GOTHENBURG, SWEDEN - Neurofibromatosis type 1 is a diagnosis every dermatologist should be able to make, according to Dr. Sirkku Peltonen.
Be sure to check the armpits, she said. Examining the axillae in search of a few small freckles often makes the difference between diagnosing neurofibromatosis type 1 (NF1) and overlooking this cancer predisposition syndrome.
"The armpits are so easy to forget – and then you lose the chance to make the diagnosis," said Dr. Peltonen of the University of Turku (Finland).
Diagnosis of NF1 is not difficult, she said. Of children aged 6 years or older, 95% can be clinically diagnosed based on the presence of at least two of the following features: six or more café au lait spots, each more than 5 mm in their greatest diameter; axillary or inguinal freckling; a first-degree relative with NF1; or pseudoarthrosis of the tibia, a finding present in only about 3% of individuals with NF1. These four features, from a longer list of diagnostic criteria established by the National Institutes of Health, are the most relevant to dermatologists (JAMA 1997;278:51-7). The flat, pigmented café au lait macules usually appear by a child’s first birthday.
"If you see four or five café au lait spots, suspect NF1 and look for more," Dr. Peltonen said at the annual congress of the European Academy of Dermatology and Venereology.
Freckles under the armpit appear by 6 years of age. Prior to that, the diagnosis is typically made on the basis of the requisite café au lait spots in a child having a family history of NF1. However, half of patients with NF1 have a sporadic mutation and no family history of the disease, making early diagnosis considerably more difficult.
Laboratory analysis of NF1 is available in challenging cases, most of which involve young children. It is a laborious, expensive process because the NF1 gene, located on chromosome 17, band q11, is large, and hundreds of mutations have been identified to date, said Dr. Peltonen.
In her experience, laboratories vary widely in their ability to perform a high-quality analysis of mutations of the NF1 gene. She singled out the laboratories at the Ghent (Belgium) University and the University of Alabama at Birmingham as being particularly good when it comes to the diagnosis of NF1. Testing costs more than $1,300, she said.
The incidence of NF1, formerly known as von Recklinghausen’s disease, is roughly 1 in 3,000 live births, noted Dr. Peltonen. Inheritance is autosomal dominant with 100% penetrance. This means everyone who has the inherited form of NF1 ought to be readily diagnosable.
NF1 is a multisystem condition. Common features include cognitive impairment in 80% of patients, learning difficulties in 50%-60%, and speech abnormalities in 30%, as well as eye and skeletal abnormalities. Affected children are at risk for social exclusion because of their appearance. A dermatologist who diagnoses NF1 needs to be ready to make a referral to a physician who is familiar with the syndrome for regular follow-up, she said.
Children with NF1 are at 100-fold increased risk for brain tumors, compared with unaffected children. The lifetime risk of developing a malignant peripheral nerve sheath tumor is 10%-15%. Thirty percent or more of patients with NF1 have one or more plexiform neuromas, which are at risk for malignant transformation. The cancers can appear at any age, although most often not until after the teenage years.
Danger signs of malignancy in patients with NF1 include neurogenic pain in the extremities, a painful mass, or accelerated growth of an existing plexiform neuroma, she added.
The majority of adults with NF1 develop cutaneous neurofibromas. These were traditionally thought to have their origin in small dermal nerve twigs containing Schwann cells. In soon-to-be-published work, however, Dr. Peltonen and his coworkers have shown that the tumors actually arise from multipotent stem cells closely associated with hair follicles.
The cutaneous neurofibromas never become malignant. Nevertheless, they have a huge negative impact on quality of life, she said.
Patients consider cutaneous neurofibromas to be the greatest burden of NF1 because they are painful and unsightly. Dermatologists can do patients a great service by removing the benign cutaneous tumors, said Dr. Peltonen. The CO2 laser is effective for this purpose. Dozens of tumors can be removed under local anesthesia in one appointment, and patients are very appreciative. Dr. Peltonen has one patient who travels 9 hours each way for excision of cutaneous neurofibromas.
"I usually make a circle around the tumor and then cut in between dermis and the tumor while pulling on it at the same time," she said. "It’s quite easy to get the tumor out of the skin, and the holes heal nicely."