American Journal of Medical Genetics 43716-721 (1992)

Pigmentary Dysplasias and Chromosomal Mosaicism: Report of 9 Cases Hirofumi Ohashi, Masato Tsukahara, Ichiro Murano, Kenji Naritomi, Kazue Nishioka, Susumu Miyake, and Tadashi Kajii Department of Pediatrics (H.O., M.T., I.M., T.K.) and Department of Dermutology (KNi.), Yamaguchi University School of Medicine, Ube; Department of Pediatrics, University of the Ryukyus School of Medicine, Okinawa (K. Na.); and Division of Pediatrics, Kagawa Prefectural Central Hospital, Takamatsu (S.M.), Japan

Chromosomes were studied in 9 individuals with pigmentary dysplasias of the skin and other abnormalities. Of the 9 individuals, 5 were chromosomalmosaics in both blood lymphocytes and skin fibroblasts (46,XY/47,XY,+ 13; 46,XXl47,XX,+ 14;46,XY/47,XY,+ 18;46,XX/47,XX, + 18;46,XX/47,XX,+ mar),while the other 4 individuals were chromosomally normal in both tissues studied. The pigmentary dysplasias involved hypo- or hyperpigmented patches/flecks or lines/whorls. The latter ran along Blaschko lines on the back, abdomen and the limbs. These patterns varied not only between individuals but also between different regions of an individual.The possibility of chimerism was studied but ruled out (1132 to 1/256) in 7 individuals, using chromosomal heteromorphisms in the patients and their parents as markers. o 1992 wiley-USS,Inc.

Interest in chromosomal analysis of the individuals with pigmentary dysplasia was aroused in 1985, when its association with chromosomal mosaicism was confirmed [Flannery et al., 1985; Fujimoto et al., 1985; Ishikawa et al., 1985; Miller and Parker, 19851. We are aware of at least 53 individuals with the disorder chromosomally analyzed since then. Of these, 32 were found to have mosaicism, while the other 21 were apparently chromosomally normal. We would like to add another 9 individuals with pigmentary dysplasias, 7 of whom were analyzed for chimerism.

CLINICAL REPORTS

Nine patients with pigmentary dysplasias of the skin are described. Of these, 4 patients (patients 1-4) were chromosomally normal, while the other 5 (patients 5-9) were mosaics; 5 (patients 1-4, 6) were karyotyped in view of pigmentary dysplasias, while the other 4 (patients 5,7-9) were referred to us because of mosaicism. Their clinical manifestations are summarized in TaKEY WORDS pigmentary dysplasia, chroble I. Pigmentary dysplasias in patients 1 , 3 , 6 , 7 ,and 9 mosomal abnormality,mosaiinvolved hypopigmented patchedflecks or lines/whorls; cism the latter ran along Blaschko lines on the back, abdomen and the limbs (Figs. 1, 4, 5). These findings were compatible with hypomelanosis of Ito. Patients 4 and 5 had hyperpigmented whorls/streaks/lines (Figs. 2, 3). INTRODUCTION Patients 2 and 8 had generally dark pigmentation of the Pigmentary dysplasia is a disorder characterized by skin on the right half of the body and the right limbs, linear, swirly, or patchy, hypo- or hyperpigmented areas intermingled with mottledllinear depigmented areas on of the skin, associated with mental retardation and var- both sides. Of the 9 patients, 8 were mentally retarded or delayed ious combinations of malformations. Of these, the hypopigmented form has been called hypomelanosis of Ito in development, while patient 6 was developmentally [Ito, 19521. The hypo- or hyperpigmented lines often normal at age 20 months. All except patient 1 had varfollow Blaschko lines on the back and the limbs. It is now ious combinations of congenital malformations, 5 (paclear that the disorder represents mosaicism of 2 kinds tients 1-3,5,6) had seizures, and two (patients 2 and 8) of melanocytes with different pigmentary potentials, showed hemihypertrophy accompanied by left-right difdue to genetic or chromosomal mosaicism or chimerism ference in skin pigmentation. Patients 7 and 8, both [Findlay and Moores, 1980; Hall, 1988; Thomas et al., with trisomy 18 mosaicism, were described in detail elsewhere [Murano et al., 19911. 1989; Flannery, 19901. Received for publication May 29,1991; revision received November 19, 1991. Address reprint requests to Hirofumi Ohashi, M.D., Department of Pediatrics, Yamaguchi University School of Medicine, Ube, Yamaguchi-ken, 755 Japan.

0 1992 Wiley-Liss, Inc.

CYTOGENETIC STUDIES Chromosomes in cultured peripheral blood lymphocytes from patients 1-4 were normal, whereas those from patients 5-9 were normal/abnormal mosaics (Ta-

Pigmentary Dysplasias

717

TABLE I. Clinical Characteristics of Patients with Pigmentary Dysplasias Patient No. 1

Age (years) 6 mo

Karyotype 46,XY

2

21

46,XX

3

3

46,XX

3

46,XX

5

46,XY/47,XY, + 13

4

Code No. U89-024

U89-390

5

Pigmentation patterns Hypopigmented bands on the inner aspects of the thighs; hyperpigmented line in the lower mid-abdomen Skin on the right side is generally darker than the left; mottledkwirling areas of hypopigmentation on the left chest; hypopigmented lines on the left arm Hypopigmented, V-shaped streakdines on the back

Reticulate whorls and streaks of hyperpigmentation along Blaschko lines over the entire body except for the face, palms and soles Hyperpigmented lines running from the buttocks to posterior thighs and legs Hypopigmented flecks and occasional lines on the body and limbs

20 mo

46,XX/47,XX, + 14

7"

15

46,XX/47,XX, + 18

Linear hypopigmented area on the right chest; V-shaped hypopigmented patterns on the back

8"

19

46,XY147,XY, + 18

Dark right side of the body with sharp demarcation at the midline; linear hypopigmented areas on the posterior surface of the right leg

9

8

46,XXJ47,XX, +mar

Hypopigmented patches on the body; lines on the limbs

6

a

UO606-82-9

Other clinical mainfestations Hypotonia; delayed develop ment; infantile spasms Mental retardation; seizures; short stature; asymmetry Wl);scoliosis; strabismus

Delayed development; seizures; sparse hair; depressed nose; short 5th fingers; radial deviation of right 2nd and 3rd fingers Mental retardation; large ears; fused teeth

Mental retardation; seizures; right hemiparesis; head asymmetry; strabismus Normal development; seizures; short nose; malformed ears; ASD, VSD; short and incurved right 5th finger Mental retardation; short stature; bushy eyebrows; bulbous nose; simple ears; kyphoscoliosis; absence of 12th ribs; contractures of knee and ankle joints Mental retardation; short stature; total asymmetry (l>r); bushy eyebrows; bulbous nose; simple ears; kyphoscoliosis; hemivertebrae; VSD; joint contractures; rocker bottom feet Mental retardation; conductive deafness; scoliosis; stabismus; subcutaneous cleft palate; malformed ears; accessory nipples; camptodactyly of right fingers; hypoplasia of left toes

Murano et al., 1991.

ble 11).The abnormal cell lines included trisomies 13,14, and 18, and an additional submetacentric chromosome of an unknown origin, of the size of a D group chromosome (patient 9). Chromosomes in cultured skin fibroblasts from both dark skin and light skin areas were studied in 7 patients, while those from an area of unspecified color were analyzed in the other 2 patients (patients 3 and 7). Between 30 and 100 metaphases were counted in each culture, In general, the frequencies of chromosomally abnormal cells were higher in skin fibroblasts than in lymphocytes.Marked differences were noted in patients 8 and 9 in the frequencies of the abnormal cells between the dark and light skin areas.

The possibility of pigmentary dysplasias resulting from chimerism was studied in 7 patients (patients 1,2, 4-6,8, and 91, using sequential Q-and R-banding heteromorphisms as markers [Niikawa and Kajii, 19751. Chromosomesfrom the patients and their parents were analyzed. In the mosaic patients (patients 5,6,8, and 91, chromosomally normal and abnormal cell lines were compared with each other for chromosomal heteromorphisms. In the apparently non-mosaic patients (patients 1,2,and 4), 10 cells each were studied for possible differences in chromosomal heteromorphisms. None of the 7 patients thus studied proved to be a chimera. Assuming that chimerism arises from fertilizationof the ovum and the second polar body by 2 different spermatozoa, the

718

Ohashi et al.

and Parker, 1985; Rott et al., 1986; Turleau et al., 1986; Wertelecki et al., 1986; Happle, 1987; Glover et al., 1989; Cantu et al., 1989; Thomas et al., 1989; Sybert et al., 1990; Ritter et al., 1990; Chitayat et al., 1990; Muran0 et al., 1991; Wulfsberg et al., 19911. They included 37 chromosomallyabnormal and 25 chromosomally normal individuals. The 37 : 25 abnormal : normal ratio is likely to be biased for abnormals. Of the 5 individuals prospectively studied in the present series, one was chromosomally abnormal while 4 were normal. Most of the chromosomally abnormal individuals reported were mosaics with either numerical or structural chromosome abnormalities, while 3 [Happle, 1987;Sybert et al., 19901 involved Wautosome translocations with X-inactivation mosaicism. In addition to these, a t least 30 individuals with mosaic tetrasomy 12p have been described during the same period [Reynoldset al., 1987,for references]. The disorder, called Pallister/Killian syndrome, is, in most instances, accompanied by pigmentary dysplasias and is diagnosable based on a characteristic combination of malformations. Together, the Fig. 1. Patient 1(46,XY).Irregularly demarcated bands of hypopig- numerical chromosomal abnormalities found in mosaics mentation on the inner aspects of the thighs. A Age 6 months. B: Age 2 with pigmentary dysplasias included monosomy X, auyears. Difficult to discern the pitmentary dysplasia. C: Photographed tosomal trisomies involving chromosomes 8,13,14,18, with ultraviolet illumination. or 22, and triploidy. Those with structural chromosome aberrations involved various portions of chromosomes7, chances of these patients being a chimera were calcu- 12,13,14,15, 18, X, and Y. While a number of chromosomes were involved in the mosaicism, they tended to be lated to be 1/32 to 11256 (Table 11). those that are compatible with live birth, either as moDISCUSSION saics or as nonmosaics. Thus it is noteworthy that triWe are aware of 62 individuals with pigmentary dys- somy 21, most frequent among autosomal trisomies in plasias chromosomally analyzed since 1985, including liveborn infants, was not involved. The patterns of pigmentary dysplasia in these pathe 9 individuals in the present series [Flannery et al., 1985;Fujimoto el al., 1985; Ishikawa et al., 1985; Miller tients were highly variable, not only between individ-

Fig. 2. Patient 4 (46,XX). Hyperpigmented whorls and lines running along the lines of Blaschko.

Pigmentary Dysplasias

719

Fig, 3. Patient 5 (46,XY/47,XY,+ 13).Hyperpigmented lines at the posterior surfaces of the thighs and legs.

uals but also between different regions of an individual. However, the patterns in most instances roughly followed Blaschko lines, with longitudinal lines in the limbs, V-shaped curves over the back, and sigmoid curves over the abdomen. These patterns showed a midline effect, with the patterns on the left and right sides being independent of each other. The pattern is caused by the random arrangement of melanoblast precursors with different pigmentary potentials along the length of the neural crest, and by such parameters as their relative migration potential, relative proliferative capacity, and their interaction with neighboring dermal cells.

Fig. 4. Patient 6 (46,XX/47,XX,+ 14). Hypopigmented patches and occasional lines (ultraviolet illumination).

The mechanisms that result in melanocyte mosaicism would include not only chromosome mosaicism, but also genetic mosaicism due to somatic mutation, half chromatid mutation, random X-inactivation in the female, or chimerism. The archetypal paradigm of narrow bands is one of the many patterns that human mosaics may demonstrate. The hyperpigmented, mottled whorls and streaks in

TABLE 11. Chromosomal Characteristics of Patients in Present Series % abnormal cells

Patient No. 1

2 3 4 5 6 7" 8"

9

Age studied (years) 6 mo 21 3 3 5 20 mo 15 19 2 19 8

"Murano et al., 1991.

Karyotype 46,XY 46,XX 46,XX 46,XX 46,XY/47,XY, + 13 46,XX/47.XX, + 14 46;XX/47;XX; + 18 46,XY/47,XY, + 18 46,XX/47,XX, +mar

Lymphocytes 0 0 0 0 9 3 97 100 40 9 49

Dark 0 0

0 71 8

Skin fibroblasts Unspecified Light color 0 0 0 (right) 0 61 7

Probability of chimerism 1/64 1I64

-

1/64 1I64 1/32

94 (left) 49 56

0 97

1I64

11256

720

Ohashi et al.

in these chimeras included: (1)a flag-like rectangular pattern, (2) a pattern of rounded units analogous to the cafe-au-lait patches in von Recklinghausen disease, and (3) a striate pattern. The patterns seen in these individuals tended to be large. This would indicate that the earlier in the development mosaic cells are formed, the larger the patterns of pigmentary dysplasia. Further studies on pigmentary dysplasia and chromosomal and genetic mosaicism would answer this and other questions.

ACKNOWLEDGMENTS We are indebted to Drs. T. Hayashi, T. Shinohara, Y, Sugio, and H. Tonoki for referring patients, and to Mr. T. Iikura for expert advice on ultraviolet photography.

REFERENCES

Fig. 5. Patient 9 (46,XX/47,XX,+mar). Hypopigmented macules on the body.

patient 4, for instance, were reminiscent of the skin patterns in incontinentia pigmenti, an X-linked dominant trait with male lethality. However, the pigmentary dysplasia in the patient was not preceded by an inflammatory or vesicular stage, as is the case with incontinentia pigmenti. A girl we reported previously is of interest in this connection [Kajii et al., 19851. The 19-month-old girl had an (X;13)(p11.21;q12.3)translocation, bilateral retinoblastoma and distinct pigmentary dysplasia of the skin, which we then interpreted as a sign of incontinentia pigmenti. She had sharply demarcated, macular, linear and swirled hyperpigmented patterns on the trunk and limbs, rather than the irregular, marble-cake patterns typical of incontinentia pigmenti. The pigmentation was preceded by erythematous eruptions with linearly aligned vesicles. It could be that the girl had both incontinentia pigmenti and pigmentary dysplasia, the latter resulting from random X-inactivation. Our attempt at detecting chimeras among our patients with pigmentary dysplasias was not rewarding. Chimeras are apparently rare among pigmentary dysplasias, although most of the previously reported instances were not adequately studied for the possibility [Donnai et al., 19881.At least 16 humanchaimeras have been reported, seven with pigmentary dysplasia of the skin [cf. Benirschke, 1972, for 11 cases; Corey et al., 1978;Fitzgerald et al., 1979;Findlay and Moores, 1980; Goudie et al., 19851. Since most chimeras have been ascertained by anomalous blood typing results, it is unlikely that there is an ascertainment bias for skin pigmentation in these cases. The pigmentary dysplasias

Benirschke K (1972):Chimerism, mosaicism and hybrids. Proceeding of the Fourth International Congress of Human Genetics, Paris, Sept 6-12, 1971. Excerpta Medica Foundation. Cantu ES, Thomas IT, Frias JL (1989):Unusual cytogenetic mosaicism involving chromosome 14 abnormalities in a child with an MW MCA syndrome and abnormal pigmentation. Clin Genet 36:189-195. Chitayat D, Friedman JM, Johnston MM (1990):Hypomelanosis of Itoa nonspecific marker of somatic mosaicism: Report of case with trisomy 18 mosaicism. Am J Med Genet 35:422-424. Corey MJ, Miller JR, MacLean, Chown B (1978): A case of XWXY mosaicism. Am J Hum Genet 19:378-387. Donnai D, Read AP, McKeown C, Andrews T (1988):Hypomelanosis of Ito: A manifestation of mosaicism or chimerism. J Med Genet 25:809-818. Findlay GH, Moores PP (1980):Pigment anomalies of the skin in the human chimaera: Their relation to systematized naevi. Br J Dermatol 103:489-498. Fitzgerald PH, Donald RA, Kirk RL (1979): A true hermaphrodite dispermic chimera with 46,XX and 46,XY karyotypes. Clin Genet 15:89-96. Flannery DB (1990):Pigmentary dysplasias, hypomelanosis of Ito, and genetic mosaicism. Am J Med Genet 35:18-21. Flannery DB, Byrd JR, Freeman WE, Perlman SA (1985): Hypomelanosis of Ito: A cutaneous marker of chromosomal mosaicism. Am J Hum Genet 37:A93. Fujimoto A, Lin MS, Korula SR, Wilson MG (1985):Trisomy 14 mosaicism with t(14;15)(ql1;pll)in offspring ofa balanced translocation carrier mother. Am J Med Genet 22:333-342. Glover MT, Brett EM, Atherton DJ (1989):Hypomelanosis ofIt0: Spectrum of the disease. J Pediatr 115:75-80. Goudie RB, Jack AS, Goudie BM (1985): Genetic and developmental aspects of pathological pigmentation patterns. Curr Top Pathol 74:103-139. Hall J G (1988): Revie and hypotheses: Somatic mosaicism: Observations related to clinical genetics. Am J Hum Genet 43:355-363. Happle R (1987):The lines of Blaschko: A developmental pattern visualizing functional X-chromosome mosaicism. Curr Probl Dermatol 17:5-18. Ishikawa T, Kanayama M, Sugiyama K, Katoh T, Wada Y (1985): Hypomelanosis of Ito associated with benign tumors and chromosomal abnormalities: A neurocutaneous syndrome. Brain Dev 7:45-49. Ito M (1952): Studies on melanin. XI. Incontinentia pigmenti achromians: A singular case of nevus depigmentosus systematicus bilateralis. Tohoku J Exp Med 55 (Suppl):57-59. Kajii T, Tsukahara M, Fukushima Y, Hata A, Matsuo K, Kuroki Y (1985): Translocation (X,13) (p11.21;q12.3)in a girl with incontinentia pigmenti and bilateral retinoblastoma. Ann G n 6 t 28:219-223. Miller CA, Parker WD (1985):Hypomelanosis of Ito: Association with chromosomal abnormality. Neurology 35:607-610.

Pigmentary Dysplasias Murano I, Ohashi H, Tsukahra M, Tonoki H, Okino F, Atsumi M, Kajii T (1991): Pigmentary dysplasias in long survivors with mosaic trisomy 18: Report of two cases. Clin Genet 39:68-74. Niikawa N, Kajii T (1975):Sequential Q- and acridine orange-marker technique. Humangenetik 30:83-90. Reynolds JF, Daniel A, Kelly TE, Gollin SM, Stephan MJ, Carey J , Adkins WN, Webb MJ, Char F, Jimenez J F , Opitz J M (1987): Isochromosome 12p mosaicism (Pallistermosaic aneuploidy or Pallister-Killian syndrome): Report of 11 cases. Am J Med Genet 27:257-274. Ritter CL, Steele MW, Wenger SL, Cohen BA (1990): Chromosome mosaicism in hypomelanosis of Ito. Am J Med Genet 35:14-17. Rott HD, Ulmer R, Haneke E (1986):Hypomelanosis ofIto and chromosomal mosaicism in fibroblasts. Lancet 2:343. Sybert BP, Pagon RA, Donlan M, Bradley CM (1990): Pigmentary abnormalities and mosaicism for chromosomal aberration: Associa-

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tion with clinical features similar to hypomelanosis of Ito. J Pediatr 116:581-586. Thomas IT, Frias J L , Cantu ES, Lafer CZ, Flannery DB, Graham J G (1989): Association of pigmentary anomalies with chromosomal and genetic mosaicism and chimerism. Am J Hum Genet 45:193-205. Turleau C, Taillard F, Doussau de Bazignan M, Delepine N, Desbois JC, de Grouchy J (1986):Hypomelanosis of Ito (incontinentia pigmenti achromians) and mosaicism for a microdeletionof 15ql. Hum Genet 74185-187. Wertelecki W, Breg WR, Graham J M Jr,Iinuma K, Puck SM, Sergovich FR (1986): Trisomy 22 mosaicism syndrome and Ullrich-Turner stigmata. Am J Med Genet 23:739-749. Wulfsberg EA, Wassel WC, Polo CA (1991):Monozygotictwin girls with diploid/triploid chromosome mosaicism and cutaneous pigmentary dysplasia. Clin Genet 39:370-375.