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Piebaldism and Neurofibromatosis Type 1: Horses of VeryDifferent Colors
Richard A. Spritz, Peter H. Itin,� and David H. GutmannwHuman Medical Genetics Program and Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado, USA; �Department ofDermatology, Kantonsspital Aarau, Switzerland; wNeurofibromatosis Program and Department of Neurology, St Louis Children’s Hospital, Washington UniversitySchool of Medicine, St Louis, Missouri, USA
Tom Fitzpatrick made many protean contributions in manydiverse areas of clinical dermatology and melanobiology, andamong his lifelong interests were the pigmentary anomaliesof various single gene Mendelian disorders. He was the firstto show that the white spots of piebaldism generally lackmelanocytes (Breathnach et al, 1965; Jimbow et al, 1975),whereas the dark spots of neurofibromatosis type 1 (NF1)contain macromelanosomes (Jimbow et al, 1973) or, as hecalled them, ‘‘melanin macroglobules’’ (Nakagawa et al,1984; Martuza et al, 1985). These studies were all publishedin the Journal, and opened the door to better understandingof the cell biology of these two genetic diseases.
Fitz also led the way towards establishing guidelines toassist in the clinical diagnosis of both piebaldism (Mosherand Fitzpatrick, 1988) and NF1 (Fitzpatrick et al, 1981;Fitzpatrick and Martuza, 1986; Mackool and Fitzpatrick,1992). These efforts notwithstanding, a point of confusionremains in the relationship between these two distinctdisorders. Several case reports have been published (andseveral others have eventually not been published) describ-ing patients with both piebaldism and NF1 (Chang et al,1993; Tay, 1998; Angelo et al, 2001), which the authorsclaimed represent a nonrandom, causal relationship. In fact,none of these patients, or any of their relatives, had any ofthe nonpigmentary features of NF1, such as cutaneousneurofibromas, the sine qua non of NF1, although thepatient described by Tay (1998) reportedly had Lischnodules on ophthalmologic examination. Each of theseauthors explicitly based their clinical diagnoses of NF1 onthe presence of two established NF1 diagnostic criteria(National Institutes of Health Consensus DevelopmentConference, 1988). We suggest that proposing a causalrelationship between NF1 and piebaldism is premature,based on the known clinical features, genetic etiology, andmolecular pathogenesis of these two distinct disorders.
First, piebaldism is an autosomal dominant disorder ofhypopigmentation, in which affected individuals present withareas of cutaneous depigmentation, associated with a virtualabsence of melanocytes. In contrast, NF1 is an autosomaldominant disorder of hyperpigmentation, in which affectedindividuals exhibit hyperpigmented macules (cafe-au-laitspots), skinfold freckling, and pigmented iris hamartomas(Lisch nodules), associated with increased numbers ofmelanocytes and macromelanosomes (Nakagawa et al, 1984).
Second, the genetic bases for these two disorders aredistinct. Piebaldism results from mutations of the KIT gene
on chromosome 4q12 (Giebel and Spritz, 1991; Spritz et al,1993; Spritz, 1994) or the SLUG (SNAI2) gene on chromo-some 8q11 (Sanchez-Martın et al, 2003), whereas NF1results from mutations of the NF1 gene on chromosome17q11.2 (Viskochil et al, 1990; Wallace et al, 1990).
Third, the molecular pathogeneses of piebaldism andNF1 represent polar opposites. Inactivating mutations ordeletions of the KIT (receptor tyrosine kinase) or SLUG (zincfinger neural crest transcriptional factor) genes result indecreased receptor tyrosine kinase signaling, impairedmelanoblast development, and a decrease in melanogen-esis (Spritz, 1994, 1998). In contrast, inactivating mutationsor deletions in the NF1 gene result in hyperactivation of theRAS proto-oncogene and enhanced receptor tyrosinekinase signaling. In addition, studies on NF1-associatedneurofibromas have demonstrated increased KIT expres-sion and activity (Hirota et al, 1993; Ryan et al, 1994;Badache et al, 1998).
Lastly, recent studies on mice have suggested that NF1inactivation would result in a partial correction of thepigmentary abnormalities in piebaldism. Mice with aninactivating mutation in the Kit gene exhibit severe coatcolor defects, which were reversed (60%–70% correction)when these mice were bred with mice harboring aninactivating mutation in the Nf1 gene (Ingram et al, 2000).These results argue that the coexistence of NF1 and KITmutations in humans might partially abrogate the hypopig-mentary defects seen in piebaldism.
The finding of six or more cafe-au-lait spots and axillaryor inguinal freckling is indeed considered sufficient to makethe diagnosis of NF1 using established diagnostic criteria(National Institutes of Health Consensus DevelopmentConference, 1988; Gutmann et al, 1997). Cafe-au-lait spotsare a common feature of piebaldism, however (Smith andSchultz, 1955; Ansari, 1960; Grupper et al, 1970; Selmano-witz et al, 1977; Gatto et al, 1985; Kuster, 1987; Spritz et al,1993; Syrris et al, 2000), and axillary and/or inguinalfreckling, although not explicitly described, also occursfrequently (Fig 1) (our unpublished observations; W. Kuster,personal communication). We have previously pointed outthat this has resulted in a number of patients withpiebaldism being misdiagnosed with NF1 (Spritz, 1998),even by experts (e.g., Riccardi, 1993). In order to establish adirect cause and effect relationship between piebaldismand NF1, future studies will require that the mutationalstatus of the KIT and NF1 genes in the probands be proven
Copyright r 2004 by The Society for Investigative Dermatology, Inc.
xxxiv
and their relatives be examined as well to demonstrateadditional nonpigmentary features of NF1 in these indivi-duals (e.g. neurofibromas).
DOI: 10.1046/j.0022-202X.2004.22235.x
Address correspondence to: Richard A. Spritz, MD, Professor andDirector, Human Medical Genetics Program, University of ColoradoHealth Sciences Center, 4200 E. Ninth Ave, B161, Denver, CO 80262.Email: [email protected]
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Figure 1A patient with autosomal dominant piebaldism due to a KIT genemutation. This patient is heterozygous for an R791G missensesubstitution in the kinase domain of the KIT polypeptide (Spritz et al,1993). Note cafe-au-lait spots and axillary freckling. Her mother issimilarly affected (as are many other relatives), but neither have anynonpigmentary features of NF1.
EDITORIAL xxxv122 : 2 FEBRUARY 2004