American Journal of Medical Genetics 126A:89–92 (2004)

Clinical Report

Unilateral Linear Hyperpigmentation of the SkinWith Ipsilateral Sectorial Hyperpigmentationof the Retina

Carsten H. Meyer,1* Pia Freyschmidt-Paul,2 Rudolf Happle,2 and Peter Kroll1

1Department of Ophthalmology, Philipp University of Marburg, Marburg, Germany2Department of Dermatology, Philipp University of Marburg, Marburg, Germany

A 32-year-old Caucasian man had a mosaichyperpigmentation on his left arm, arrangedin a pattern following the lines of Blaschko.In addition, a mosaic hyperpigmentationwas noted in his left eye, in the form ofgrouped congenital hypertrophy of theretinal pigment epithelium (CHRPE). Such‘‘bear tracks’’ are segmentally oriented, well-demarcated, flat, hyperpigmented lesionsoriginating with small dots at the optic diskand expanding towards the periphery. Wehypothesize that these mosaic pigmentarylesions involving the skin and the eye on thesame side of the body may have originatedfrom an early postzygotic mutation and thusmay be etiologically related.� 2003 Wiley-Liss, Inc.

KEY WORDS: grouped congenital hyper-trophy of the retinal pig-ment epithelium (CHRPE);bear tracks; pigmentarymosaicism of the hyper-pigmented type; lines ofBlaschko; postzygotic muta-tion; embryogenesis

INTRODUCTION

Pigmentary mosaicism of the human skin mayrepresent either hyperpigmentation or hypopigmenta-tion. Several distinct patterns can be distinguished but

the system of Blaschko’s lines is the commonestarrangement [Happle, 1993; Traupe, 1999]. These linesreflect the dorso-ventral outgrowth of precursor cells ofthe various components of the skin. In this way, theyvisualize the stream, distribution, migration, and pro-liferation of embryonic tissue [Happle, 1985].

Grouped congenital hypertrophy of the retinalpigment epithelium (CHRPE) represents a sectorialhyperpigmentation of the ocular fundus. These well-demarcated, flat, hyperpigmented lesions tend to origi-nate with smaller spots from the margin of the optic diskand to expand in the periphery. Because this pattern isreminiscent of an animal footprint, grouped CHRPE isalso called ‘‘bear tracks’’ [Mann, 1932; Perera, 1939;Tower, 1948; Buettner, 1975; Shields et al., 1975].

Here we describe a patient with unilateral mosaichyperpigmentation of the skin associated with ipsilat-eral grouped CHRPE.

CLINICAL REPORT

A 32-year-old Caucasian man presented with a 3-month history of blurred vision. He was born at termafter an uneventful pregnancy. The delivery was un-complicated; his birth weight was 3,250 g. His earlypsychomotor development was within the normal range.He attended a regular school with average achieve-ments. The patient reported that a segmental pigmenta-tion had been noted during his first months of life on hisleft shoulder. At physical examination a hyperpigmen-ted streak following the lines of Blaschko was noted onhis left shoulder and upper arm (Fig. 1). A skin biopsywas not performed.

Ophthalmologic examination revealed a well-correct-ed visual acuity 20/20 in the right eye and 20/25 in theleft eye. A visual field testing with the Goldman peri-metry demonstrated absence of visual field defects orscotomas in both eyes. On slit lamp examination theanterior segment appeared normal in both eyes, therewere no segmental changes in the lens or iris. Fundusexamination of the right eye was unremarkable.Biomicroscopy of the left fundus revealed characteristic

*Correspondence to: Dr. Carsten H. Meyer, M.D., Departmentof Ophthalmology, Philipp University of Marburg, Robert-Koch-Strasse 4, 35037 Marburg, Germany.E-mail: meyer_eye@yahoo.com

Received 7 February 2003; Accepted 7 July 2003

DOI 10.1002/ajmg.a.20483

� 2003 Wiley-Liss, Inc.

pigmented patches limited to a triangular sector of theretina. This grouped CHRPE expanded from the edgeof the optic nerve to the periphery. The size of the in-dividual lesions varied from less than 0.5 mm nearthe optic disc to larger lesions in the periphery (Fig. 2).The transient subjective blurred central vision was notrelated to CHRPE in the fundus periphery.

DISCUSSION

The concept of pigmentary mosaicism is now well-established and has been proven in many cases at thecellular level [Happle, 2002]. A mosaic pattern followingthe lines of Blaschko is noted in various X-linked male-lethal or X-linked non-lethal skin diseases [Happle,1985], in analogy to the variegated coat patterns ofmice [Lyon, 1962]. A sectorial pattern was previouslydemonstrated in the eyes of women heterozygous forvarious X-linked ocular diseases [Happle and Kuchle,1983; Rott and Rix, 1984; Rott and Koniszewski, 1987].Women heterozygous for the gene of the X-linkedLowe syndrome frequently show sectorial cataracts[Koniszewski and Rott, 1985]. Women heterozygousfor X-linked ocular albinism show a streaky or patchyhypopigmentation of the fundus in the midperipherywith orientation to the optic nerve [Rott and Rix, 1984;Lang et al., 1990]. A similar retinal pattern of localizedcolor blindness was demonstrated in female carriers fordichromasia [Born et al., 1976]. On the other hand, asegmental hyperpigmentation simultaneously involv-ing the retinal fundus and the skin has been describedin chimeric mice [Jaenisch, 1985]. Mosaic areas of

Fig. 1. Segmental hyperpigmentation involving the left shoulder alongthe lines of Blaschko. The border of the hyperpigmentation was marked withblack dots.

Fig. 2. Biomicroscopy of the left eye: Pigmented patches expanding from the edge of the optic nerve to the periphery in the inferior sector of the retina.

90 Meyer et al.

hypopigmentation involving the retinal fundus weredescribed in patients with so-called hypomelanosis of Ito[Amon et al., 1990; Rott et al., 1990]. Patients withsegmental neurofibromatosis (NF1) may also demon-strate segmental cutaneous pigmentations, and ipsi-or contralateral eye lesions such as Lisch nodules[Ruggieri and Huson, 2001]. In hypomelanosis Ito,many different forms of chromosomal mosaicism havebeen documented, but in most cases no cytogeneticabnormalities have been found, leaving the possibilitythat the mosaic is present at the molecular level [Kusterand Konig, 1999]. The same will certainly hold true forpigmentary mosaicism of the hypermelanotic type aspresent in our patient.

Analogously, the present case of coexistent linearcongenital hyperpigmentation of the skin and ipsilat-eral grouped CHRPE may likewise have a commonorigin in the form of an early postzygotic mutation. Un-fortunately, no cytogenetic analysis of cells of the skinlesion could be performed to ascertain or to rule outmosaicism at the cytogenetic level.

Permanent pigmented fundus lesions were first recog-nized by Mauthner [1868]. These pigmented lesionspresent clusters of abnormal retinal pigment epithelium(RPE) cells consistent with congenital hamartoma of theRPE [Laqua and Wessing, 1979]. Hoeg [1911] namedthem ‘‘grouped pigmentation of the retinal pigmentepithelium’’ for the first time. Leber [1916] mentionedsome patients with grouped retinal hyperpigmentationand additional ‘‘cutaneous nevi,’’ but described no seg-mental pattern of the skin lesions. Tower [1948] hypo-thesized that the localized accumulations of RPE maydevelop within the secondary optic vesicle during theevolution of the two retinal layers. The clinical featuresof grouped CHRPE are characteristic. The sectorialshape of the spotty hyperpigmentation constitutes ahallmark of grouped CHRPE that originates from theedge of the optic nerve in one sector of the fundus. Thesmaller spots are usually located near the optic disk,whereas the peripheral lesions are less numerous butlarger. Larger hyperpigmentations may be dividedduring growth into smaller spots surrounded by normalpigmentation. The shape of grouped CHRPE may beoval or falciform with convex borders, with one spotfitting into the concave border of the next one. Eachgroup contains 3 to 30 foci that may vary in size from0.1 mm to 3.0 mm in diameter. Histopathologicalsections of CHRPE plaques revealed a thickened RPEcontaining 1.6 times higher concentrations of pigmentedgranules as compared to the surrounding perpendicularwild-type RPE [Regillo et al., 1993]. Lesions of groupedCHRPE are not progressive. They can be observed innewborn and older children, thus providing evidencethat this anomaly is congenital. Grouped CHRPE hasbeen observed in families and an autosomal dominantmode of inheritace with variable expression has beenassumed [de Jong and Delleman, 1988; Renardel deLavalette et al., 1991], but paradominant transmission[Happle, 1999] may be considered as an alternativeexplanation for such exceptional cases of familial ag-gregation. The sectorial pattern of grouped CHRPE mayalso occur in albinotic spots of variable size [Parke et al.,

1984; Fuhrmann et al., 1992]. These congenital groupedhypomelanotic spots were called ‘‘polar bear tracks.’’

Grouped CHRPE arranged in a sectorial patternshould not be confused with multiple CHRPE dissemi-nated over the entire fundus on both eyes [Shields et al.,1992]. Such bilateral, multiple CHRPE can be asso-ciated with familial adenomatous polyposis coli (FAP)or Gardner syndrome [Gardner and Richard, 1950;Traboulsi et al., 1987]. A mutation of the adenomatouspolyposis coli (APC) gene on 5q21 [Nishisho et al., 1991]was found to be responsible. FAP patients with amutation beyond exon 9 may present multiple CHRPE,whereas mutations upstream of exon 9 do apparentlynot cause ophthalmic lesions [Caspari et al., 1995]. In arecent review we differentiated the ophthalmic featuresof solitary, grouped, and multiple CHRPE, and theirspecific clinical implication as a screening tool for FAP orGardner syndrome [Meyer et al., 2002].

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