FaCD Online Syndrome Fact Sheet

Last updated: 07 Mar 2013

Name: Neurofibromatosis, type 1

Synonym: NF1, von Recklinghausen disease, incl.: Hereditary Spinal Neurofibromatosis, Neurofibromatosis-Noonan syndrome

Mode of Inheritance: AD

OMIM number: 162200

Genes

NF1, mapped to 17q11.2

Tumor features

astrocytoma
breast cancer
carcinoid of the small intestine
gastrointestinal autonomic nerve tumors (GANT)
gastrointestinal leiomyomas
gastrointestinal neurofibromas
gastrointestinal stromal tumor (GIST)
glioma of the brain
juvenile myeloid / myelomonocytic leukemia (JMML)
juvenile xanthogranuloma
malignant peripheral nerve sheath tumor (= neurofibrosarcoma, malignant schwannoma)
neurofibroma of the skin
neurofibroma, plexiform
optic glioma
pheochromocytoma
rhabdomyosarcoma

Tumor features (possible)

astroblastoma
bone, giant cell tumor of
gangliocytic paraganglioma
gastrointestinal leiomyosarcoma
glioblastoma (multiforme)
hepatocellular cancer (hepatoma)
leukemia, acute lymphoblastic (ALL)
leukemia, acute myeloid (AML, incl. ANLL)
malignant fibrous histiocytoma
medulloblastoma
melanoma, cutaneous
melanoma, uveal (choroidal, ciliary body, iris)/ocular
neuroblastoma, adrenal
non-Hodgkin lymphoma
paraganglioma, nonchromaffin (incl.: glomus tumor/chemodectoma)
schwannoma (neurilemmoma), peripheral nerve
thyroid cancer, medullary
Wilms' tumor (nephroblastoma)

Non-tumor features

axillary freckling
café au lait spots
developmental delay/mental deficiency/mental retardation
hemihypertrophy
iris, Lisch nodules
macrocephaly
meningioangiomatosis
scoliosis
seizures

Non-tumor features (possible)

bone marrow monosomy 7 karyotype

Comment

Characteristic findings are the cafe-au-lait spots and cutaneous neurofibromas (predominantly of the trunk), axillary freckling and Lisch noduli of the iris. Less specific features are learning difficulties (in approximately one third of the patients, severe mental retardation is rare), macrocephaly and scoliosis. A high proportion of patients (30-60%) show benign unidentified bright objects (UBO's = unidentified neurofibromatosis objects UNO's) without mass effect on MRI of the brain (possibly a minority undergoes malignant transformation[1]. Asymptomatic plexiform neurofibromas probably exist in a high percentage of NF1 patients[2].

Although a range of tumors have been reported in NF1 patients[3-8, 58, 62], the risk of neoplasms other than optic gliomas is probably lower than suggested in the earlier publications[9]: the overall risk is probably not strongly increased[10], not higher than 5 % [6]. The most typical tumors are: optic gliomas[55] (15%? in NF1; highest risk before the age of 7 years; incidence of symptomatic tumors in NF1 ranges between 1.5% and 7.5%[11]; of all optic glioma cases 25-70% have NF1[11]), malignant peripheral nerve sheath tumors (MPNST, incl.: neurofibrosarcoma, malignant schwannoma) which arise in particular in the plexiform neurofibromas and have a poor prognosis[12], juvenile chronic myelogenous leukemia (often associated with xanthogranuloma and considered to be a subtype of myelodysplastic syndrome’s CMML [13-16], pheochromocytoma, rhabdomyosarcoma[17;18] and (mainly duodenal) carcinoid. In a series of 658 patients with soft tissue sarcomas, a clinically identified genetic disease represented 3% of all cases and most of these cases (14/19) were related to NF1[51]. Gastrointestinal involvement in NF1 is not rare, possibly 25 % of NF1 cases feature G.I. tumors: neurofibromas are the most frequent, others are neurofibrosarcomas, (duodenal) carcinoids, leiomyomas and rarely leiomyosarcoma, gastrointestinal autonomic nerve tumors (GANT, ganglioneuromas), GIST, and small intestinal adenocarcinomas [40-49,52-54]. Intestinal neurofibromatosis has been recognized as a specific entity not associated with germline NF1 mutations and rather than neurofibromas these tumors are stromal tumors (GIST). Several studies point to an increased breast cancer risk in NF1 women[58-62]

A much wider range (possibly reflecting chance occurrences) has been reported, including Wilms tumor[6;19], (uveal) melanoma[6;8;20-25], paraganglioma[26], ganglioneuroma/blastoma[27], NHL, ALL, AML and monosomy 7 MDS[28-30], giant cell bone tumor[31], malignant fibrous histiocytoma[21;32;33], dysembryoplastic neuroepithelial tumors[34], medulloblastoma[19], glioblastoma[56], astroblastoma[57], and hepatocellular cancer[35].

Between and within NF1 families the severity of the disease may differ considerably. NF1 is caused by germline (and somatic second hit) mutations in the NF1 gene, encoding neurofibromin, which is thought to act as tumor suppressor. The disorder is almost 100 % penetrant. In approximately 50 % of cases, patients have a new mutation.

Diagnostic criteria for NF1:
The disorder can be diagnosed if two or more of the following features are found in a patient:

6 or more cafe-au-lait spots of the skin, which should be over 5 mm in prepubertal and over 15 mm in postpubertal individuals
2 or more neurofibromas of any type or 1 plexiform neurofibroma
axillary and/or inguinal freckling
optic glioma
2 or more Lisch noduli of the iris
a distinctive osseous lesion (sphenoid dysplasia, thinning of long bone cortex)
a first-degree relative diagnosed with NF1

The usual order of appearance of the above mentioned clinical features is: cafe-au-lait macules, axillary freckling, Lisch nodules and neurofibromas. Nearly all NF1 patients meet the criteria for diagnosis by the age of 8 years, however, only approximately 46% of sporadic NF1 cases does so at the age of 1 year[36].

A number of authors have reported on a disorder what appears to be a subset of NF1: Hereditary (or Familial) Spinal Neurofibromatosis[37-39], which is characterized by the predominance of spinal cord neurofibromas. Mutations in NF1 have been found in this disorder[39].

Some patients with neurofibromatosis type 1 have facial features resembling those of Noonan syndrome patients. The genetic background of this particular neurofibromatosis-Noonan phenotype is unknown. As in Noonan syndrome, ALL has been reported in patients with the NF-Noonan syndrome[50].

Links

Neurofibromatosis, Inc. 23 1 08
The Children's Tumor Foundation 23 1 08
The Neurofibromatosis Association of Australia (NFAA) Inc. 24 1 08
The Neurofibromatosis Association, UK 24 1 08

References