Summer 2009

Genetic Advances — Unique Care at Pathway Clinic

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.

Unifying Diagnoses Lead to More Effective Treatments

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.

Caring for the Whole Patient

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."

Clinical Indicators for an NF/Ras Pathway Referral

NF1

  • Skin spots (café au lait macules, armpit and groin freckling)
  • Neurofibromas
  • Developmental delay and learning disabilities
  • Short stature or macrocephaly

NF2

  • Bilateral vestibular schwannomas (tinnitus, hearing loss and balance dysfunction)
  • Schwannomas of other cranial and peripheral nerves
  • Meningiomas

Noonan and LEOPARD syndromes

  • Dysmorphic features
  • Skin spots (lentigenes, café noir spots)
  • Short stature
  • Pulmonary valve stenosis or other heart defect

Cardiofaciocutaneous syndrome

  • Dysmorphic features
  • Heart defects
  • Skin rashes and sparse hair
  • Developmental delay
  • Severe GI problems and failure to thrive

Costello syndrome

  • Coarse facial features
  • Heart defects
  • Failure to thrive
  • Developmental delay
  • Deep palmar and plantar creases

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.

A Syndrome Symposium

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.

Related Information

News Releases

Acid Reflux Linked to Poor
Dental Health

At this year's Pediatric Academic Societies meeting, UCSF researchers reported on the first study to examine the relationship between acid reflux and pediatric dental health. They found that children who have symptoms of chronic acid reflux are significantly more likely to have dental erosions than those without reflux symptoms.

Most Teens Don't Get
Preventive Care

The majority of adolescents in the United States do not obtain the appropriate level of preventive health care services, despite broad professional consensus recommending annual doctor visits for this age group, according to a UCSF study.