Multiple or familial café-au-lait spots is neurofibromatosis type 6: Clarification of a diagnosis
- Author(s): Madson, Justin G
- et al.
Published Web Locationhttps://doi.org/10.5070/D33d56c2q8
Multiple or familial café-au-lait spots is neurofibromatosis type 6: Clarification of a diagnosisOklahoma University Health Sciences Center Oklahoma City, Oklahoma
Justin G Madson MD PhD
Dermatology Online Journal 18 (5): 4
A café-au-lait macule (CALM) is an evenly pigmented macule or patch of variable size. Solitary CALMs are common birthmarks in up to 2.5 percent of normal neonates and their incidence rises to up to 25 percent in preschool-aged children. Two or more CALMs occur much less frequently. Multiple lesions may warrant investigation to identify an underlying disease including neurofibromatosis types 1 (NF1), neurofibromatosis type 2, McCune-Albright syndrome, and neurofibromatosis type 1-like syndrome. Considered a hallmark and diagnostic criteria for NF1 is the presence of 6 or more CALMs greater than 0.5 cm in prepubertal individuals. Rare reports describe families which demonstrate the phenomenon of multiple CALMs without other stigmata of NF1 or evidence of other systemic disease. Herein is a description of the condition and justification for this entity to be named Neurofibromatosis type 6.
A café-au-lait macule (CALM) is an evenly hyperpigmented, sharply demarcated macule or patch of any size. Generally, CALMs are tan to dark brown and can be of any size and located anywhere on the body except the palms, soles, and scalp. Because they can exceed 1 cm and thus be more correctly termed a patch, they are also referred to as café-au-lait spots. For simplicity, regardless of size, they will henceforth be termed CALMs. Frequently, CALMs are not appreciated at birth but become more noticeable in the first few years of life. A solitary CALM is a common finding occurring in up to one fourth of all Caucasian school-aged children . The finding of three or more CALMs in children with no known underlying disorder is much less frequent at up to 0.3 percent. A study of 41 children with 6 or more CALMs demonstrated that 80 percent were eventually diagnosed with neurofibromatosis type 1 (NF1) . Further studies have confirmed the threshold of 6 CALMs for the diagnosis of NF1 [3, 4, 5].
Multiple CALMs have been associated with many diseases including, but not limited to, all types of neurofibromatosis, McCune-Albright syndrome, neurofibromatosis type 1-like syndrome, Watson syndrome, Noonan syndrome, tuberous sclerosis, LEOPARD syndrome, Cowden disease, multiple endocrine neoplasia 1 and 2B, ataxia-telangectasia, and Bloom syndrome [5, 6]. All of the aforementioned disorders, except neurofibromatosis type 6 (NF6), have other cutaneous and extracutaneous distinguishing features .
NF1 (162200, ORPHA636) is a relatively common autosomal dominant disorder occurring in about 1 in 3000 individuals in the United States [6, 9]. It is caused by a mutation in the NF1 gene on 17q11.2 encoding neurofibromin, which is involved in the mitogen activated protein kinase signaling cascade . Many deletions have been recorded in NF1 and most cause premature termination . A diagnosis of NF1 is made when two or more of the seven diagnostic features are present on an individual (Table) . Frequently in NF1, the presence of multiple CALMs is the first feature noticed in a child and other features do not appear until later in childhood, delaying the diagnosis . This delay can present a diagnostic challenge; it is often a difficult decision whether or not to pursue further workup for entities such as optic gliomas.
Diagnostic criteria for neurofibromatosis type 1 
- 6 or more CALMs over 5 mm in greatest diameter in prepubertal individuals and over 15mm in greatest diameter in postpubertal individuals
- Two or more neurofibromas of any type or one plexiform neurofibroma
- Axillary or inguinal freckling
- 2 or more Lisch nodules
- Optic glioma
- A distinctive osseous lesion such as sphenoid wing dysplasia or thinning of long bone cortex with or without pseudoarthrosis
- A first-degree relative with NF1 by the above criteria
Neurofibromatosis type 2 (NF2; 101000, ORPHA637) is an autosomal dominant condition with tumors of the eighth cranial nerve being its hallmark . NF2 is caused by mutations in the gene NF2 at 22q12.2, which encodes merlin, also known as schwannomin . Merlin inhibits cell proliferation and is involved in cell signaling and the cytoskeleton . Whereas CALMs are not part of the diagnostic criteria, they occur in over 40 percent of patients, although rarely with more than 6 [17, 18, 19].
McCune-Albright syndrome (174800, ORPHA562) is a sporadic disease caused by post-zygotic mutations in the GNAS1 gene, which is involved in G-protein signaling . Classically, a large segmental CALM(s) is present with a characteristic “coast of Maine” border. Completing the triad of findings in this syndrome are polyostotic fibrous dysplasia often occurring under the CALM and endocrine abnormalities such as precocious puberty .
Neurofibromatosis type 1-like syndrome (NFLS or Legius Syndrome; 611431, ORPHA137605) can present with multiple CALMs and axillary freckling with or without other stigmata of NF1 . This is an autosomal dominant syndrome, which can also feature macrocephaly, a Noonan-like facies and learning disabilities. NFLS is caused by a mutation in the SPRED1 gene which acts as a negative regulator of the mitogen-activated protein kinase signaling cascade .
Multiple café-au-lait spots (114030) is described as a condition similar to, but distinct from NF1 in that there are no other changes of NF1. Specifically, there is an absence of neurofibromas and Lisch nodules . Others have also demonstrated the phenomenon of multiple CALMs without other features of NF1 [23-27]. Linkage studies have been inconclusive with some demonstrating close linkage to the NF1 gene on 17q11.2, whereas other studies have not shown this [24, 25, 26, 28]. Similarly, neurofibromatosis type 6 (NF6, ORPHA2678) is a rare disorder considered to be neurofibromatosis with only CALMs . It is also referred to as multiple café-au-lait syndrome, familial café-au-lait spots, and multiple café-au-lait spots. Ring chromosome 11 has been reported with multiple CALMs and whether there is an interaction with the NF1 gene is uncertain .
The terminology of the syndromes is overlapping and redundant. It is apparent from the above descriptions that “neurofibromatosis type 6” is the same as “multiple café-au-lait syndrome,” “familial café-au lait spots,” and “multiple café-au-lait spots.” A conundrum exists in the entity’s nomenclature concerning whether it should be designated as neurofibromatosis or not as others have argued . NF6, as described in the aforementioned cases, technically qualifies as NF1 in the size and number of CALMs; a first-degree relative would have NF1 by similar criteria . Because only two criteria need be met, a patient in these features could be strictly considered to have NF1. However, an exception to these strict criteria is clearly warranted if no other systemic findings are ever present. Additionally, some linkage studies have shown NF6 to be allelic to the NF1 gene . Over 90 percent of patients with NF1 have multiple café-au-lait macules but they are not necessary for the diagnosis . Thus, it appears likely that NF6 is at least occasionally a form fruste of NF1.
If a gene that causes NF6 exists and is not linked to the NF1 gene, the diagnosis of NF6 can still be made. The NF1 gene is quite distinct from the NF2 gene in both chromosomal location and function. Nonetheless, NF1 and NF2 carry the same surname of “neurofibromatosis” and are only distinguished by type. Indeed, the frequency of neurofibromas is decreased in NF2 compared to NF1 . It is important to eliminate the redundant names involving the term “café-au-lait.” A patient may erroneously be diagnosed with an aforementioned “café-au-lait” condition because CALMs are usually the first sign to appear . For various reasons, genetic testing may not be done if only CALMs are present . The significance of the CALMs is not as easily elucidated if that patient later develops systemic features of another disorder, most likely NF1. Keeping the term neurofibromatosis as part of the disease name, even with “Type 6” attached, will continually alert physicians of potential complications. A consolidation of terms is necessary, in this author’s opinion, to eliminate the terms “multiple café-au-lait spots” and “multiple café-au-lait syndrome” in favor of one unifying diagnosis of NF6.
References1. Burwell RG, James NJ, Johnston DI. Cafe-au-lait spots in schoolchildren. Archives of disease in childhood. 1982;57(8):631-2. [PubMed]; Central PMCID: PMC1627749].
2. Korf BR. Diagnostic outcome in children with multiple cafe au lait spots. Pediatrics. 1992;90(6):924-7. [PubMed].
3. Nunley KS, Gao F, Albers AC, Bayliss SJ, Gutmann DH. Predictive value of cafe au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1. Arch Dermatol. 2009;145(8):883-7. [PubMed].
4. Lammert M, Friedman JM, Kluwe L, Mautner VF. Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol. 2005;141(1):71-4. [PubMed].
5. Shah KN. The diagnostic and clinical significance of cafe-au-lait macules. Pediatric clinics of North America. 2010;57(5):1131-53. [PubMed].
6. Tsao H. Neurofibromatosis and Tuberous Sclerosis. In: Bolognia JL, Jorizzo JL, Rapini RP, editors. Dermatology. 2nd ed. New York: Elsevier Limited; 2008. p. 825-839.
7. Online Mendelian Inheritance in Man - OMIM [cited 2012 February 29]. Available from: http://omim.org.
8. Orpha.net [cited 2012 February 29]. Available from: http://www.orpha.net.
9. Riccardi VM. Neurofibromatosis: phenotype, natural history, and pathogenesis. 2nd ed. Baltimore: Johns Hopkins University Press; 1992. ix, 498 p. p.
10. Trovo-Marqui AB, Tajara EH. Neurofibromin: a general outlook. Clinical genetics. 2006;70(1):1-13. [PubMed].
11. Griffiths S, Thompson P, Frayling I, Upadhyaya M. Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Familial cancer. 2007;6(1):21-34. [PubMed].
12. National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, Md., USA, July 13-15, 1987. Neurofibromatosis. 1988;1(3):172-8. [PubMed].
13. Landau M, Krafchik BR. The diagnostic value of cafe-au-lait macules. Journal of the American Academy of Dermatology. 1999;40(6 Pt 1):877-90; quiz 891-2. [PubMed].
14. Mulvihill JJ, Parry DM, Sherman JL, Pikus A, Kaiser-Kupfer MI, Eldridge R. NIH conference. Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis). An update. Annals of internal medicine. 1990;113(1):39-52. [PubMed].
15. Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, et al. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell. 1993;72(5):791-800. [PubMed].
16. Curto M, McClatchey AI. Nf2/Merlin: a coordinator of receptor signalling and intercellular contact. British journal of cancer. 2008;98(2):256-62. [PubMed]; PubMed Central PMCID: PMC2361439.
17. Evans DG, Ramsden RT, Shenton A, Gokhale C, Bowers NL, Huson SM, et al. Mosaicism in neurofibromatosis type 2: an update of risk based on uni/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification. Journal of medical genetics. 2007;44(7):424-8. [PubMed]; PubMed Central PMCID: PMC2598002.
18. Spitz JL. Genodermatoses: a clinical guide to genetic skin disorders. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2005. xix, 400 p.
19. Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA: The journal of the American Medical Association. 1997;278(1):51-7. [PubMed].
20. Diaz A, Danon M, Crawford J. McCune-Albright syndrome and disorders due to activating mutations of GNAS1. Journal of pediatric endocrinology & metabolism: JPEM. 2007;20(8):853-80. [PubMed].
21. Stevenson D, Viskochil D, Mao R, Muram-Zborovski T. Legius Syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews. Seattle (WA)1993.
22. Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, et al. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nature genetics. 2007;39(9):1120-6. [PubMed].
23. Riccardi VM. Pathophysiology of neurofibromatosis. IV. Dermatologic insights into heterogeneity and pathogenesis. Journal of the American Academy of Dermatology. 1980;3(2):157-66. [PubMed].
24. Abeliovich D, Gelman-Kohan Z, Silverstein S, Lerer I, Chemke J, Merin S, et al. Familial cafe au lait spots: a variant of neurofibromatosis type 1. Journal of medical genetics. 1995;32(12):985-6. [PubMed]; PubMed Central PMCID: PMC1051784.
25. Charrow J, Listernick R, Ward K. Autosomal dominant multiple cafe-au-lait spots and neurofibromatosis-1: evidence of non-linkage. American journal of medical genetics. 1993;45(5):606-8. [PubMed].
26. Hoo JJ, Shrimpton AE. Familial hyper- and hypopigmentation with age-related pattern change. American journal of medical genetics Part A. 2005;132A(2):215-8. [PubMed].
27. Whitehouse D. Diagnostic value of the cafe-au-lait spot in children. Archives of disease in childhood. 1966;41(217):316-9. [PubMed]; PubMed Central PMCID: PMC2019578.
28. Brunner HG, Hulsebos T, Steijlen PM, der Kinderen DJ, vd Steen A, Hamel BC. Exclusion of the neurofibromatosis 1 locus in a family with inherited cafe-au-lait spots. American journal of medical genetics. 1993;46(4):472-4. [PubMed].
29. Fagan K, Suthers GK, Hardacre G. Ring chromosome 11 and cafe-au-lait spots. American journal of medical genetics. 1988;30(4):911-6. [PubMed].
30. Ferner RE. The neurofibromatoses. Practical neurology. 2010;10(2):82-93. [PubMed].
31. Riccardi VM. Diagnostic and management considerations posed by multiple cafe au lait spots. Arch Dermatol. 2009;145(8):929-30. [PubMed].
© 2012 Dermatology Online Journal