Familial hyper- and hypopigmentation with age-related pattern change

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  • American Journal of Medical Genetics 132A:215218 (2005)

    Research LetterFamilial Hyper- and Hypopigmentation WithAge-Related Pattern Change

    To the Editor:

    Wewish to report on an unusual genetic condition in a threegeneration family of French-Canadian ancestry with cafe-au-lait and hypopigmented macules/patches. As noted in thepedigree (Fig. 1), there are several father-to-son transmissions

    strongly suggesting an autosomal dominant mode of inheri-tance. The youngest affected family member (III:4, Fig. 2a,b)showedone cafe-au-lait spot andonehypopigmentedmacule asearly as the neonatal period. The oldest affected living familymember is 77 years old [I:1]. During childhood, the cafe-au-lait or hypopigmented macules/patches were circumscribed,

    clearly distinguishable from the surrounding normal skin, anddid not follow the lines of Blaschko (Figs. 3a,b and 4a,b).However, as the affected family members grow older, bothkinds of circumscribed macules/patches fade, and, at the sametime, more and more hyper- and hypopigmented frecklingappears. We initially thought that the father of the children(II:4, Fig. 5a,b) did not have similar finding, but upon closerexamination, faint cafe-au-lait spots were still present andhyper- and hypopigmented freckles were apparent. The adults

    Fig. 1. Pedigree showing haplotypes of microsatellite markers flanking the NF1 gene on 17q11.2. Individual III:3 has inherited a different haplotypefrom the rest of the affected individuals indicating that this condition is not linked to the NF1 gene.

    *Correspondence to: Joe J. Hoo, M.D., Department of Pedia-trics, Division of Genetics, SUNYUpstateMedical University, 750E. Adams St., Syracuse, NY 13210-2339.E-mail: hooj@upstate.edu

    Received 18 March 2004; Accepted 2 August 2004

    DOI 10.1002/ajmg.a.30381

    2004 Wiley-Liss, Inc.

  • assured us, when they were young, they had the same skinfindings as the young generation. The freckling was mostobvious in the 56-year-old individual (II:1, Fig. 6a,b).No other symptoms of neurofibromatosis type 1 [NF1;

    OMIM#162200] were noted in the family. There was no familymemberwith skin papules/nodules or plexiform growth. Therewas no history of mental deficit, speech impediment, braintumor, or spine problem. The involvement of the NF1 gene inthis family was ruled out by linkage analysis using poly-morphic microsatellite probes flanking the NF1 gene onchromosome 17q11 (Fig. 1). None of the affected familymembers showed any other feature of either tuberous sclerosis[TS, OMIM #191100] or Noonan syndrome [NFNS, OMIM#601321]. Similarly, there was no family history of leukemia,glioma, or hereditary non-polyposis colon cancer, which mightindicate a mutation of a mismatch repair gene, for example,MSH2 orMLH1 [Vilkki et al., 2001; Whiteside et al., 2002].

    Familial cafe-au-lait spotswithout other features ofNF1hasbeenrepeatedly reported [NF6,OMIM#114030,Brunneretal.,1993; Charrow et al., 1993; Arnsmeier et al., 1994; Abeliovichet al., 1995]. Charrow et al. [1993] and Brunner et al. [1993]excluded the involvement of NF1 gene, however, Abeliovichet al. [1995] reported a family showing linkage with a LODscore 3.61. This family is different from the above families, asthere is a concurrent presence of hyperpigmentation [cafe-au-lait spots] and hypopigmentation. Furthermore, the changeof pattern with progressive age, from circumscribed and

    Fig. 2. A small cafe-au-lait spot (a) and a small hypopigmented macule(b) are noted (arrows) in the 2-month-old infant (III:4).

    Fig. 3. An affected girl (III:3) at 3 years (a) and 8 years (b) of age,showing various sizes of hyperpigmented and hypopigmented macules/patches.

    216 Hoo and Shrimpton

  • large cafe-au-lait and hypopigmented macules/patches tohyperpigmented and hypopigmented freckling, is unique tothis family.Concurrent presence of hyper- and hypopigmentedmacules/

    patches has been observed in patients with tuberous sclerosis,though very uncommon also in patient with NF1. Westerhofet al. [1978] described the concurrent presence of hyper- andhypopigmented patches in a three-generation family with theaffected family members also showing growth retardation andmental deficiency. Happle et al. [1997] coined the term cutistricolor describing the coexistence of congenital hyper- andhypopigmented macules adjacent to each other on a back-ground of normal skin. Baba et al. [2003] recently describedtwo sisters, who were characterized by cutis tricolor with theskin pattern following the lines of Blaschko. This family has

    Fig. 4. An affected boy (III:2) at 6 yaers (a) and 11 years (b) of age,showing both hyperpigmented and hypopigmented macules/patches ofvariable sizes.

    Fig. 5. Their father (II:4) at 39 years of age. The arrows denote the fewlargeand faint cafe-au-lait spots onhis left chest (a) andonhis lumbar region(b). Fine hyper- and hypopigmented freckles are faintly noticeable over hischest and epigastric region (a), as well as over his back (b).

    Research Letter 217

  • unique clinical findings andwe have excludedNF1 as the geneinvolved.

    ACKNOWLEDGMENTS

    Dr. Rudolf Happle of Philipp University, Marburg/Germanyand Dr. Amy Paller of Childrens Memorial Hospital, Chicagoare appreciated for the discussion and suggestion.

    REFERENCES

    Abeliovich D, Gelman-Kohan Z, Silverstein S, Lerer I, Chemke J, Merin S,Zlotogora J. 1995. Familial cafe-au-lait spots: A variant of neurofibro-matosis type 1. J Med Genet 32:985986.

    Arnsmeier SL, Riccardi VM, Paller AS. 1994. Familial multiple cafe au laitspots. Arch Dermatol 130:14251426.

    Baba M, Seckin D, Akcali C, Happle R. 2003. Familial cutis tricolor: Apossible example of paradominant inheritance. Eur JDermatol 13:343345.

    Brunner HG, Hulsebos T, Steijlen PM, der Kinderen DJ, van der Steer A,Hamel BC. 1993. Exclusion of the neurofibromatosis 1 locus in a familywith inherited cafe-au-lait spots. Am J Med Genet 46:472474.

    Charrow J, Listernick R,Ward K. 1993. Autosomal dominantmultiple cafe-au-lait spots and neurofibromatosis-1: Evidence of non-linkage. Am JMed Genet 45:606608.

    Happle R, Barbi G, Eckert D, Kennerknecht I. 1997. Cutis tricolor:Congenital hyper- and hypopigmented macules associated with asporadicmultisystembirthdefect: Anunusual example of twin spotting?J Med Genet 34:676678.

    Vilkki S, Tsao JL, Loukola A, Poyhonen M, Vierimaa O, Herva R, AaltonenLA, Shibata D. 2001. Extensive somatic microsatellite mutations innormal human tissue. Cancer Res 61:45414544.

    Westerhof W, Beemer FA, Cormane RH, Delleman JW, Faber WR,de Jong JG, van der Schaar WW. 1978. Hereditary congenitalhypopigmented and hyperpigmented macules. Arch Dermatol 114:931936.

    Whiteside D, McLeod R, Graham G, Steckley JL, Booth K, Somerville MJ,Andrew SE. 2002. A homozygous germ-line mutation in the humanMSH2 gene predisposes to hematological malignancy andmultiple cafe-au-lait spots. Cancer Res 62:359362.

    Joe J. Hoo*Department of Pediatrics, SUNYUpstate Medical University, SyracuseNew York

    Antony E. ShrimptonDepartment of Pathology, SUNYUpstate Medical University, SyracuseNew York

    Fig. 6. The hyper- and hypopigmented macules are distinctively demonstrated on the thigh (a) and the abdomen (b) of a 56-year-old affected familymember (II:1). The arrows denote the margin of a large and fading cafe-au-lait spot on his thigh (a).

    218 Hoo and Shrimpton