melanocytic nevi in turner syndrome
TRANSCRIPT
Pediatric Dermatology Vol. 11 No. 2 120-!24
Melanocytic Nevi in Turner SyndromeBrad Becker, M.D.,* Nicholas Jospe, M.D.,t and Lowell A. Goldsmith, M.D.*
[peparttnents of * Dermatology tmd f Pediatrics,-University of Rochester School of Medicine and~^ Dentistry,JRochester,'\New York]
Abstract: One morphologic feature of Turner syndrome is increasednumbers of melanocytic nevi; however, little attention has been given totheir characterization. The development of a melanoma in one of our pa-tients with Turner syndrome prompted this study. We prospectively ex-amined 10 patients with the disease, confirmed by karyotype. All patientsunderwent full body skin examination noting the number, size, distribu-tion, and degree of ciinicai atypia of melanocytic nevi. Representative andunusual lesions were photographed. An average of 115 nevi were seen,with the majority measuring 1 to 5 mm. Most were located on the back andextremities. Clinical atypia was uncommon. Our patients had larger num-bers of benign-appearing nevi than the general population. Large num-bers of melanocytic nevi is a risk factor for melanoma, suggesting thatthese patients have an increase in one risk factor. Longitudinal studiesare indicated to ciarify this issue; nevertheless, we recommend periodicskin examinations and the reguiar use of sunscreens for individuals withTurner syndrome, i
Turner syndrome is a common genetic disorderof females characterized by sexual infantilism,webbed neck, cubitus valgus, short stature, gonada!dysgenesis., lymphedema, and the presence of onlyone normal X chromosome (1-3). Although the ge-netic and endocrinologic aspects of the syndromehave been studied extensively, little has been re-ported on its cutaneous manifestations. Commonlymentioned skin findings include webbed neck, hy-poplastic nails, keloids and hypertrophic scars, dryskin, seborrheic dermatitis, abnormal dermato-glyphics, and increased numbers of pigmented nevi.Despite frequent reports of the increased preva-lence of pigmented nevi (4), little attention has beengiven to the characterization of these nevi.
We have been following a 61-year-old womanwith Turner syndrome (45,XO) who developed alentigo maligna melanoma on her back (Breslow
depth 1.5 mm. Clark level 3) in her fifties, and whosubsequently had a biopsy-proved dysplastic nevus(not included in Table 1). Clinically, she has over200 nevi, several of which are greater than 6 mmwith atypical features (asymmetry, border irregular-ity, color variegation). No family members wereavailable for examination, and we were uncertain asto whether this represented an instance of mela-noma in the setting of the familial atypical mole syn-drome. Her constellation of findings prompted us tostudy prospectively young women with Turner syn-drome to characterize their melanocytic nevi.
MATERIALS AND METHODS
Ten patients with Turner syndrome were recruitedconsecutively from the Pediatric Endocrinologyand Research Unit at the University of Rochester,and one patient was seen in the dermatology prac-
Address correspondence to Lowell A. Goldsmith. M.D..University of Rochester, 601 Elmwood Avenue, Box 697, Roch-ester, N V ^ 2
120
Becker et al: Melanocytic Nevi in Turner Syndrome 121
tice at the University of Rochester. All patients (orparents) gave written informed consent and under-went a complete examination. Nevi were defined asbrown to black, macular to papular lesions greaterthan or equa! to 1 mm in diameter. They were dif-ferentiated from lentigines by being palpable or hav-ing accentuated skin markings on tangential illumi-nation. Ephelides were differentiated from nevi onthe basis of less pigmentation and a history of dark-ening with exposure to sun. All nevi were counted,and their size, color, distribution, and degree ofclinical atypia were recorded. Representative le-sions were photographed and reviewed.
RESULTS
Table 1 summarizes historical data and informationon the nevi in our 10 patients. Ages ranged from 7 to35 years (mean 13.3 yrs excluding the 35-year-old).Half of the patients had a 45,XO karyotype, and theremainder had partial deletions of X or mosaicism.All 10 subjects were receiving estrogen supple-ments, were using estradiol patches. 7 had beentreated with or were still receiving human recombi-nant growth hormone and oxandrolone, and 3 hadbeen treated only with oral estrogen.
Age of onset of nevi was unknown in most pa-tients, with only one acknowledging their presenceat birth. One patient had a history of blistering sun-burns, and none had a personal or family history ofmelanoma. Al! patients were of European ancestry.The majority had type 3 skin (sometimes burns, al-ways tans) by history. The average number of neviper patient was 115 (range 5-268); most were on theextremities and back. The average size was 1 to 5
mm. Patients with large nevi tended to have a fewlarge ones; typically, fewer than five measured be-tween 5 and 9 mm, with the majority being smallerand appearing benign clinically. Within any individ-ual, nevi were generally uniform in size, with regu-lar borders and even pigmentation. Various mor-phologies were noted, including macular. papular,targetoid, mulberry-like, halo nevus, and congenital(pebbly surface with coarse hairs) (Fig. 1). Severalpatients had strikingly darkly pigmented nevi mea-suring 2 to 9 mm.
DISCUSSION
In 1938 Turner described a syndrome characterizedby sexual infantilism, webbed neck, and cubitusvalgus (3). Since that time, many other associatedclinical features have been reported (1,2).
Melanocytic nevi are commonly mentioned as afeature of the syndrome. Studies in which preva-lence of nevi was noted showed a range between25% and 100% of patients (2,5,6). Few reports dis-cussed the numbers or the clinical and histologicmorphology of nevi. Polani reported 15 or more me-lanocytic nevi in girls (7), whereas Amano et al de-scribed one patient with an organoid nevus and 50more melanocytic nevi with histology showing com-mon compound or intradermal features (8). It hasbeen reported that there is no increased rate of ma-lignant degeneration (1). One case report describedan 11-year-old girl who, in addition to having 21normal-appearing melanocytic nevi, had oneunusual-appearing pigmented lesion that showed acombined nevus (common compound nevus andSpitz nevus) on histology (9). Although there is one
TABLE 1. Ciinicai and Skin Findings in JO Patients with Turner Syndrome
Age(yrs)
15181412
3518137
11
12
Karyotype
XO46Xdel(x)pllXOXO
Mosaic unkXO90%. XO -1- fr46Xi(Xq)XOX0( 1,44X0-9)
XO
Onsetof Nevi
Unknown6 yrsUnknownUnknown
UnknownUnknown11 yrsUnknownBirth
Unknown
BlisteringSunburn
NoNoYesNo
NoNoNoNoNo
No
SkinType*
IIIIII11III
IIIIIIIIIIIII
IV
Lymphedemaat Birth
YesNoYesYes
YesNoYesNoYes
No
No. ofNevi
205136
5135
10260
2688699
58
%ofDistributionby Body Sitet
11/25/32/7/254/35/44/2/150/60/20/20/0
19/35/23/7/17
0/39/48/7/627/0/47/10/1711/34/34/3/193/48/24/8/16
17/16/21/11/34
12/34/0/17/36
Size*(mm)
1-3 (6 X 4)M2-32-3 (4 X 8,
4 x 5 )1-23-52-51-21-3 (5 X 3,
5 x 3 ,4 x 2 )
2-5 (9 X 6)
* n usually bum, tan less than average: III sometimes mild bum. tan about average; IV rarely burn, tan more than average.t Percentage of face/arms/legs/chest/abdomen/back.t Range; larger nevi noted in parentheses.
122 Pediatric Dermatology Vol. 11 No. 2 June 1994
Figure 1. The back of patient no, 7 with more than 30nevi ranging between 2 and 5 mm, and varying in pig-mentation.
case report of a woman who developed choroidalmelanoma limited to the orbit (10), we are unawareof any prior reports of cutaneous melanoma in a pa-tient with Turner syndrome.
Our patients (except no. 3) had large numbers ofmelanocytic nevi. with an average of 115. This issignificantly higher than the average number re-ported to date. Nevus counts in the general popula-tion range between 12 and 43 (11-18) depending onthe definition used for melanocytic nevi. Manystudies use 2 mm as a cut-off size; however, studiesin which all nevi were counted, without regard tosize, still revealed fewer than 40 per person (11,14.!5). Nevi increase in size and number throughoutchildhood and adolescence (19). In one study, strat-ifying the numbers by decades revealed an averageof 4 in the first decade, 18 in the second, and 29 inthe third (16). Given that the average age of our pa-tients was 13.3 years, we would expect our averageof 115 to underestimate the final number of nevi tobe seen in an adult with Turner syndrome. Thus,overall 90% of our patients had a significantly
Figure 2. Close-up of nevus on right shoulder of pa-tient #10 showing a large darkly pigmented, pebblysurfaced papule with slightly irregular borders.
higher number of nevi than the general population.In our small group of patients we could not establisha relationship between numbers and karyotypic ab-normality.
Nevertheless, none of our patients met the strictdefinition of the classic atypical mole syndrome.This syndrome is defined clinically by 100 or moremelanocytic nevi, one or more melanocytic nevi 8mm or larger in greatest diameter, and one or moremelanocytic nevi with atypical clinical features (20).
The large number of nevi in Turner syndrome isof concern since data exist supporting the relation-ship of pigmented nevi in the development of mela-noma (11,21-29). Case control studies have shownan association between numbers of pigmented neviand the risk of melanoma (11,25-29). When specifi-cally looking at large numbers of banal acquirednevi, the risk of melanoma increased (27.30,31).One case control study found nevus count a betterpredictor of melanoma risk than sun exposure, haircolor, complexion, or propensity to sunburn (32).Although larger typical-appearing nevi (5-10 mm)
Becker et al: Melanocytic Nevi in Turner Syndrome 123
were associated with higher risk, small ones (!-5mm) were as well (32). One study stratified risk ofmelanoma with respect to numbers of nondysplasticnevi. Patients with il to 25 nevi had a relative riskof 1.6, those with 26 to 50 nevi had a relative risk of4.4, those with 51 to 100 nevi had a relative risk of5.4, and patients with more than 101 banal nevi hada relative risk of 9.8 (30,33).
What can explain the increased number of nevi inTurner syndrome? Absence of (or abnormality in)an X chromosome is unlikely to be primarily re-sponsible, because patients with Noonan syndromeare also reported to have an increased number ofpigmented nevi (34). This disorder shares manyclinical features with Turner syndrome, includingshort stature, webbed neck, shield chest, lymphe-dema. dystrophic nails, keloids, and increased num-bers of pigmented nevi (35), but lacks abnormalitiesin the X chromosome. In addition, two of three pa-tients reported with a mosaic trisomy 22 with mor-phologic features of Turner syndrome had numer-ous pigmented nevi (36). Einally, a 14-year-old girlwith an ill-defined genetic disorder characterized byshort stature, dysmorphic facies, progressive deaf-ness, left ventricular hypertrophy, degeneration ofthe liver, and frequent otitis media and urinary tractinfections had numerous pigmented nevi (37).Therefore, several other disorders with features incommon with Turner syndrome, without the karyo-type abnormalities, also display many pigmentednevi.
Hormones may play a role in the pattern of neviin Turner syndrome. It is known that acquirednevomelanocytic nevi may enlarge during puberty(38) and may increase in number and size, as well asbecome darker during pregnancy (39). The fact thatpatients with Turner syndrome have elevated levelsof luteinizing hormone and follicle-stimulating hor-mone during infancy, as well as higher levels at age10 and 11 years compared with normal girls (40),raises interesting questions about the possible roleof hormones in the development and transformationof nevi. It is unclear at this time what rote hormonaltherapies might play in the development and growthof nevi.
After our studies were completed., it was re-ported that with growth hormone administration thegrowth rate of nevi was twofold greater in patientswith Turner syndrome and hypopituitary disease(41).
We have attempted to characterize the nevi in 10patients with Turner's Syndrome. Eurther longitu-dinal studies of similar patients should be encour-
aged to define more precisely the nature of the me-lanocytic disorder, both biologically and withregard to overall health. On the basis of our dataand the literature, we cannot conclude that the fre-quency of cutaneous melanoma is increased inTurner syndrome. The increased number of nevisuggests these patients should be followed closelyand periodically during pediatric and endocrino-logic examinations, and that documentation of skinlesions and biopsy of suspicious lesions be ob-tained. An educational program on sun protectionand use of sunscreens with a sun protection factorof 15 or greater is prudent as well.
REFERENCES
1. Hall J, Gilchrist D. Turner's syndrome and its vari-ants. Pediatr Clin North Am 1990;37:1421-1440.
2. Lippe B. Turner's syndrome. Endocrinol Metab ClinNorth Am 1991 ;20:121-152.
3. Turner HH. A syndrome of infantilism, congenitalwebbed neck and cubitus valgus. Endocrinology1938 ;23:566-578.
4. Hall JG, Sybert VP. Williamson RA. et al. Turner'ssyndrome. West J Med 1982:137:32^4.
5. Engel E, Forbes A. Cytogenetic and clinical findingsin 48 patients with congenitally defective or absentovaries. Medicine 1965;44:135-164.
6. Ferguson-Smith M. Karyotype-phenotype correla-tions in gonadal dysgenesis and their bearing on thepathogenesis of malformations. J Med Genet 1%5;2:142-155.
7. Polani PE. Turner's syndrome and allied conditions,clinical features and chromosome abnormalities. BrMed Bull 1961:17:200-205.
8. Amano M. et al. Turner's syndrome (in Japanese).Hifu Shinryo 1988:10:925-928.
9. Kato H, Kato K, Kitajima Y. Unusual form of mela-nocytic nevus associated with Turner's syndrome.Dermatologica 1991:182:188-190.
10. Buckley CA, Cheng H. Intraocular melanoma, diabe-tes, and Turner's syndrome: presentation with pro-ptosis. BrOphthalmo! 198I;65:460-463.
11. Swerdlow AJ, English J. MacKie RM, et al. Benignmelanocytic naevi as a risk factor for malignant mel-anoma. Br Med J I986;292:1555-1559.
12. Pack GT, Lenson N, Gerber DM. Regional distribu-tion of moles and melanomas. Arch Surg 1952;65:862-870.
13. Nieholls EM. Development and elimination of pig-mented moles, and the anatomical distribution of pri-mary malignant melanoma. Cancer !973;32:191-195.
14. Cooke KR. Spears GFS, Skegg DCG. Frequency ofmoles in a defined population. J Epidemiol Commu-nity Health 1985:39:48-52.
15. MacKie RM. Smyth JF, Soutar DS. et al. Malignantmelanoma in Scotland 1979-1983. Lancet 1985:2:859-862.
16. Eitzsimons CP, et al. A study of total number and dis-
124 Pediatric Dermatology Vol. 11 No. 2 June 1994
tribution of melanocyte nevi in British population[abstr]. BrJ Dermatol 1984:111:9.
17. Nieholls EM. Development and elimination of pig-mented moles, and the anatomic distribution of pri-mary malignant melanoma. Cancer I973;32:191-195.
18. Augustsson A. Stierner U, Suurkula M, Rosdahl I.Prevalence of common and dysplastic naevi in aSwedish population. Br J Dermatol 1991:124:152-156.
19. Gallagher RM. McLean DI, Yang CP, et al. Ana-tomic distribution of acquired melanocytic nevi inwhite children. A comparison with melanoma: theVancouver mole study. Arch Dermatoi 1990:126:466-471.
20. Tiersten A. Grin CM, Kopf AW, et al. Prospectivefollow-up for malignant melanoma in patients withatypical-mole (dysplastic -nevus) syndrome. J Der-matol Surg Oncol 1991:17:44-48.
21. Milton GW. The diagnosis of malignant melanoma.In: McCarthy WH. ed. Melanoma and skin cancer.Sydney: Government Printer. 1973:163-174.
22. Scott JP, Jolly KD. Mackinnon MJ. Carke AM. Mel-anoma in Otago and Southland. N Z Med J 1980:92:422-424.
23. Elder DE, Greene MH. Bondi EE. Clark WH. Ac-quired melanocytic nevi and melanoma: the dysplas-tic nevus syndrome. In: Ackerman BA, ed. Pathol-ogy of malignant melanoma. New York: Masson.1981:185-215.
24. Sagebiel RW. Histopathology of borderline and earlymalignant melanomas. Am J Surg Pathol 1979:3:543-555.
25. Rhodes AR. Sober AJ. Mihm MC, Eitzpatrick TB.Possible risk factors for primary cutaneous malignantmelanoma. Clin Res I98O:28:252A.
26. Reynolds P, Austin D. Thomas J. Familial and occu-pational risks associated with malignant melanoma ofthe skin. AmJ Epidemiol 1982:116:570.
27. Holman CDJ, Armstrong BK. Pigmentary traits, eth-nic origin, benign nevi. and family history as risk fac-tors for cutaneous malignant melanoma. J Natl Can-cer Inst 1984;72:257-266.
28. Green A, Maclennan R, Siskind V. Common ac-
quired naevi and risk of malignant melanoma. Int JCancer 1985:35:297-300.
29. Sorahan T, Grimley RP. The aetiological significanceof sunlight and fluorescent lighting in malignant mel-anoma. A case-control study. Br J Cancer 1985;52:765-769.
30. Roth ME. Important melanocytic lesion in childhoodand adolescence. Pediatr Dermatol 1991:38:791-809.
31. Green A, BainC, McLennan R. et al. Risk factors forcutaneous melanoma in Queensland. Recent results.Cancer Res 1986:102:78-97.
32. Grob JJ. Gouvernet J, Aymar D, et al. Count of be-nign melanocytic nevi as a major indicator of risk fornonfamilial nodular and superficial spreading mela-noma. Cancer 1990:66:387-395.
33. Kaye VN. Dehner LP. Spindle and epithelioid cellnevus (Spitz nevus). Arch Dermatol 1990:126:1581-1583.
34. Wyre HW. Cutaneous manifestations of Noonan'ssyndrome. Arch Dermatol 1978;l 14:929-930.
35. Nora J, Nora AH, Sinha AK. Spangler RD, LubsHA. The Ullrich-Noonan syndrome (Turner pheno-type). Am J Dis Child 1974:127:48-55.
36. Wertelecki W, Breg WR, Graham JM. Linuma K,Puck SM, Sergovic FR. Trisomy 22 mosaicism syn-drome and Ullrich-Turner stigmata. Am J Med Genet1986:23:739-749.
37. Wong WA. Cohen MM. Miller M. Pruzansky S,Rosenthal IM, Solomon LM. Case report for syn-drome identification. Cleft Palate J I979;16:286-290.
38. Foycar E. et al. A histopathologic evaluation of ne-vocellular nevi in pregnancy. Arch Dermatol 1985;121:350-354.
39. Sanchez J, Figueroa L, Rodriguez E. Behavior of me-lanocytic nevi during pregnancy. Am J Dermato-pathol 1984:6(suppl !):89-91.
40. Vliel GV. Hormonal changes during development inTurner's syndrome. Acta pgediatr Scand 1988:343:31-37.
41. Bourguignon J. Pierard G. Ernould C, et al. Effects ofhuman growth hormone therapy on melanocyticnaevi. Lancet 1993;341:15O5-15O6.