LA JOLLA, CALIF. — The way Dr. Lynne M. Bird sees it, the $1,500 gene sequencing test for neurofibromatosis type 1 in children is rarely necessary because it usually does not change clinical management.
She favors a watchful waiting approach in children who present with the hallmark symptom of at least six café au lait macules that are at least 5 mm in size, “and [I] wait for the second criterion to appear,” she said at a meeting sponsored by Rady Children's Hospital and the American Academy of Pediatrics. “I follow these children as if I already knew they had NF1, monitoring them for potential complications without doing gene testing.”
The prevalence of neurofibromatosis type 1 (NF1) is 1:3,000, making it the most common neurocutaneous disorder in children. Diagnosis is made if the child meets two of seven criteria: café au lait macules; axillary or inguinal freckling; two or more neurofibromas or one plexiform neurofibroma; optic nerve glioma; two or more Lisch nodules of the iris; a distinctive osseous lesion such as pseudarthrosis or sphenoid wing dysplasia; or a family history of the disease.
About of half of cases with no family history meet criteria for the disorder by 1 year of age; 97% meet the criteria by 8 years of age.
NF1 is an autosomal, dominantly inherited disorder due to mutations in a gene on chromosome 17, which encodes the protein neurofibromin, a tumor suppressor. “Finding a mutation of the gene would also allow you to make this diagnosis,” said Dr. Bird of the division of genetics and dysmorphology at Rady Children's Hospital, San Diego. “If you have a parent with NF1 and you can determine their mutation through genetic testing, then you can offer them prenatal diagnosis. In my experience, most parents aren't concerned enough about passing NF1 on to their children that they would consider interrupting a pregnancy. But some families have experienced major complications associated with NF1, and they are very interested in not passing the gene on to their children.”
A study of nearly 1,900 patients with NF1 found that the features of the disease typically appear in a characteristic order, beginning with café au lait macules (Pediatrics 2000;105:608–14).
Sometimes macules are present at birth “but others will appear in the first few months of life and certainly by the first couple of years of age,” Dr. Bird said. “Typically the next feature is axillary freckling, which is usually evident in the school-age child. Lisch nodules will appear gradually after that, followed by neurofibromas as a sign that the child is entering puberty.”
Another clue is the presence of the Riccardi sign, a tuft of hair along the back near the spine. “This sign will often be present at birth and may be there before any of the café au lait macules show up, so you will look really smart if you make a tentative diagnosis upon seeing this,” Dr. Bird said.
Optic glioma almost always appears by 3 years of age “and certainly by 6 years of age,” she said. “In addition, there is frequent thickening of the optic nerves, which is asymptomatic and doesn't cause disease.”
A rare feature of NF1 is juvenile xanthogranuloma, which occurs in 1%–2% of cases. This skin lesion usually resolves spontaneously but is associated with an increased incidence of juvenile myeloid leukemia (JML). “When you see this, you want to at least do a complete blood count and be thinking about JML, and maybe contact your local oncologist to see if they have further recommendations for monitoring,” she advised.
In most cases, the diagnosis of NF1 is made on clinical exam, including a careful evaluation of both parents. “This condition is present in 1 in 3,000 in the general population, but I don't see anywhere near the equivalent number of kids in my clinic,” Dr. Bird said. “That tells me there is a lot of undiagnosed NF1 out there. Most parents [with NF1] are healthy; they just have spots and a few lumps on their skin.”
The best way to follow children with NF1 is to see them regularly for a complete physical examination and review of systems. There is no way to screen for every single complication of NF1 except by talking to families, said Dr. Bird, who is also with the department of pediatrics at the University of California, San Diego. “Families should be told that symptoms which are not self-limited need to be brought to your attention,” she said
Basic follow-up tests should include checking blood pressure and monitoring for scoliosis as well as an ophthalmology evaluation and an assessment of developmental skills. “Learning disabilities are common,” she said. “Expressive language delay is the area of development most commonly affected.”