When a teen arrived at UCSF Benioff Children's Hospital with a diagnosis of Noonan syndrome, medical geneticist Katherine Rauen, M.D., Ph.D., and genetic counselor Michelle Strecker recognized that something didn't add up.
"She had severe and chronic gastrointestinal problems, which is not typical of Noonan," says Strecker, who manages the hospital's NF/Ras Pathway Clinic. "The sparse eyebrows and early feeding difficulties were a better fit for CFC (cardiofaciocutaneous) syndrome — and we found a mutation in the BRAF gene, which is associated with CFC."
The finding opened the way for more aggressive GI treatment, and demonstrates the advantages of a pathway-based approach to this group of genetic syndromes.
Rauen's brainchild, the NF/Ras Pathway Clinic, operates on this belief: if genetic pathway dysregulation is responsible for syndromes that predict a wide range of debilitating conditions, then a pathway-based clinic should offer more effective treatment as well as unique translational research opportunities.
A leading expert on the clinical implications of mutations along the Ras/mitogen-activated protein kinase (MAPK) pathway, Rauen has seen firsthand the role these mutations play in one of the most common groups of inherited genetic syndromes.
The group includes neurofibromatosis (NF), Noonan, CFC, LEOPARD, Costello and other genetic syndromes. Clinical conditions associated with these syndromes run from cancer and cardiac abnormalities to hydrocephalus, headaches, epilepsy and learning and processing disorders.
"Because of multisystem involvement and resulting specialty care needs, providing comprehensive care for these individuals is a challenge," says Rauen.
To meet that challenge, the NF/Ras Pathway Clinic offers comprehensive case management, prenatal and obstetric care, and multidisciplinary referrals to a network of more than 50 specialists. And because these syndromes are lifetime afflictions, the center also facilitates the transition from pediatric to adult care.
After a phone intake that includes a complete medical history and family tree, a patient's first visit is with a medical geneticist and genetic counselor, who review the history and conduct a thorough physical exam.
"We look for phenotypic markers that form a recognizable pattern of dysmorphology," says Rauen. "A skin manifestation, for example, can help tie the clinical diagnosis down." A molecular diagnosis, which requires patient consent, can confirm the clinical diagnosis, help family members understand the overall impact on the family and help them make decisions.
The next step is to tap into the clinic's extensive network of subspecialists. "If it's Noonan, for example, we know they may be more prone to hypothyroidism, so we begin a workup and call in endocrinology," says Rauen. "The advantage is a unifying diagnosis that helps providers know what to be mindful of and facilitates more personalized medicine."
"Throughout the process, we work with the family and their primary care provider to create a joint set of goals that can include nonclinical issues," says Strecker. "We care for the whole person — and, many times, the entire family — and make sure there are no gaps in care."
Noonan and LEOPARD syndromes
For more information, contact Katherine Rauen, M.D. at (415) 514–3513, Michelle Strecker at (415) 476–9321 or the NF/Ras Pathway Clinic at (415) 476–2757.
Six patient advocacy groups will join clinicians and researchers for a two-day research symposium, titled "Genetic Syndromes of the Ras/MAPK Pathway: From Bedside to Bench and Back," on August 1 and 2, at the Doubletree Hotel in Berkeley, Calif. Katherine Rauen, M.D., Ph.D., and Lisa Schoyer of the Costello Syndrome Family Network will chair this forum on basic science and clinical issues surrounding these syndromes.
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