Large congenital melanocytic nevi may reflect paradominant inheritance implying allelic loss

ARTICLE

Auteur(s) : Retno DANARTI, Arne KÖNIG, Rudolf HAPPLE

Department of Dermatology, Philipp University, Deutschhausstrasse 9, D‐35033, Marburg, Germany

Article accepted on 11\06\2003

Key words: The large congenital melanocytic nevus (LCMN) is a disfiguring lesion covering extensive areas of the body surface. Its incidence is approximately 1 in 20,000 live births [1, 2]. Clinically, LCMN is characterized by one or more large round or irregularly shaped patches presenting at birth and commonly involving the trunk without any midline separation [3]. Often there are satellite lesions of a similar appearance in the periphery of the main lesion, or additional small nevi may be scattered over the entire skin surface [4]. Some proposed size criteria defining LCMN include those greater than 2 percent of the body surface area [5], nevi greater than 20 cm at their largest diameter [6], and nevi that cannot be excised in a single procedure [7]. The large nevi involving the head and neck may be considered as indicative of leptomeningeal involvement [8]. A precise risk of neurocutaneous melanosis for patients with LCMN is not known. A variety of abnormalities have been reported in association with LCMN, such as spina bifida occulta, hypertrophy of cranial bones, prognathism, high arched palate, scoliosis [9], atrophy of the involved limb [1, 10, 11], and cutis marmorata [12]. The impact of LCMN is serious because of a frequently associated leptomeningeal melanocytosis; a high risk of malignant transformation; a congenital esthetic problem with undesirable psychological reactions; and because it is difficult to treat [8]. The risk of malignant transformation of large congenital melanocytic nevi is increased although exact percentages are elusive. Quaba and Wallace calculated the risk of melanoma to be 8.52 percent during the first 15 years of life [5]. A longitudinal study of a large series of patients with LCMN reported a lifetime incidence of malignant transformation of 4 to 6 percent [13]. As reviewed by Kaplan [14] and Kopf et al. [6], other authors reported the incidence of malignant melanoma developing from large congenital nevi to be 2\110 (2%) [15], 5\82 (6%) [16], 4\40 (10%) [9], 6\56 (11%) [17], or 17\55 (31%) [6, 8, 14]. Most cases of LCMN, including neurocutaneous melanosis, are sporadic [8, 18‐20]. On the other hand, when studying the literature on LCMN we found 14 familial cases, raising the question of a role of genetic factors.

Methods and results

A literature review revealed 7 familial cases of large congenital melanocytic nevi and 7 reports on large congenital melanocytic nevi with a family history of congenital medium size\small nevi. They are presented in Table I and Table II. In several of these patients, satellite lesions or disseminated small nevi were likewise present. A neurological involvement was reported in none of these families.

Discussion

The vast majority of LCMN do not show familial occurrence [8, 18‐20]. In these congenital disorders, genetic mosaicism probably originates virtually always from a postzygotic mutation, which would explain why LCMN is usually sporadic [1]. One might hypothesize that in a heterozygous individual, a somatic mutational event may cause loss of the corresponding wild‐type allele (loss of heterozygosity, LOH) at the LCMN locus, resulting in a cell that is either homozygous or hemizygous for the LCMN gene.

In 1986, one of us provided a tentative explanation why several disorders always occur sporadically, always show a mosaic pattern with a highly variable arrangement, and virtually never involve the entire integument [21]. The theory of an autosomal lethal gene surviving by mosaicism was based on the assumption that the presence of such mutation in a zygote would lead to death of the embryo at an early stage of development. Cells bearing the mutation can survive only in a mosaic state, in close proximity with normal cells. In principle, an individual with a mosaic state of a lethal gene cannot transmit the mutation to the next generation; if transmitted, the zygote with the lethal mutation will die in utero. According to this concept, the phenotype of LCMN should always occur sporadically [22]. However, as an exception from this rule, the possibility of paradominant inheritance may be considered in familial cases of LCMN.

In reviewing the literature on LCMN we found several reports of LCMN occurring in more than one member of a given family, indicating the presence of some genetic factor. Goodman et al. [23] have postulated that some cases of LCMN may be genetically determined by an autosomal dominant gene with variable expressivity. However, these rare familial cases do not display a consistent Mendelian pattern of inheritance. The hypothesis of autosomal dominant inheritance with variable expressivity [23] cannot explain why this disease always occurs in a mosaic pattern.

Cockayne [24] thought that such nevi are likely to be inheritable but felt that their mode of inheritance is probably rather complex.

Goodman et al. [23] postulated that some cases of giant pigmented hairy nevus may be genetically determined by an "autosomal dominant gene with variable expressivity".

Cantú et al. [25] discussed several hypotheses to explain the discordant occurrence of giant pigmented nevus in monozygotic twins: non‐penetrance of the gene in one parent and in the normal twin; a gametic half‐chromatid mutation; and a postzygotic double‐strand mutation occurring after the two‐cell stage replications. They also discussed the possibility of an autosomal recessive gene as the cause of giant pigmented nevus. A homozygous individual would be expected to have the entire skin surface affected; since no individual has been reported with such features, the homozygous mutation would probably be lethal. However, a heterozygous could have, by somatic recombination, a homozygous cell line so that the giant pigmented nevus would become manifest [25].

This mosaic arrangement may be best explained by paradominant inheritance [26]. Individuals heterozygous for a paradominant mutation are, as a rule, phenotypically normal and, therefore, the gene can be transmitted without any clinical expression through many generations. The trait only becomes manifest when a somatic mutation occurs at an early stage of embryogenesis. This leads to a clonal population of homozygous or hemizygous cells and creates a mosaic phenotype.

This concept would explain why LCMN occurs virtually always sporadically, and why the exceptional cases of familial aggregation of this trait do not show any consistent Mendelian pattern [26].

A list of phenotypes that may be explained by paradominant inheritance now includes: (1) Becker nevus, (2) sebaceous nevus, (3) speckled lentiginous nevus, (4) lateral telangiectatic nevus, (5) Sturge‐Weber‐Klippel‐Trenaunay syndrome, (6) nevus anemicus, (7) unilateral nevoid telangiectasia, (8) Proteus syndrome, (9) Poland anomaly, (10) cutis marmorata telangiectatica congenita [3, 26‐30] and (11) LCMN.

The presence of congenital medium‐sized or small melanocytic nevi in family members would reflect LOH occurring in a heterozygous embryo at a later developmental stage.

References

1 . Itin PH, Lautenschlager S. Lower and upper extremity atrophy associated with a giant congenital melanocytic nevus. Pediatr Dermatol 1998; 15: 287‐9.

2 . Castilla EE, da Graça Dutra M, Orioli‐Parreiras IM. Epidemiology of congenital pigmented naevi: I. Incidence rates and relative frequencies. Br J Dermatol 1981; 104: 307‐15.

3 . Happle R. Mosaicism in human skin: Understanding the patterns and mechanisms. Arch Dermatol 1993; 129: 1460‐70.

4 . Slaughter JC, Hardman JM, Kempe LG, Earle KM. Neurocutaneous melanosis and leptomeningeal melanomatosis in children. Arch Pathol 1969; 88: 298‐304.

5 . Quaba AA, Wallace AF. The incidence of malignant melanoma (0 to 15 years of age) arising in "large" congenital nevocellular nevi. Plast Reconstr Surg 1986; 78: 174‐81.

6 . Kopf AW, Bart RS, Hennessey P. Congenital nevocytic nevi and malignant melanomas. J Am Acad Dermatol 1979; 1: 123‐30.

7 . Pilney FT, Broadbent TR, Woolf RM. Giant pigmented nevi of the face: Surgical management. Plast Reconstr Surg 1967; 40: 469‐74.

8 . Reed W, Becker SW Sr, Becker SW Jr. Giant pigmented nevi, melanoma, and leptomeningeal melanocytosis: A clinical and histopathological study. Arch Dermatol 1965; 91: 100‐19.

9 . Conway H. Bathing trunk nevus. Surgery 1939; 6: 585‐97.

10 . Skidmore RA, Ivker RA, Resnick SD. Upper extremity atrophy associated with a giant congenital melanocytic nevus. Pediatr Dermatol 1995; 12: 272‐4.

11 . Caradona SA, Skidmore R, Gupta A, Bush CH, Ford MJ. Giant congenital melanocytic nevus with underlying hypoplasia of the subcutaneous fat. Pediatr Dermatol 2000; 17: 387‐90.

12 . Siemens HW, Waardenburg PJ. ber ausgedehnte multiple, bilateraleTierfellnaevi bei dem einen von zwei eineiigen Zwilingen. Arch Dermatol Syph (Berlin) 1927; 153: 145‐56.

13 . Lorentzen M, Pers M, Bretteville‐Jensen G. The incidence of malignant transformation in giant pigmented nevi. Scand J Plast Reconstr Surg 1977; 11: 163‐7.

14 . Kaplan EN. The risk of malignancy in large congenital nevi. Plast Reconstr Surg 1974; 53: 421‐8.

15 . Pers M. Naevus pigmentosus giganticus (in Danish). Ugeskr Laeger 1963; 125: 613‐9.

16 . Lanier VC Jr, Pickrell KL, Georgiade NG. Congenital giant nevi: Clinical and pathological considerations. Plast Reconstr Surg 1976; 58: 48‐54.

17 . Greeley P, Midleton AG, Curtin JW. Incidence of malignancy in giant pigmented nevi. Plast Reconstr Surg 1965, 36, 26‐37.

18 . Curth H. Genetik der mit Pigmentstörungen einhergehenden Dermatosen. In: Gottron H, Schnyder UW, eds. Vererbung von Hautkrankheiten. Handbuch der Haut‐ und Geschlechtskrankheiten, Ergänzungswerk 7. Berlin‐Heidelberg‐New York: Springer‐Verlag, 1966: 750‐860.

19 . Koch G. Genetic aspects of phacomatoses. In: Vinken P, Bruyn GW, eds. Handbook of clinical neurology. North Holland: Amsterdam, 1972: 488‐561.

20 . Kadonaga JN, Frieden IJ. Neurocutaneous melanosis: Definition and review of the literature. J Am Acad Dermatol 1991; 24: 747‐55.

21 . Happle R. Cutaneous manifestation of lethal genes. Hum Genet 1986; 72: 280.

22 . Happle R. Lethal genes surviving by mosaicism: A possible explanation for sporadic birth defects involving the skin. J Am Acad Dermatol 1987; 16: 899‐906.

23 . Goodman RM, Caren J, Ziprkowski M, Padeh B, Ziprkowski L, Cohen BE. Genetic considerations in giant pigmented hairy naevus. Br J Dermatol 1971; 85: 150‐7.

24 . Cockayne E. Inherited abnormalities of the skin and its appendages. London: Oxford University Press, 1933: p 298.

25 . Cantú JM, Urrusti J, Hernandez A, Del Castillo V, Macotela‐Ruiz E. Discordance for giant pigmented nevi in monozygotic twins. Ann Genet 1973; 16: 289‐92.

26 . Happle R. Klippel‐Trenaunay syndrome: Is it a paradominant trait¿ Br J Dermatol 1993; 128: 465‐6.

27 . Happle R. Loss of heterozygosity in human skin. J Am Acad Dermatol 1999; 41: 143‐64.

28 . Happle R, König A. Familial naevus sebaceus may be explained by paradominant transmission. Br J Dermatol 1999; 141: 377.

29 . Steijlen PM, van Steensel MA. Paradominant inheritance, a hypothesis explaining occasional familial occurrence of sporadic syndromes. Am J Med Genet 1999; 85: 359‐60.

30 . Danarti R, Happle R, König A. Paradominant inheritance may explain familial occurrence of cutis marmorata telangiectatica congenita. Dermatology 2001; 203: 208‐11.

31 . Gould G, Pyle WL. Anomalies and curiosities of medicine. Philadelphia: Saunders, 1897: p 233‐4.

32 . Sachs O. 19jähriger Patient mit schwimmhosenartigem Naevus. Arch Dermatol Syph 1912; 115: 399‐400.

33 . Beck E. Tierfellnaevus. Zentralbl Haut‐ und Geschl Kr 1927; 21: 404.

34 . Bhatavadekar D. An interesting case of naevus. Indian Med Gaz 1925; 60: 479‐80.

35 . Voigtländer V, Jung EG. Giant pigmented hairy nevus in two siblings. Humangenetik 1974; 24: 79‐84.

36 . Hecht F, LaCanne KM, Carroll DB. Inheritance of giant pigmented hairy nevus of the scalp. Am J Med Genet 1981; 9: 177‐8.

37 . Duchesne M. Pronostic du naevus pigmentaire géant: Etude multicentrique rétrospective de 102 cas. Thesis, Bordeaux, 1984.

38 . Spitzer L. Spontaner Rckgang eines Riesennaevus. Dermatol Z 1905; 12. Cited after Meirowsky E. Idiotypische Pigmentanomalien. In: Jadassohn J, ed. Handbuch der Haut‐ und Geschlechtskrank‐heiten, vol. 4. Springer, Berlin 1933: 589‐795.

39 . Pickrell K, Clay RC. Giant naevus of the thigh succesfully treated by complete excision and primary grafting. Arch Surg 1944; 48: 319‐24.

40 . Russel J, Reyes RG. Giant pigmented nevi. J Am Med Ass 1959; 171: 2083‐6.

41 . Groh V, Schnyder UW. Zur Klinik und Genetik kongenitaler Pigmentnävi. Hautarzt 1984; 35: 240‐8.