The Quarterly Consultis a quarterly supplement to the Bulletin highlighting pediatric clinical expertise. If you have an item of interest to include in the Quarterly Consult, contact Dr. Steve Dassel at 206-625-7373, mailbox 8588.

By Steve Dassel, MD

Seattle Children's Hospital opened a new Neurofibromatosis Clinic, held on the third Friday of each month.

I recently discussed the condition with the clinic's leader, Dr. Stephanie Wallace, attending physician at Seattle Children's and assistant professor in the Division of Genetics and Developmental Medicine, Department of Pediatrics, at the University of Washington.

Dr. Wallace is from Seattle and attended Bothell High School. She received her undergraduate degree at the University of Washington, and received her medical degree and post-doctoral training at UCLA. She returns to Seattle as a clinical geneticist.

Also participating in the clinic is Dawn Earl, ARNP, a certified nurse practitioner in genetics. Earl also did her undergraduate training at the University of Washington and graduate work at UCLA.

Darci Sternen, a certified genetic counselor, completes the neurofibromatosis (NF) team. Sternen received her master's in genetic counseling from University of California at Berkeley.

Q: Dr. Wallace, please put neurofibromatosis in perspective. As I recall, there are two types: an opticcutaneous-musculoskeletal form called von Recklinghausen disease and an eighth nerve tumor form of the condition. Have more types been described?

A: There are several different forms of neurofibromatosis.

The incidence, genetic etiology, natural history and management of the different forms vary considerably. Individuals that are referred to Genetics for "rule-out neurofibromatosis" typically have some features of neurofibromatosis type 1 (NF-1).

This is the most common type, with an incidence of about 1 in 3,000 to 4,000.

Q: What are the clinical manifestations of NF-1?

A: The diagnosis of NF-1 is based on the presence of at least two of the following seven clinical criteria:

  • Greater than five café au lait spots of sufficient size (prepubertal greater than 0.5 cm, and postpubertal greater than 1.5 cm)
  • Optic glioma
  • Two or more Lisch nodules
  • Two or more neurofibromas, or one plexiform neurofibroma
  • A distinct osseous lesion (such as sphenoid dysplasia or pseudoarthrosis)
  • Axillary and/or inguinal freckling
  • A first-degree relative with NF-1

Q: I was taught that greater than five café au lait spots of sufficient size virtually made the diagnosis of NF-1. That is no longer true?

A: No, two criteria are necessary for the diagnosis of NF-1.

There are families and individuals with café au lait macules that do not have neurofibromatosis. Less than five café au lait macules without any other physical or cognitive issues should not raise significant concern.

Q: Remind me, please, what are Lisch nodules?

A: These are hamartomas found on the iris. They do not affect vision. They can be a useful sign to confirm the diagnosis of NF-1.

Q: In patients with café au lait spots, I know these spots need not be present at birth. Is there an age at which one can reassure the parents that if there are no other criteria they can relax?

A: The clinical features of NF-1 develop over time. Children are followed if they have one or more criteria.

If a child does not have six or more café au lait macules by the age of 2 years, the risk for developing NF-1 is quite low.

Q: How sensitive is a negative family history for neurofibromatosis type 1?

A: 50% of individuals with neurofibromatosis type 1 are the first affected members of their family.

Q: Are there any other findings that may be helpful for the diagnosis of NF-1?

A: Stature that is within the normal range but less than expected from the mid-parental height. The head size is often large, with disproportionate macrocephaly.

School achievement and coordination can be affected. ADD or ADHD are also common in children with NF-1.

Q: What should a primary care physician do if concerned about the presence of NF-1 in a patient?

A: An ophthalmologist may provide the Neurofibromatosis Clinic with useful information, so a referral to ophthalmology before a referral to our clinic would be an efficient first step.

However, a negative ophthalmologic exam does not rule out the possibility of NF-1.

Q: What medical surveillance is necessary for patients with NF-1 or with findings that are suspicious for NF-1?

A: An ophthalmology evaluation and a hearing evaluation are important. A head MRI is not part of the workup unless the patient has focal neurological deficits.

Hypertension is not uncommon in individuals with NF-1. Annual blood pressure assessment and further evaluation is necessary if hypertension is present. Scoliosis is a complication of NF-1, so a spinal exam should be part of the yearly physical exam of any child with suspected or known NF-1.

Academic achievement can be affected and should be followed closely. There is an increased risk for certain malignancies.

Annual physical exams are recommended, with close attention paid to asymmetry, unexplained pain or rapid growth of a neurofibroma, or changes in vision or hearing.

Q: What is in the differential diagnosis for NF-1?

A: The most common conditions that overlap with NF-1 are:

  • Autosomal dominant café au lait macules without other features of NF-1
  • Segmental NF-1
  • McCune-Albright syndrome
  • Watson syndrome
  • Noonan syndrome
  • Fragile X syndrome
  • PTEN hamartoma syndromes (Proteus, Bannayan-Riley-Ruvalcaba, Cowden syndromes)

Q: How do you work with community providers once a positive diagnosis of NF-1 has been made?

A: If there is a suspicion or confirmation of a diagnosis of NF-1, we can provide information to the family about the genetics of the condition, and we explain the inheritance pattern and recurrence risk.

We typically examine the parents for physical features of NF-1 and occasionally we identify an affected parent. If a parent is affected, he or she has a 50% chance with each pregnancy of having an affected child.

If a parent is suspected to have NF-1, we make the appropriate referral to an adult genetics center. We also review the preventative medicine issues with the family.

The child does not need to come to the Neurofibromatosis Clinic on a regular basis if the primary care provider is comfortable following the family. We also can help make referrals and follow complications that arise if the condition becomes too complicated for the primary care provider to manage.

Some primary care providers are very comfortable and familiar with NF-1 and others are not.

Q: What services does Children's offer for children with NF-1?

A: Children's has a variety of specialists who attend in the NF-1 clinic.

These include neurologists, neurosurgeons, neuroradiologists, hematologists/oncologists, audiologists, ophthalmologists and orthopedists who can help respond to complications. Other providers are available as needed.

Q: Describe the range of disability that NF-1 causes?

A: NF-1 is extremely variable even within a family. Approximately 40% of patients have no significant complications. But for some patients, the disease can be life threatening.

Q: Let's spend a little bit of time on the clinical manifestations of NF-2.

A: NF-2 is typically an adult-onset condition. It can be confusing, because it shares the same name as neurofibromatosis type 1, but it is a very different disorder.

Patients with NF-2 are followed in an adult center or in a general genetics clinic. Individuals with NF-2 need to meet one of the following descriptions for clinical diagnosis:

  • Bilateral vestibular schwannomas
  • A unilateral vestibular schwannoma and a first-degree relative with NF-2
  • Any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities and a first-degree relative with NF-2
  • A unilateral vestibular schwannoma and any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
  • Multiple meningiomas and a unilateral vestibular schwannoma
  • Multiple meningiomas and any two of: schwannoma, glioma, neurofibroma, cataract

Q: How may we refer patients to the Neurofibromatosis Clinic, Stephanie?

A: Referrals can be faxed to 206-985-3121 or called into 206-987-2080.

Clinical questions can be sent to me. I am also available by phone at 206-987-3408.

Thank you, Stephanie.