Neurofibromatosis 1

Excerpt

Clinical characteristics: Neurofibromatosis 1 (NF1) is a multisystem disorder characterized by multiple café au lait macules, intertriginous freckling, multiple cutaneous neurofibromas, and learning disability or behavior problems. About half of people with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically. Plexiform neurofibromas can cause pain, neurologic deficits, and abnormalities of involved or adjacent structures. Less common but potentially more serious manifestations include optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, vasculopathy, and gastrointestinal, endocrine, or pulmonary disease.

Diagnosis/testing: The diagnosis of NF1 is established in a proband with two or more of the characteristic clinical features or one characteristic clinical feature and a heterozygous NF1 pathogenic variant.

Management: Treatment of manifestations: Referral to specialists for treatment of abnormalities of the eye, central or peripheral nervous system, cardiovascular system, lungs, endocrine system, spine, or long bones. Treatment of optic gliomas is generally unnecessary as they are usually asymptomatic and clinically stable. Surgical removal or other non-surgical methods to ablate disfiguring or uncomfortable discrete cutaneous or subcutaneous neurofibromas. Surgical treatment of diffuse or large plexiform neurofibromas is possible but may be associated with damage to involved nerves or adjacent tissues. Complete surgical excision, when possible, of malignant peripheral nerve sheath tumors is the treatment of choice; chemotherapy may be beneficial in some individuals. Management of other malignancies per oncologist with experience in NF1. Pain management may require referral to pain specialist. Individualized developmental and educational interventions may be beneficial, and methylphenidate treatment often benefits individuals with attention-deficit/hyperactivity disorder. Dystrophic scoliosis often requires surgical management, whereas nondystrophic scoliosis can usually be treated conservatively. Vitamin D and calcium supplementations to decrease risk of osteoporosis; bisphosphonate treatment may be helpful.

Targeted therapy: MEK inhibitors selumetinib or mirdametinib can reduce the size and symptoms associated with inoperable plexiform neurofibromas in many individuals with NF1.

Surveillance: Annual physical examination by a physician familiar with the disorder; ophthalmologic examination annually in children, and regularly but less frequently in adults; developmental assessment of children; regular blood pressure monitoring; MRI for identification and follow up of clinically suspected intracranial or other tumors that are not apparent on physical examination. Begin annual mammography in women at age 30 years with consideration of annual breast MRI in women between ages 30 and 50 years. Individuals with NF1 whole-gene deletions, large or growing plexiform neurofibromas or intracranial tumors, symptomatic vascular disease, progressive osseous lesions, or other serious disease manifestations require more frequent targeted follow up.

Genetic counseling: NF1 is inherited in an autosomal dominant manner. Approximately half of affected individuals have NF1 as the result of a de novo NF1 disease-causing variant. Each child of an individual with NF1 has a 50% chance of inheriting the disease-causing variant. Penetrance is close to 100%; thus, a child who inherits an NF1-causing variant is expected to develop features of NF1, but the features may be considerably more (or less) severe in an affected child than in the affected parent. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the disease-causing variant in a family is known.