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Neurofibromatosis type 6(NF6)

MedGen UID:
396266
Concept ID:
C1861975
Disease or Syndrome
Synonyms: Multiple cafe-au-lait spots; NF6
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
HPO: HP:0007565
OMIM®: 114030
Orphanet: ORPHA2678

Definition

Neurofibromatosis type 6 (NF6), also referred as café-au-lait spots syndrome, is a cutaneous disorder characterized by the presence of several café-au-lait (CAL) macules without any other manifestations of neurofibromatosis or any other systemic disorder. [from ORDO]

Clinical features

From HPO
Neurofibroma
MedGen UID:
45058
Concept ID:
C0027830
Neoplastic Process
A rare benign peripheral nerve sheath tumor characterized by a well-demarcated intraneural or diffusely infiltrative extraneural space-occupying lesion consisting of Schwann cells, perineurial-like cells, and fibroblasts. It presents as a cutaneous nodule, a circumscribed mass in a peripheral nerve, a plexiform enlargement of a major nerve trunk, or with diffuse but localized involvement of skin and subcutaneous tissue. Multiple neurofibromas are typically associated with neurofibromatosis 1. Malignant transformation occurs almost exclusively in plexiform neurofibromas and neurofibromas of major nerves.
Lisch nodules
MedGen UID:
395461
Concept ID:
C1860334
Finding
The presence of pigmented, oval and dome-shaped raised hamartomatous nevi of the iris..
Neurofibroma
MedGen UID:
45058
Concept ID:
C0027830
Neoplastic Process
A rare benign peripheral nerve sheath tumor characterized by a well-demarcated intraneural or diffusely infiltrative extraneural space-occupying lesion consisting of Schwann cells, perineurial-like cells, and fibroblasts. It presents as a cutaneous nodule, a circumscribed mass in a peripheral nerve, a plexiform enlargement of a major nerve trunk, or with diffuse but localized involvement of skin and subcutaneous tissue. Multiple neurofibromas are typically associated with neurofibromatosis 1. Malignant transformation occurs almost exclusively in plexiform neurofibromas and neurofibromas of major nerves.
Lisch nodules
MedGen UID:
395461
Concept ID:
C1860334
Finding
The presence of pigmented, oval and dome-shaped raised hamartomatous nevi of the iris..
Neurofibroma
MedGen UID:
45058
Concept ID:
C0027830
Neoplastic Process
A rare benign peripheral nerve sheath tumor characterized by a well-demarcated intraneural or diffusely infiltrative extraneural space-occupying lesion consisting of Schwann cells, perineurial-like cells, and fibroblasts. It presents as a cutaneous nodule, a circumscribed mass in a peripheral nerve, a plexiform enlargement of a major nerve trunk, or with diffuse but localized involvement of skin and subcutaneous tissue. Multiple neurofibromas are typically associated with neurofibromatosis 1. Malignant transformation occurs almost exclusively in plexiform neurofibromas and neurofibromas of major nerves.
Neurofibromatosis type 6
MedGen UID:
396266
Concept ID:
C1861975
Disease or Syndrome
Neurofibromatosis type 6 (NF6), also referred as café-au-lait spots syndrome, is a cutaneous disorder characterized by the presence of several café-au-lait (CAL) macules without any other manifestations of neurofibromatosis or any other systemic disorder.
Lisch nodules
MedGen UID:
395461
Concept ID:
C1860334
Finding
The presence of pigmented, oval and dome-shaped raised hamartomatous nevi of the iris..
  • Abnormality of head or neck
    • The following clinical feature is unrelated to Neurofibromatosis type 6
    • Lisch nodules
  • Abnormality of the eye
    • The following clinical feature is unrelated to Neurofibromatosis type 6
    • Lisch nodules
  • Abnormality of the integument
  • Abnormality of the nervous system
    • The following clinical feature is unrelated to Neurofibromatosis type 6
    • Neurofibroma
  • Neoplasm

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVNeurofibromatosis type 6
Follow this link to review classifications for Neurofibromatosis type 6 in Orphanet.

Conditions with this feature

Neurofibromatosis, type 1
MedGen UID:
18013
Concept ID:
C0027831
Neoplastic Process
Neurofibromatosis 1 (NF1) is characterized by multiple café au lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, iris Lisch nodules, and choroidal freckling. About half of people with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically. Learning disabilities are present in at least 50% of individuals with NF1. Less common but potentially more serious manifestations include optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, and vasculopathy.
Café-au-lait macules with pulmonary stenosis
MedGen UID:
107817
Concept ID:
C0553586
Disease or Syndrome
Watson syndrome is an autosomal dominant disorder characterized by pulmonic stenosis, cafe-au-lait spots, decreased intellectual ability (Watson, 1967), and short stature (Partington et al., 1985). Most affected individuals have relative macrocephaly and Lisch nodules and about one-third of those affected have neurofibroma (Allanson et al., 1991).
Johnson neuroectodermal syndrome
MedGen UID:
167092
Concept ID:
C0796002
Disease or Syndrome
Johnson neuroectodermal syndrome has characteristics of alopecia, anosmia or hyposmia, conductive deafness with malformed ears and microtia and/or atresia of the external auditory canal and hypogonadotropic hypogonadism. So far, less than 30 cases have been described in the literature. Other variable features include a congenital heart defect, facial asymmetry, intellectual deficit, cleft palate, choanal stenosis and an increased tendency for dental caries. The syndrome is transmitted as an autosomal dominant trait. The combination of developmental anomalies present in patients with this syndrome is suggestive of an embryological defect in the formation of the neuroectodermal derivatives of cephalic neural crest.
Fanconi anemia, complementation group J
MedGen UID:
323015
Concept ID:
C1836860
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
Neurofibromatosis type 6
MedGen UID:
396266
Concept ID:
C1861975
Disease or Syndrome
Neurofibromatosis type 6 (NF6), also referred as café-au-lait spots syndrome, is a cutaneous disorder characterized by the presence of several café-au-lait (CAL) macules without any other manifestations of neurofibromatosis or any other systemic disorder.
Neurofibromatosis-Noonan syndrome
MedGen UID:
419089
Concept ID:
C2931482
Disease or Syndrome
A variant of neurofibromatosis type 1 characterized by the combination of features of neurofibromatosis type 1, such as café-au-lait spots, iris Lisch nodules, axillary and inguinal freckling, optic nerve glioma and multiple neurofibromas; and Noonan syndrome, with features such as short stature, typical facial features, congenital heart defects and unusual pectus deformity.
Fanconi anemia, complementation group G
MedGen UID:
854017
Concept ID:
C3469527
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart
MedGen UID:
934739
Concept ID:
C4310772
Disease or Syndrome
RERE-related disorders are characterized by neurodevelopmental problems with or without structural anomalies of the eyes, heart, kidneys, and genitourinary tract and mild sensorineural hearing loss. Hypotonia and feeding problems are common among affected individuals. Developmental delay and intellectual disability range from mild to profound. Behavior problems may include attention-deficit/hyperactivity disorder, self-injurious behavior, and autism spectrum disorder. A variety of eye anomalies (coloboma, optic nerve anomalies, microphthalmia, and/or Peter's anomaly) and vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia) have been reported. Congenital heart defects, most commonly septal defects, have also been described. Genitourinary abnormalities include vesicoureteral reflux, and cryptorchidism and hypospadias in males. Sensorineural hearing loss can be unilateral or bilateral.
Mismatch repair cancer syndrome 2
MedGen UID:
1750327
Concept ID:
C5436806
Disease or Syndrome
Mismatch repair cancer syndrome-2 (MMRCS2) is an autosomal recessive childhood cancer predisposition syndrome characterized by hematologic malignancy, brain tumors, and gastrointestinal tumors. Multiple cafe-au-lait spots reminiscent of neurofibromatosis type I (NF1; 162200) may be present. Microsatellite instability may be detected in tumor samples (Muller et al., 2006). For a discussion of genetic heterogeneity of mismatch repair cancer syndrome (MMRCS), see MMRCS1 (276300).
Mismatch repair cancer syndrome 3
MedGen UID:
1733656
Concept ID:
C5436807
Disease or Syndrome
Mismatch repair cancer syndrome-3 (MMRCS3) is an autosomal recessive childhood cancer predisposition syndrome characterized by brain tumors, hematologic malignancy, and gastrointestinal tumors. Multiple cafe-au-lait spots, axillary freckling, and, rarely, Lisch nodules reminiscent of neurofibromatosis type I (NF1; 162200) may be present (Hegde et al., 2005, Ostergaard et al., 2005). Microsatellite instability may be detected in tumor samples (Hegde et al., 2005). For a discussion of genetic heterogeneity of mismatch repair cancer syndrome, see MMRCS1 (276300).
Mismatch repair cancer syndrome 4
MedGen UID:
1745382
Concept ID:
C5436817
Disease or Syndrome
Mismatch repair cancer syndrome-4 (MMRCS4) is an autosomal recessive childhood cancer predisposition syndrome characterized by early-onset leukemia/lymphoma, brain tumors, colorectal/gastrointestinal cancers, and other rare malignancies, including rhabdomyosarcoma (summary by Li et al., 2015). Cafe-au-lait spots are usually present (De Vos et al., 2006). For a discussion of genetic heterogeneity of mismatch repair cancer syndrome, see MMRCS1 (276300).

Recent clinical studies

Etiology

Ahlawat S, Ly KI, Fayad LM, Fisher MJ, Lessing AJ, Berg DJ, Salamon JM, Mautner VF, Babovic-Vuksanovic D, Dombi E, Harris G, Plotkin SR, Blakeley J; REiNS International Collaboration.
Neurology 2021 Aug 17;97(7 Suppl 1):S111-S119. Epub 2021 Jul 6 doi: 10.1212/WNL.0000000000012437. PMID: 34230200
Curtis-Lopez CM, Soh C, Ealing J, Gareth Evans D, Burkitt Wright EMM, Vassallo G, Karabatsou K, Joshi George K
J Clin Neurosci 2020 Jul;77:98-105. Epub 2020 May 13 doi: 10.1016/j.jocn.2020.05.014. PMID: 32417129
Rauen KA, Alsaegh A, Ben-Shachar S, Berman Y, Blakeley J, Cordeiro I, Elgersma Y, Evans DG, Fisher MJ, Frayling IM, George J, Huson SM, Kerr B, Khire U, Korf B, Legius E, Messiaen L, van Minkelen R, Nampoothiri S, Ngeow J, Parada LF, Phadke S, Pillai A, Plotkin SR, Puri R, Raji A, Ramesh V, Ratner N, Shankar SP, Sharda S, Tambe A, Vikkula M, Widemann BC, Wolkenstein P, Upadhyaya M
Am J Med Genet A 2019 Jun;179(6):1091-1097. Epub 2019 Mar 25 doi: 10.1002/ajmg.a.61125. PMID: 30908877Free PMC Article
Lara-Corrales I, Moazzami M, García-Romero MT, Pope E, Parkin P, Shugar A, Kannu P
J Cutan Med Surg 2017 Sep/Oct;21(5):379-382. Epub 2017 Apr 27 doi: 10.1177/1203475417708163. PMID: 28448720
Batista PB, Bertollo EM, Costa Dde S, Eliam L, Cunha KS, Cunha-Melo JR, Darrigo Junior LG, Geller M, Gianordoli-Nascimento IF, Madeira LG, Mendes HM, Miranda DM, Mata-Machado NA, Morato EG, Pavarino ÉC, Pereira LB, Rezende NA, Rodrigues Lde O, Sette JB
Arq Neuropsiquiatr 2015 Jun;73(6):531-43. doi: 10.1590/0004-282X20150042. PMID: 26083891

Diagnosis

Moshref R, Mirdad A
Am J Case Rep 2021 Sep 13;22:e933090. doi: 10.12659/AJCR.933090. PMID: 34516541
Ahlawat S, Ly KI, Fayad LM, Fisher MJ, Lessing AJ, Berg DJ, Salamon JM, Mautner VF, Babovic-Vuksanovic D, Dombi E, Harris G, Plotkin SR, Blakeley J; REiNS International Collaboration.
Neurology 2021 Aug 17;97(7 Suppl 1):S111-S119. Epub 2021 Jul 6 doi: 10.1212/WNL.0000000000012437. PMID: 34230200
Rauen KA, Alsaegh A, Ben-Shachar S, Berman Y, Blakeley J, Cordeiro I, Elgersma Y, Evans DG, Fisher MJ, Frayling IM, George J, Huson SM, Kerr B, Khire U, Korf B, Legius E, Messiaen L, van Minkelen R, Nampoothiri S, Ngeow J, Parada LF, Phadke S, Pillai A, Plotkin SR, Puri R, Raji A, Ramesh V, Ratner N, Shankar SP, Sharda S, Tambe A, Vikkula M, Widemann BC, Wolkenstein P, Upadhyaya M
Am J Med Genet A 2019 Jun;179(6):1091-1097. Epub 2019 Mar 25 doi: 10.1002/ajmg.a.61125. PMID: 30908877Free PMC Article
Lara-Corrales I, Moazzami M, García-Romero MT, Pope E, Parkin P, Shugar A, Kannu P
J Cutan Med Surg 2017 Sep/Oct;21(5):379-382. Epub 2017 Apr 27 doi: 10.1177/1203475417708163. PMID: 28448720
Blakeley JO, Bakker A, Barker A, Clapp W, Ferner R, Fisher MJ, Giovannini M, Gutmann DH, Karajannis MA, Kissil JL, Legius E, Lloyd AC, Packer RJ, Ramesh V, Riccardi VM, Stevenson DA, Ullrich NJ, Upadhyaya M, Stemmer-Rachamimov A
Am J Med Genet A 2017 Jun;173(6):1714-1721. Epub 2017 Apr 24 doi: 10.1002/ajmg.a.38239. PMID: 28436162

Therapy

Wilson BN, John AM, Handler MZ, Schwartz RA
J Am Acad Dermatol 2021 Jun;84(6):1667-1676. Epub 2020 Aug 6 doi: 10.1016/j.jaad.2020.07.105. PMID: 32771543
Wang J, Wei G, Wang Z, Huang H
J Med Case Rep 2019 Nov 30;13(1):349. doi: 10.1186/s13256-019-2292-4. PMID: 31783902Free PMC Article
Rauen KA, Alsaegh A, Ben-Shachar S, Berman Y, Blakeley J, Cordeiro I, Elgersma Y, Evans DG, Fisher MJ, Frayling IM, George J, Huson SM, Kerr B, Khire U, Korf B, Legius E, Messiaen L, van Minkelen R, Nampoothiri S, Ngeow J, Parada LF, Phadke S, Pillai A, Plotkin SR, Puri R, Raji A, Ramesh V, Ratner N, Shankar SP, Sharda S, Tambe A, Vikkula M, Widemann BC, Wolkenstein P, Upadhyaya M
Am J Med Genet A 2019 Jun;179(6):1091-1097. Epub 2019 Mar 25 doi: 10.1002/ajmg.a.61125. PMID: 30908877Free PMC Article
Rosset C, Vairo F, Cristina Bandeira I, Fonini M, Netto CBO, Ashton-Prolla P
Expert Rev Mol Diagn 2018 Jun;18(6):577-586. Epub 2018 Apr 27 doi: 10.1080/14737159.2018.1468256. PMID: 29685074
Seidlin M, Holzman R, Knight P, Korf B, Rangel Miller V, Viskochil D, Bakker A; Children’s Tumor Foundation.
PLoS One 2017;12(6):e0178639. Epub 2017 Jun 23 doi: 10.1371/journal.pone.0178639. PMID: 28644838Free PMC Article

Prognosis

Curtis-Lopez CM, Soh C, Ealing J, Gareth Evans D, Burkitt Wright EMM, Vassallo G, Karabatsou K, Joshi George K
J Clin Neurosci 2020 Jul;77:98-105. Epub 2020 May 13 doi: 10.1016/j.jocn.2020.05.014. PMID: 32417129
Martin E, Coert JH, Flucke UE, Slooff WM, van de Sande MAJ, van Noesel MM, Grünhagen DJ, Wijnen MHWA, Verhoef C
Pediatr Blood Cancer 2020 Apr;67(4):e28138. Epub 2019 Dec 30 doi: 10.1002/pbc.28138. PMID: 31889416
Shi B, Xu L, Li Y, Liu Z, Sun X, Zhu Z, Qiu Y
Clin Neurol Neurosurg 2019 Dec;187:105548. Epub 2019 Oct 19 doi: 10.1016/j.clineuro.2019.105548. PMID: 31669930
Lara-Corrales I, Moazzami M, García-Romero MT, Pope E, Parkin P, Shugar A, Kannu P
J Cutan Med Surg 2017 Sep/Oct;21(5):379-382. Epub 2017 Apr 27 doi: 10.1177/1203475417708163. PMID: 28448720
Batista PB, Bertollo EM, Costa Dde S, Eliam L, Cunha KS, Cunha-Melo JR, Darrigo Junior LG, Geller M, Gianordoli-Nascimento IF, Madeira LG, Mendes HM, Miranda DM, Mata-Machado NA, Morato EG, Pavarino ÉC, Pereira LB, Rezende NA, Rodrigues Lde O, Sette JB
Arq Neuropsiquiatr 2015 Jun;73(6):531-43. doi: 10.1590/0004-282X20150042. PMID: 26083891

Clinical prediction guides

Janusz JA, Klein-Tasman BP, Payne JM, Wolters PL, Thompson HL, Martin S, de Blank P, Ullrich N, Del Castillo A, Hussey M, Hardy KK, Haebich K, Rosser T, Toledo-Tamula MA, Walsh KS; REiNS International Collaboration.
Neurology 2021 Aug 17;97(7 Suppl 1):S73-S80. Epub 2021 Jul 6 doi: 10.1212/WNL.0000000000012422. PMID: 34230205
Curtis-Lopez CM, Soh C, Ealing J, Gareth Evans D, Burkitt Wright EMM, Vassallo G, Karabatsou K, Joshi George K
J Clin Neurosci 2020 Jul;77:98-105. Epub 2020 May 13 doi: 10.1016/j.jocn.2020.05.014. PMID: 32417129
Talaei-Khoei M, Riklin E, Merker VL, Sheridan MR, Jordan JT, Plotkin SR, Vranceanu AM
J Neurooncol 2017 Jan;131(2):413-419. Epub 2016 Nov 29 doi: 10.1007/s11060-016-2314-7. PMID: 27900643
Morris SM, Acosta MT, Garg S, Green J, Huson S, Legius E, North KN, Payne JM, Plasschaert E, Frazier TW, Weiss LA, Zhang Y, Gutmann DH, Constantino JN
JAMA Psychiatry 2016 Dec 1;73(12):1276-1284. doi: 10.1001/jamapsychiatry.2016.2600. PMID: 27760236Free PMC Article
Batista PB, Bertollo EM, Costa Dde S, Eliam L, Cunha KS, Cunha-Melo JR, Darrigo Junior LG, Geller M, Gianordoli-Nascimento IF, Madeira LG, Mendes HM, Miranda DM, Mata-Machado NA, Morato EG, Pavarino ÉC, Pereira LB, Rezende NA, Rodrigues Lde O, Sette JB
Arq Neuropsiquiatr 2015 Jun;73(6):531-43. doi: 10.1590/0004-282X20150042. PMID: 26083891

Recent systematic reviews

Thirunavu VM, Mohammad LM, Kandula V, Beestrum M, Lam SK
J Pediatr Hematol Oncol 2021 May 1;43(4):135-143. doi: 10.1097/MPH.0000000000002060. PMID: 33480655
Gao B, DeCotiis K, Bobrowski A, Koyle M, O'Kelly F
J Pediatr Urol 2020 Jun;16(3):357-365. Epub 2020 Apr 30 doi: 10.1016/j.jpurol.2020.04.021. PMID: 32467024
Lu VM, Ravindran K, Graffeo CS, Perry A, Van Gompel JJ, Daniels DJ, Link MJ
J Neurooncol 2019 Sep;144(2):239-248. Epub 2019 Jun 28 doi: 10.1007/s11060-019-03234-8. PMID: 31254266
Nguyen T, Chung LK, Sheppard JP, Bhatt NS, Chen CHJ, Lagman C, Kaprealian T, Lee P, Nghiemphu PL, Yang I
Neurosurg Rev 2019 Mar;42(1):85-96. Epub 2017 Sep 13 doi: 10.1007/s10143-017-0904-2. PMID: 28900754
Lloyd SKW, King AT, Rutherford SA, Hammerbeck-Ward CL, Freeman SRM, Mawman DJ, O'Driscoll M, Evans DG
Clin Otolaryngol 2017 Dec;42(6):1329-1337. Epub 2017 Apr 26 doi: 10.1111/coa.12882. PMID: 28371358

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