thought of moving anytime soon. A colleague mentioned that Connecticut Children’s was looking for a division chief of pediatric endocrinology, so I decided to take a look. I saw the tremendous energy and innovation everywhere and how Connecticut Children’s and UConn Health were growing in leaps and bounds like no other places I had ever seen. I was impressed by Bioscience Connecticut that had turned UConn Health into an amazing campus able to provide cutting-edge education, research and clinical care. I was inspired by people like Dr. Juan Salazar and his passion and commitment towards advancing the collaborative mission of Connecticut Children’s and UConn to make us one of the best centers in the country for taking care of children and advancing pediatrics research. I also saw that I had the opportunity to have my laboratory in the Center for Regenerative Medicine and Skeletal Development at UConn Health led by Dr. David Rowe, a world-renowned researcher in bone disease and the first division chief of pediatric endocrinology. Do you see many national & global patients here at Connecticut Children’s? Most of the AHO patients whom I see are from other states and countries, although I already have seen 5 patients from Connecticut with AHO. I have seen AHO patients from just about every state throughout the USA and also from 6 continents. For example, I will be seeing a patient from Belgium in the next few weeks. I also see OI patients from all over this country and overseas. I recently saw an OI patient from Tanzania, and just this past week, I saw families from Texas and Virginia. What has been the most rewarding experience in your career so far? The most rewarding experience that I have on a regular basis is figuring out the diagnosis and treatment for a child who has been undiagnosed and then being able to change their life’s course through appropriate diagnosis, management, and treatment. Overall, being able to conduct bedside-to-bench research has been what has made my career so rewarding on a day-to-day basis because I am able to address fundamental questions in the laboratory that are raised by my experiences seeing patients and then take the insights gained by laboratory studies and translate them into new therapeutic approaches to improve the lives of my patients. Fundamentally, improving the health and quality of lives of my patients is what brings me the most fulfillment. What is one condition that you wish more people knew about? Albright hereditary osteodystrophy is a rare condition that I really wish more people knew about because it could be detected much earlier if health practitioners were more informed and aware. The name alone is complicated, and what makes things even more complicated is that there are 2 subtypes, pseudohypoparathyroidism type 1a (called PHP1A) and pseudopseudohypoparathyroidism (called PPHP) which are very different from one another but which both fall under the category of AHO. Even the names of the conditions are difficult to say and to remember. PHP1A can be devastating, causing profound hormonal and biochemical problems, even leading to seizures from low serum calcium levels. When diagnosed early, many bad sequelae can be prevented. In addition, mothers with PPHP can have children with PHP1A due to a complex genetic mechanism, and the findings of PPHP are subtle but usually noticeable if one is aware of the condition. Many times a mother with PPHP finds out about her own condition when her child with PHP1A is diagnosed; by then, a lot of damage may have already been done. Therefore, greater awareness would definitely lead to better outcomes for all of these patients. Is there anything else you’d like to share? I would like to see more recent graduates of medical and dental schools decide to follow the path of becoming clinician-investigators and performing bedside-to-bench research. I have found this to be incredibly fulfilling, and I believe that this is very important if we want to continue to make important advances in medicine. Fewer people in training are following this path of becoming clinician-investigators, which is a shame because physicians who both see patients and do bench research are in a unique position to translate clinical findings into the development of treatments. Learn more about Dr. Germain-Lee and Connecticut Children’s Division of Endocrinology.