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Past Opitz winners discuss the influence of the award on their careers

AJMG's John M. Opitz Young Investigator Award honors the journal's founding editor-in-chief, Dr. Opitz, who was one of the first physicians to recognize and characterize human congenital anomaly syndromes.

AJMG is currently seeking nominations for the award. (Visit for more information.) Given annually since 2002, the award recognizes a significant paper by a researcher who has completed doctoral training within the past 10 years or is younger than 40. A committee selects the winner from among other young authors whose papers have appeared in the Journal in the past year.

Below, past award recipients discuss the award's influence on their careers and why young geneticists should submit papers.

The impetus for the winning paper was Dr. Wheeler's interest in correlating the partial urorectal septum malformation (URSM) sequence with embryology to determine how USRM malformation develops. Her research determined that the partial URSM sequence is a milder expression of the full URSM sequence, marked by a lack of perineal or anal openings, and differentiated the sequence from VATER association [Wheeler et al., 2001].

Dr. Wheeler has fond memories of working on her paper with Dr. Opitz, who was editor of AJMG in 2002. “I'd get back drafts of my paper with red ink everywhere, but he really made my paper better,” she recalls. Her memory of Dr. Optiz's visit to the Floating Hospital for Children at Boston's New England Medical Center “has kept me interested in research, although I see patients full-time.”

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Patricia Wheeler, MD, Chief, Division of Genetics, Nemours Children's Clinic, Orlando, Fla.

That research currently focuses on VATER association and clinical correlation of microarray abnormalities.

Dr. Wheeler encourages young researchers to write papers that “explain how genetics affect an individual clinically.”Many papers focus on narrow topics, leaving readers to wonder about their relationship to clinical care, she says.

Dr. Gripp was a pediatric resident at the A. I. duPont Hospital for Children when she met her first patients with Costello syndrome (CS). As a genetics fellow, she realized that rhabdomyosarcoma (RMS), a cancer of the soft tissue, was under-reported among children with CS.

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Karen Gripp, MD, Professor of Pediatrics and Chief, Division of Medical Genetics, A.I. Dupont Hospital for Children in Wilmington, Del.

Dr. Gripp and a team studied 5 thennew cases of RMS in patients with CS, which when combined with previously reported cases meant the frequency of tumors among children with CS could be as high as 17%. Their winning paper recommends a screening protocol for CS that includes regular ultrasound of the abdomen and pelvis [Gripp et al., 2002].

Since then, CS research has come a long way, says Dr. Gripp, who is former director duPont's CS program. “Back in 2001 to 2003, there was little information regarding Costello syndrome, practically nothing,” she says. As a result, clinicians had few answers for families of children with CS.Withmore CS studies, that situation is changing. “Being able to inform families is why I keep doing research,”Dr. Gripp adds.

As an AJMG associate editor, a former editorial boardmember, and member of the current award committee, Dr. Gripp encourages researchers thinking of submitting papers to keep in mind the Journal's focus on embryology and dysmorphology, as well as research with clinical applications. “Today, so many papers are focused purely on molecular aspects of disease,” she says. “But most of all, the paper should be about something you really care about.”

Dr. Rauch's paper grew out of her love of genetics.

“From the time I got in touch with genetics I was fascinated by it,” she says. Early in her training, Dr. Rauch became especially intrigued by the underlying causes of developmental disorders and genotype-phenotype correlation. She saw determining such correlations as key to helping patients and their families.

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Anita Rauch, MD, Director and Chair of Medical Genetics, University of Zurich, Switzerland

Dr. Rauch's paper delineates a clinically recognizable 5q35.3 subtelomeric deletion syndrome of approximately 3.5 Mb. Clinicians should consider the deletion in infants with pronouncedmuscular hypotonia, postnatal short stature, and bellshaped thorax with pectus, the paper suggests [Rauch et al., 2003]. It is one of many papers Dr. Rauch wrote about genotypephenotype correlation early in her career.

Because 5q35.3 subtelomeric deletion syndrome is extremely rare, Dr. Rauch no longer studies it, but she continues to investigate other microdeletion syndromes. One of her recently published papers found that mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression, for example [Zweier et al., 2010].

Dr. Rauch says winning the Opitz award increased her professional visibility and helped her obtain an academic position.

Dr. Roberts' paper is notable not just for the knowledge she added to the field, but also because it helps demonstrate how quickly technology can advance.

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Amy E. Roberts, MD, Medical Geneticist, Children's Hospital Boston

Her paper explored potential clinical indications for then-new subtelomeric fluorescence in situ hybridization (FISH) testing by quantifying abnormalities in 13 children with chromosomal abnormalities. Common abnormalities involved chromosome 1p, and included partial monosomy, complex rearrangements, and partial trisomy. The paper calls for more frequent use of FISH because it helped adjust the recurrence risk, focus medical screening and monitoring, and aid family planning and diagnosis [Roberts et al., 2004].

Since 2005, however, FISH testing for subtelomeric rearrangements has largely been replaced by array comparative genomic hybridization (CGH), Dr. Roberts says. Her paper highlights both the need for clinicians to keep track of rapidly changing testing technology and the value of publishing information about it. “Publishing papers in journals is the way different centers communication with each other,” Dr. Roberts says, adding that without communication and collaboration among centers, “it's difficult to find the significance of a new finding.”

Winning the Opitz award “was a great validation for me as a new medical geneticist starting on a clinical research career,” she says. One barrier to Optiz award submissions is that young researchers are often unaware of the award. Dr. Roberts points out that mentors can submit papers done by their trainees.

Dr. Merks' paper came out of a conversation with his boss about how malformations seemed more common among children with cancer than other youngsters.

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Johannes Hans M. Merks, MD, PhD, Pediatric Oncologist Emma Children's Hospital, Academic Medical Center in Amsterdam, The Netherlands

Embryonic cancers, for example, are increased in children with Beckwith- Wiedemann syndrome and leukemia is more common in children with Down syndrome, Dr. Merks notes. He and colleague Raoul Hennekam, MD, PhD, Professor in the Departments of Clinical Genetics and Pediatrics at Amersterdam's Academic Medical Center, gave 1,073 children with cancer morphological examinations. They diagnosed a syndrome in 3.9% of these patients, and suspected the presence of a syndrome in 3.3%, leading them to note a possible association. According to their paper, 20 of 42 syndrome diagnoses they gave weren't recognized in patients prior to this study, showing that physicians commonly miss these diagnoses [Merks et al., 2005].

Winning the Opitz award has spurred invitations to speak at conferences and convince others “that all children with cancer need an examination by a clinical geneticist,” Dr. Merks says. While this idea is widely accepted in both Europe and the U.S., lack of clinician time and money mean most pediatric cancer patients don't see geneticists. Dr. Merks, therefore, is developing a tool to help clinicians decide which cancer patients are most likely to have a genetic syndrome.

Dr. Yoon's winning paper identified new skeletal and dental abnormalities in patients with Andersen-Tawil syndrome (ATS) and proposed new criteria for its diagnosis.

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Grace Yoon, MD, Clinical Geneticist, Department of Pediatrics, The Hospital for Sick Children, Assistant Professor, University of Toronto

ATS arises from a mutation in the KCNJ2 gene and causes episodes of muscle weakness and sometimes general paralysis. Children with ATS also have distinctive facial features.

Dr.Yoon, who was a neurogenetics fellow at the University of California, San Francisco when she wrote the paper, knew that variable expression complicates the diagnosis of ATS. She sought to delineate the spectrum of clinical manifestations of ATS.

Her paper expanded those clinical features to include dental and skeletal abnormalities in patients with KCNJ2 mutations. Based on her evaluation of 10 patients with confirmed mutations, she proposed extending the ATS diagnostic dysmorphology criteria to include delayed eruption of permanent teeth, oligodontia, and dental root anomalies, micrognathia, small hands and feet, brachydactyly, 2- 3 toe syndactyly, and toe clinodactyly [Yoon et al., 2006].

Dr. Yoon says the best thing a fellow can do is “work with a great mentor.” She says she feels particular gratitude to basic scientist Louis Ptacek,MD, Professor of Neurology and Director of the Division of Neurogenetics at the University of California, San Francisco (UCSF), for supporting the project and to neurologist Bruce Miller, MD, Professor of Neurology and Psychiatry at UCSF, for teaching her the importance of considering the whole patient in her approach to complex presentations of disease.

She encourages other young researchers to submit papers. “Focus on doing well at what you feel passionate about. The recognition will follow,” she says.

Mowat-Watson syndrome (MWS), caused by haploinsuffiency of the ZFHX1B gene on chromosome 2, is a disorder that even geneticists aren't very familiar with.

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Margaret P. Adam, MD, Associate Professor of Pediatrics in the Division of General Medicine, University of Washington School of Medicine

Sometimes MWS is mistaken for Angelman syndrome (AS) because the disorders' cognitive symptoms overlap. But it's easy to differentiate between the disorders if you know what MWS signs to look for, Dr. Adam says.

Her paper came out of her experience as a trainee at Emory University School of Medicine. Dr. Adam saw many children who had small heads and suffered from seizures, which can be signs of AS. But she also knew that MWS produces specific facial features, such as microcephaly, medially flared and broad eyebrows, prominent columella, pointed chin and uplifted earlobes. Lacking an accurate test for either disorder, Dr. Adam sought to better characterize MWS.

Dr. Adam's study of 12 children diagnosed with MWS calls for considering this diagnosis in any patient with severely impaired or absent speech, especially if he or she also has seizures and anomalies involving the pulmonary arteries or pulmonary valves. Her work on MWS continues with her current study of whether early puberty in some patients is a symptom of the disorder [Adam et al., 2006].

Dr. Adam, who gets referrals from across the U.S., describes winning the Opitz award as an opportunity that boosted her professional reputation. She recalls writing her first medical journal paper as a daunting task. Young researchers might not realize that the journal editing process is extensive, and that perfection isn't necessary, she says. “So many of us want our papers just so,” Dr. Adam says, “but that sort of thinking just slows us down.”

While seeing Hutterite patients with Meckel syndrome (MKS) at Alberta Children's Hospital, Dr. Boycott, then a medical genetics resident, often thought the diagnosis was not quite right.

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Kym M. Boycott, MD, PhD, Medical Geneticist, Regional Genetics Program Children's Hospital of Eastern Ontario

“While children with that diagnosis generally don't live beyond age 1, some of our Hutterite patients lived much longer, even until age 20,” she recalls.

MKS is a rare, autosomal recessive disorders that generally involves occipital encephoele, cystic kidneys, fibrotic changes of the liver, and polydactyly.MKS can overlap clinically with Joubert syndrome and the group of conditions known as Joubert syndrome related disorders (JSRD).

Boycott began the research for her winning paper after the diagnosis of the first Hutterite child with JSRD. She reviewed 10 previous cases for evidence of misdiagnosis. Her goal was to get children possibly affected with JSRD proper ongoing care, including renal ultrasound, kidney function tests, and treatment for high blood pressure. The youngest children would get the benefits of early treatment, she adds.

Her paper describes 10 Hutterite youngsters, 7 of whom had been previously diagnosed with MKS. It concludes that JSRD is a recognizable dysmorphic syndrome in the Hutterite population and that it is caused by a novel, and as yet unidentified, gene [Boycott et al., 2007]. That paper helped Boycott get a 3-year grant to identify the JSRD gene and begin to understand its role in neurodevelopment. She expects to publish the findings later this year.

The award helped her demonstrate productivity and expertise and develop a research program on a rare disease, Boycott says.

She encourages young genetic researchers to both submit papers for this year's award and seek help from their mentors. “Senior authors and the person who nominates you are interested in your future. Young researchers succeed with the support of people who have been doing this work for decades,” she says. Dr. Unger decided to write her winning paper on clinical and radiographic delineation of odontochondrodysplasia after making this rare diagnosis in utero. The parents were very upset, and Dr. Unger was frustrated with the dearth of published data on this condition, also known as Goldblatt syndrome so she set out to better describe it.

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Sheila Unger, MD, Medical Associate, Service of Medical Genetics, Centre Hospitalier Universitai Vaudois in Lausanne, Switzerland

She studied 6 children, including a brother and sister. The main radiographic features were congenital platysponsyly with coronal clefts, and several metaphyseal changes, particularly in the hands, wrists, and knees. Radiographic features also include meomelic limb shortening and coaxa valga. The main physical signs are short stature, joint laxity, narrow chest, scoliosis, and dentinogenesis imperfecta. The paper notes that signs seen in the newborn period aren't entirely specific and that the 2 differential diagnoses are spondylymetaphyseal Sedaghatian type or platyspondylic lethal dysplasia, Torrance type [Unger et al., 2008].

At the time the paper was published, the molecular cause wasn't known, but Dr. Unger has since found it after studying an additional 6 patients. She has not yet submitted her research for publication.

Dr. Unger encourages young geneticists to submit their work for the award for three reasons: Having a paper published will make research available to other geneticists, enhance a researcher's professional reputation, and aid attempts to recruit rare disease research subjects, she explains.

Dr. Sousa was training in dysmorphology at Great Ormond Street Hospital in London when his professor suspected Nicolaides– Baraitser Syndrome in a patient.

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Sergio B. Sousa, MD, PhD, student, Institute of Child Health in London, England

With only 5 reported cases, little was known about NBS. Dr. Sousa and his professor, Dr. Raoul Hennekam, MD, PhD, began contacting colleagues fromacross the globe to find more cases. “The group of patients with the suspicion of this diagnosis became progressively larger,” Dr. Sousa says.

His paper is a detailed comparison of symptoms in 23 patients. The symptoms include severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, prominent finger joints, and broad distal phalanges. Some of the features are progressive with time, the paper notes, adding that microarray analysis performed in 14 of the patients gave normal results [Sousa et al., 2009].

After finishing his clinical training as a medical geneticist in February of 2009, Dr. Sousa started a PhD program at the Institute of Child Health in London later that year. His PhD work has included study of both NBS's cause and Portuguese families with rare, undescribed syndromes. His AJMG paper conferred professional status that's helped Dr. Sousa gather necessary clinical data and professional contacts for his current research, he says.

Advances in technology and an emerging international interest in rare diseases make them ripe for study by young researchers, Dr. Sousa says, adding that researchers already working on rare diseases should submit their work to the Opitz award committee. “The only clever way to move forward on this field is to join forces and work in international multicenter collaborative studies,” Dr. Sousa says.


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