neurofibromatosis type 1

Digital cases

 HPC:105 : Neurofibroma in NF1
 HPC:411 : Diffuse neurofibroma in NF1

Definition: Neurofibromatosis-1 (NF-1) is a multisystem disorder presenting with a variety of clinical and imaging manifestations. Neural and non-neural tumours, and unusual benign miscellaneous conditions, separately or combined, are encountered in variable locations.

Autosomal dominant tumor predisposition syndrome. Neurofibromatosis 1 (NF1), also known as Von Recklinghausen’s disease, is one of the most common genetic diseases with a prevalence of between 1 in 2,000 to 3,000. This estimation, however, can be higher as unrecognized cases are common because of the “formes frustes” of this condition.

Neurofibromatosis type 1 is a relatively common disorder, with a frequency of almost 1 in 3000. Although approximately 50% of the patients have a definite family history consistent with autosomal dominant transmission, the remainder appear to represent new mutations. In familial cases, the expressivity of the disorder is extremely variable, but the penetrance is 100%.

NF1 is a pleiotropic congenital multiple dysplasia syndrome. The cardinal features of NF1 and NF2 are multifocal hyperplasia and neoplasia in the supportive tissues throughout the entire nervous system which include the nerve sheath elements of the cranial, spinal and peripheral nerve as well as glial and meningeal elements of the central nervous system.

Neoplastic transformation of ganglionic elements resulting in pheochromocytomas, peripheral neuroblastomas and ganglioneuromas may also occur. The patients are predisposed to develop neurofibroma, plexiform neurofibroma and malignant peripheral nerve sheath tumor (MPNST).

About 2-5% of NF1 patients will develop MPNST (risk of general population is 0.0001%). Although a plexiform raises a strong suspicion of NF1, only about 30% of NF1 patient develop plexiform neurofibroma.

Patient with NF1 also develop astrocytoma (particularly astrocytoma of the optic nerve-hypothalamus region), pheochromocytoma, and juvenile myelomonocytic leukemia. A10-fold increased risk of learning problems have also been described in NF1 patients.

Neurofibromatosis type 1 has three major features: (1) multiple neural tumors (neurofibromas) dispersed anywhere on or in the body; (2) numerous pigmented skin lesions, some of which are café au lait spots; and (3) pigmented iris hamartomas, also called Lisch nodules. A bewildering assortment of other abnormalities (cited later) may accompany these cardinal manifestations.

Synopsis

 cephalic anomalies

• macrocephaly
• sphenoid dysplasia
• Lisch nodules (iris hamartomas)
• glaucoma
• hypertelorism

 vascular anomalies

• renal artery stenosis

 skeletal anomalies (17702004, 17317783)

• scoliosis (17945135, 15712001)
• spina bifida
• congenital pseudarthrosis (11571375) of the tibia (17657556, 16773574, 16735097), of the radius and ulna (15680576, 11315302)
• anterolateral bowing of the lower leg (17666887)
• thinning of long bone cortex
• local bony overgrowth
• absent patellae

  cutaneous anomalies

• cafe-au-lait spots
• axillary freckling
• inguinal freckling
• multiple cutaneous neurofibromas

 renal anomalies

• NF1-associated horseshoe kidney (15150783, 417177)

 cerebrospinal anomalies

• aqueductal stenosis
• hydrocephalus
• intrathoracic meningocele (1681023)

 tumor predisposition

• NF1-associated neurofibromas
  • NF1-associated localized neurofibroma
  • NF1-associated plexiform neurofibroma and elephantiasis neuromatosa
  • NF1-associated diffuse neurofibroma

• malignant peripheral nerve sheath tumor (MPNST or neurofibrosarcoma) (14508395)
• plexiform neurofibroma
• optic glioma
• meningiomas
• embryonal rhabdomyosarcoma (3277029, 19766846)
• Wilms tumor
• ameloblastic fibroma
• ossifying fibroma of the bones
• gastrointestinal stromal tumor (multiple GISTs) (15897742, 16096406, 17255767, 16330947)

• endocrine tumors
  • duodenal carcinoid
  • pancreatic somatostatinoma
  • pancreatic insulinoma (16861979)
  • parathyroid adenoma
  • pheochromocytoma

Associations

 multiple subcutaneous lipomas (15150783)
 juvenile polyp in ascending colon (15150783)
 congenital intrahepatic portosystemic venous shunt (15150783)
 horseshoe kidney (15150783)

Etiology

 NF1-associated neurofibromatosis

Variants

 mosaic neurofibromatosis type 1 (mosaic NF1)

Differential diagnosis

 tumor predisposition syndromes
 DNA mismatch repair cancer syndrome (MIM.276300)

• MLH1-associated cancer syndrome
• MSH2-associated cancer syndrome

 hamartomatous syndromes

• Proteus syndrome
• Bannayan-Riley-Ruvalcaba syndrome
• Cowden syndrome

Pathogenesis

 The neurofibromas arise within or are attached to nerve trunks anywhere in the skin, including the palms and soles, as well as in every conceivable internal site, including the cranial nerves.

 Three types of neurofibromas are found in individuals with neurofibromatosis type 1: cutaneous, subcutaneous, and plexiform. Cutaneous, or dermal, neurofibromas are soft, sessile, or pedunculated lesions that vary in number from a few to many hundreds. Subcutaneous neurofibromas grow just beneath the skin; they are firm, round masses that are often painful. The cutaneous and subcutaneous neurofibromas may be less than 1 cm in diameter; moderate-sized pedunculated lesions; or huge, multilobar pendulous masses, 20 cm or more in greatest diameter.

 The third variant, referred to as plexiform neurofibroma, diffusely involves subcutaneous tissue and contains numerous tortuous, thickened nerves; the overlying skin is frequently hyperpigmented. These may grow to massive proportions, causing striking enlargement of a limb or some other body part. Similar tumors may occur internally, and in general the deeply situated lesions tend to be large.

 Microscopically, neurofibromas reveal proliferation of all the elements in the peripheral nerve, including neurites, Schwann cells, and fibroblasts. Typically, these components are dispersed in a loose, disorderly pattern, often in a loose, myxoid stroma. Elongated, serpentine Schwann cells predominate, with their slender, spindle-shaped nuclei. The loose and disorderly architecture helps differentiate these neural tumors from schwannomas. The latter, composed entirely of Schwann cells, virtually never undergo malignant transformation, whereas plexiform neurofibromas become malignant in about 5% of patients with neurofibromatosis type 1.42 Malignant transformation is most common in the large plexiform tumors attached to major nerve trunks of the neck or extremities. The superficial lesions, despite their size, rarely become malignant.

 The cutaneous pigmentations, the second major component of this syndrome, are present in more than 90% of patients. Most commonly, they appear as light brown café au lait macules, with generally smooth borders, often located over nerve trunks. They are usually round to ovoid, with their long axes parallel to the underlying cutaneous nerve. Although normal individuals may have a few café au lait spots, it is a clinical maxim that when six or more spots greater than 1.5 cm in diameter are present in an adult, the patient is likely to have neurofibromatosis type 1.

 Lisch nodules (pigmented hamartomas in the iris) are present in more than 94% of patients age 6 years or older. They do not produce any symptoms but are helpful in establishing the diagnosis.

 A wide range of associated abnormalities has been reported in these patients. Perhaps most common (seen in 30% to 50% of patients) are skeletal lesions, which take a variety of forms, including (1) erosive defects owing to contiguity of neurofibromas to bone, (2) scoliosis, (3) intraosseous cystic lesions, (4) subperiosteal bone cysts, and (5) pseudoarthrosis of the tibia.

 Patients with neurofibromatosis type 1 have a twofold to fourfold greater risk of developing other tumors, especially Wilms tumors, rhabdomyosarcomas, meningiomas, optic gliomas, and pheochromocytomas. Affected children are at increased risk of developing chronic myeloid leukemia.

 Although some patients with this condition have normal intelligence quotients (IQs), there is an unmistakable tendency for reduced intelligence. When neurofibromas arise within the gastrointestinal tract, intestinal obstruction or gastrointestinal bleeding may occur. Narrowing of a renal artery by a tumor may induce hypertension.

 Owing to variable expression of the gene, the range of clinical presentations is almost limitless, but ultimately the diagnosis rests on the concurrence of multiple café au lait spots and multiple skin tumors.

 The neurofibromatosis type 1 (NF1) gene has been mapped to chromosome 17q11.2. It encodes a protein called neurofibromin, which down-regulates the function of the p21Ras oncoprotein. NF1 therefore belongs to the family of tumor suppressor genes (TSGs).

Etiology

 mutations in the NF1 gene encoding neurofibromin (MIM.162200)

• 50% of cases are caused by new mutations

NF1 is transmitted in an autosomal dominant fashion. The neurofibromin gene on chromosome 17q11.2 is involved.

Whole gene deletion, single- and multiple-exon deletion, and small deletion comprised about 50% of all the mutations. The deletion can be bigger than the gene and therefore other potential genes can also be deleted which would lead to a contagious gene syndrome type of clinical presentation.

The rest of the mutations includes insertion and point mutations. Point mutations that have been identified do not cluster in hot spots. About half of the new cases of NF1 are new mutations.

The estimated rate of mutation of NF1 gene is unusually high but the cause of this high mutation rate is not known.

 NF1 microdeletions

• In 5-10% of patients, neurofibromatosis type 1 (NF1) results from microdeletions that encompass the entire NF1 gene and a variable number of flanking genes.
• Two recurrent microdeletion types are found in most cases, with microdeletion breakpoints located in paralogous regions flanking NF1 (proximal NF1-REP-a and distal NF1-REP-c for the 1.4 Mb type-1 microdeletion, and SUZ12 and SUZ12P for the 1.2 Mb type-2 microdeletion).
• A more severe phenotype is usually associated with NF1 microdeletion patients than in those with intragenic mutations.
• They have a significantly higher incidence of learning disabilities and facial dysmorphism in microdeleted patients compared to patients with intragenic NF1 mutations. (20513137)
• Microdeleted NF1 patients also showed a trend toward significance for childhood overgrowth. (20513137)

Reviews

 Rubin JB, Gutmann DH. Neurofibromatosis type 1 - a model for nervous system tumour formation? Nat Rev Cancer. 2005 Jul;5(7):557-64. PMID: 16069817

 Costa RM, Silva AJ. Mouse models of neurofibromatosis type I: bridging the GAP. Trends Mol Med. 2003 Jan;9(1):19-23. PMID: 12524206

 Gutmann DH. The neurofibromatoses: when less is more. Hum Mol Genet. 2001 Apr;10(7):747-55. PMID: 11257108

 Reed N, Gutmann DH. Tumorigenesis in neurofibromatosis: new insights and potential therapies. Trends Mol Med. 2001 Apr;7(4):157-62. PMID: 11286939

References

 NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Pasmant E, Sabbagh A, Spurlock G, Laurendeau I, Grillo E, Hamel MJ, Martin L, Barbarot S, Leheup B, Rodriguez D, Lacombe D, Dollfus H, Pasquier L, Isidor B, Ferkal S, Soulier J, Sanson M, Dieux-Coeslier A, Bièche I, Parfait B, Vidaud M, Wolkenstein P, Upadhyaya M, Vidaud D; members of the NF France Network. Hum Mutat. 2010 Jun;31(6):E1506-18. PMID: 20513137

 Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1. Sabbagh A, Pasmant E, Laurendeau I, Parfait B, Barbarot S, Guillot B, Combemale P, Ferkal S, Vidaud M, Aubourg P, Vidaud D, Wolkenstein P; members of the NF France Network. Hum Mol Genet. 2009 Aug 1;18(15):2768-78. PMID: 19417008