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Cafe au lait spots, multiple

MedGen UID:
396266
Concept ID:
C1861975
Disease or Syndrome
Synonym: Neurofibromatosis type 6
SNOMED CT: Multiple café-au-lait syndrome (1208340009); NF6 - neurofibromatosis type 6 (1208340009); Neurofibromatosis type 6 (1208340009); Familial café-au-lait spots (1208340009); Multiple café-au-lait spots (1208340009); Familial CALMs (café-au-lait macules) isolated (1208340009); Familial isolated café-au-lait spots (1208340009); Familial isolated café-au-lait macules (1208340009)
 
HPO: HP:0007565
Monarch Initiative: MONDO:0007245
OMIM®: 114030

Definition

The presence of six or more cafe-au-lait spots. [from HPO]

Clinical features

From HPO
Cafe au lait spots, multiple
MedGen UID:
396266
Concept ID:
C1861975
Disease or Syndrome
The presence of six or more cafe-au-lait spots.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCafe au lait spots, multiple
Follow this link to review classifications for Cafe au lait spots, multiple in Orphanet.

Conditions with this feature

Neurofibromatosis, type 1
MedGen UID:
18013
Concept ID:
C0027831
Neoplastic Process
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.
Café-au-lait macules with pulmonary stenosis
MedGen UID:
107817
Concept ID:
C0553586
Disease or Syndrome
Watson syndrome (WTSN) 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).
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.
Cafe au lait spots, multiple
MedGen UID:
396266
Concept ID:
C1861975
Disease or Syndrome
The presence of six or more cafe-au-lait spots.
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 1
MedGen UID:
1748029
Concept ID:
C5399763
Disease or Syndrome
Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain (usually glioblastoma), skin (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas), pancreas, and prostate. Cancer risks and age of onset vary depending on the associated gene. Several other cancer types have been reported to occur in individuals with Lynch syndrome (e.g., breast, sarcomas, adrenocortical carcinoma). However, the data are not sufficient to demonstrate that the risk of developing these cancers is increased in individuals with Lynch syndrome.
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).

Professional guidelines

PubMed

Zhang J, Tong H, Fu X, Zhang Y, Liu J, Cheng R, Liang J, Peng J, Sun Z, Liu H, Zhang F, Lu W, Li M, Yao Z
Sci Rep 2015 Jun 9;5:11291. doi: 10.1038/srep11291. PMID: 26056819Free PMC Article
Riccardi VM
Arch Dermatol 2009 Aug;145(8):929-30. doi: 10.1001/archdermatol.2009.180. PMID: 19687427

Recent clinical studies

Etiology

Castellanos E, Rosas I, Negro A, Gel B, Alibés A, Baena N, Pineda M, Pi G, Pintos G, Salvador H, Lázaro C, Blanco I, Vilageliu L, Brems H, Grinberg D, Legius E, Serra E
Clin Genet 2020 Feb;97(2):264-275. Epub 2019 Dec 12 doi: 10.1111/cge.13649. PMID: 31573083
Chiu C, Loth S, Kuhlen M, Ginzel S, Schaper J, Rosenbaum T, Pietsch T, Borkhardt A, Hoell JI
Fam Cancer 2019 Jul;18(3):353-358. doi: 10.1007/s10689-019-00121-z. PMID: 30680470
Zhang J, Li M, Yao Z
Mol Med Rep 2016 Nov;14(5):4023-4029. Epub 2016 Sep 22 doi: 10.3892/mmr.2016.5760. PMID: 27666661Free PMC Article
St John J, Summe H, Csikesz C, Wiss K, Hay B, Belazarian L
Pediatr Dermatol 2016 Sep;33(5):526-9. Epub 2016 Jul 28 doi: 10.1111/pde.12936. PMID: 27469520
Peters H, Hess D, Fahsold R, Schülke M
Hum Mutat 1999;13(4):337. doi: 10.1002/(sici)1098-1004(1999)13:4<337::aid-humu12>3.0.co;2-f. PMID: 10220149

Diagnosis

Castellanos E, Rosas I, Negro A, Gel B, Alibés A, Baena N, Pineda M, Pi G, Pintos G, Salvador H, Lázaro C, Blanco I, Vilageliu L, Brems H, Grinberg D, Legius E, Serra E
Clin Genet 2020 Feb;97(2):264-275. Epub 2019 Dec 12 doi: 10.1111/cge.13649. PMID: 31573083
Zhang J, Li M, Yao Z
Mol Med Rep 2016 Nov;14(5):4023-4029. Epub 2016 Sep 22 doi: 10.3892/mmr.2016.5760. PMID: 27666661Free PMC Article
St John J, Summe H, Csikesz C, Wiss K, Hay B, Belazarian L
Pediatr Dermatol 2016 Sep;33(5):526-9. Epub 2016 Jul 28 doi: 10.1111/pde.12936. PMID: 27469520
Yao R, Wang L, Yu Y, Wang J, Shen Y
J Dermatol 2016 May;43(5):537-42. Epub 2015 Oct 13 doi: 10.1111/1346-8138.13169. PMID: 26458495
Takenouchi T, Shimizu A, Torii C, Kosaki R, Takahashi T, Saya H, Kosaki K
Am J Med Genet A 2014 Feb;164A(2):392-6. Epub 2013 Dec 5 doi: 10.1002/ajmg.a.36288. PMID: 24311457

Therapy

Pannu AK, Sharma N
QJM 2017 Sep 1;110(9):583-584. doi: 10.1093/qjmed/hcx071. PMID: 28371884
Waheed W, Nathan MH, Allen GB, Borden NM, Babi MA, Tandan R
BMJ Case Rep 2015 Nov 3;2015 doi: 10.1136/bcr-2015-210816. PMID: 26531733Free PMC Article

Prognosis

Castellanos E, Rosas I, Negro A, Gel B, Alibés A, Baena N, Pineda M, Pi G, Pintos G, Salvador H, Lázaro C, Blanco I, Vilageliu L, Brems H, Grinberg D, Legius E, Serra E
Clin Genet 2020 Feb;97(2):264-275. Epub 2019 Dec 12 doi: 10.1111/cge.13649. PMID: 31573083
Chiu C, Loth S, Kuhlen M, Ginzel S, Schaper J, Rosenbaum T, Pietsch T, Borkhardt A, Hoell JI
Fam Cancer 2019 Jul;18(3):353-358. doi: 10.1007/s10689-019-00121-z. PMID: 30680470
Yao R, Wang L, Yu Y, Wang J, Shen Y
J Dermatol 2016 May;43(5):537-42. Epub 2015 Oct 13 doi: 10.1111/1346-8138.13169. PMID: 26458495

Clinical prediction guides

Yao R, Wang L, Yu Y, Wang J, Shen Y
J Dermatol 2016 May;43(5):537-42. Epub 2015 Oct 13 doi: 10.1111/1346-8138.13169. PMID: 26458495
Takenouchi T, Shimizu A, Torii C, Kosaki R, Takahashi T, Saya H, Kosaki K
Am J Med Genet A 2014 Feb;164A(2):392-6. Epub 2013 Dec 5 doi: 10.1002/ajmg.a.36288. PMID: 24311457
Arnsmeier SL, Paller AS
Pediatr Dermatol 1996 Mar-Apr;13(2):100-4. doi: 10.1111/j.1525-1470.1996.tb01413.x. PMID: 9122064

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