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Giant congenital melanocytic naevi : definition, malignant transformation and treatmentmodalities

Zaal, L.H.

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Citation for published version (APA):Zaal, L. H. (2009). Giant congenital melanocytic naevi : definition, malignant transformation and treatmentmodalities.

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Download date: 08 Aug 2019

6Chapter

Familial clustering of giant congenital melanocytic naevi

De Wijn RS

Zaal LH

Van der Horst CM

Accepted for publication J Plastic Reconstructive Aesthetic Surgery

Abstract

Giant congenital melanocytic naevus (GCMN) is an infrequently occurring congenital

malformation. GCMN generally occurs isolated but rare familial occurrence points to a

genetic background. We present two cases of familial GCMN: one with two affected

siblings and another with two affected double second cousins. Familial occurrence

of GCMN reported in literature is reviewed, and an overview of the embryology and

proliferation is given, illustrating the plethora of factors that might lead to GCMN

formation. The pattern of inheritance is likely not Mendelian, and discordance in

identical twins and the segmental distribution of lesions suggest a postzygotic mutation.

A polygenic paradominant inheritance explains the clinically observed transmission

pattern best. Candidate genes include those influencing neural crest development and

melanocyte proliferation.

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Introduction

Giant congenital melanocytic naevi (GCMN) are benign proliferations of cutaneous

melanocytes, present at birth or within the first weeks of life, with a minimum size of 1%

total body surface area (TBSA) at the head or 2% elsewhere. 1 Size, location, macroscopy,

and histology can vary remarkably.2 GCMN are infrequent, the frequency at birth

being estimated as one in every 20,000 live born children.3 GCMN frequently impose a

significant cosmetic and psychosocial burden to affected persons. In addition, they are

associated with an increased risk of malignant melanoma3,4 and may be associated with

neurocutaneous melanosis (NCM).5,6

Almost all GCMNs occur sporadically, but familial clustering has been reported.7-10

Discordant identical twins however are also known.11-14 Etiology and pathogenesis remain

unknown, and various mechanisms have been postulated such as erroneous neural crest

development, 15,16 activating mutations of melanocyte proliferation, 17-20 cutaneous

mosaicism and paradominant inheritance.21-23

Here we report on two familial cases of GCMN, and review familial occurrences and the

various hypotheses regarding aetiology and pathogenesis.

Materials and Methods

The Department of Plastic, Reconstructive and Hand Surgery of the Academic Medical

Centre in Amsterdam serves as a referral centre for children and adults with GCMN. We

surveyed files of all patients in search for familial occurrence of GCMN. Medline and

Embase databases were systematically searched by combining relevant search terms and

synonyms for GCMN, familial occurrence, consanguinity, chromosome abnormalities, and

the co-occurrence of pigmentation or other disorders

Results

Patient Survey

From 1991 to date, 120 patients with GCMN were treated. There were two families with

more than one member affected by GCMN. Other, likely unrelated, disorders that were

present in patients were cleft palate, congenital cataract and phenylketonuria. The latter

patient also had trisomy 21. No other chromosome abnormalities were identified.

The first patient was a boy with a typical GCMN located on the occipital region, covering

approximately 1% TBSA (Fig. 1). The lesion had an evenly brown colour with hairy

patches, was excised, and follow-up was uneventful. The boy did not have any other

77

Familial clustering of GCMN

abnormalities. A subsequent sister of the patient (Fig. 2) was born with a large GMCN of

the back and buttocks covering approximately 10% TBSA (Fig. 3). The lesion was hairy

and unevenly coloured, and excised in three stages with serial tissue expansion. The girl

was otherwise healthy and follow-up was uneventful.

The second patient was a girl with a GCMN of the abdomen, back, buttocks and upper

legs covering approximately 30% TBSA (Fig.4). The lesion was hairy, unevenly coloured

and had several satellite lesions. In addition, a soft tissue hypotrophy of the right upper

leg was noted, as well as two hypertrophic masses over the sacrum and mons pubis.

These soft and painless masses were pigmented, hairless and had a stuck-on appearance.

Most of the GCMN and both hypertrophic masses were removed in three stages using a

combination of curettage, excision and split-thickness skin grafting.

Figure 1: Family I, patient 1. A congenital pigmented lesion of the occiput measuring 3 x 7 cm.

Figure 2: Pedigree of Family I. I

II

III

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78

Figure 3: Family I, patient 2. A hairy, unevenly pigmented lesion of the back measuring >20 cm across.

Figure 4: Family II, patient 1 at birth showing a large, unevenly pigmented lesion of the back, buttocks and left upper leg as well as a hypertrophic area over the sacrum (Remainder of lesion not shown).

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Familial clustering of GCMN

Histologically, the large protuberant mass on the back was found to result from a markedly

increased amount of pale myxoid matrix accumulating between the scattered naevus cells,

which themselves were unremarkable and devoid of nuclear atypia (Fig. 5). The overall

picture was reminiscent to but still different from diffuse cutaneous neurofibroma. The

localisation within the congenital naevus and the presence of focal pigmentation strongly

suggest the lesion was an integral part of the congenital melanocytic naevus. Similar

masses have previously been described and were thought to represent neurofibromas or

neurotized naevi, based on clinical and histological examination. 24-26 This feature can be

explained by the common origin of melanoblasts and neural precursors from the neural

crest.

Figure 5: Histopathological analysis of the protuberant mass from Case 1 from family II, showing a marked increase of pale myxoid matrix accumulating between the normal nevus cells.

As one mass was positioned over the mons pubis, an endocrinological work-up was

conducted. This initially suggested a mild non-classical 21-hydroxylase deficiency, but

repeat analysis at the age of seven years gave normal results. The girl had no other

features of 21-hydroxylase deficiency. Follow-up was uneventful.

The family history showed the daughter of the sister of the mother also had a GCMN

(Figure 6). This patient had a circular pigmented lesion of the entire right arm excluding

the palm, a 10 cm lesion over the left elbow and a 15 cm lesion over the left lower leg,

in total covering approximately 11% TBSA (Fig. 7). In addition, approximately 75 0,5-3 cm

satellite lesions all over her body were present. The lesions were all hairy and unevenly

C H A P T E R 6

80

coloured. In addition, a soft tissue hypotrophy of the entire right arm was noted. She had

no other abnormalities, notably no hypertrophic masses, and was otherwise healthy. An

endocrinological work-up gave normal results.

Figure 6: Family II, patient 2 at age 12 showing a circular pigmented lesion of the entire right arm.

Figure 6: Pedigree of family II. Please note IV:4 and IV:5 are double second cousins.

I

II

III

IV 4 5

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Familial clustering of GCMN

No other cases of GCMN occurred within the two families. All patients’ parents were

physically examined for the presence of naevi and the extended family was interviewed

telephonically; a significantly increased number of naevi was not reported. No skin cancer,

pigmentation disorders or other major disorders occurred in two families.

Literature Survey

Literature search yielded four reports on familial occurrence of GCMN (Table 1).7-10 In

each family only two closely related members were affected, and in none associated

physical or genetic abnormalities were mentioned. Danarti et al.23 reviewed a further

three cases27-29 of which there was no full-text availability. A survey amongst several

patient organizations showed that there are no known familial cases in the NYU-LCMN

registry, Nevus Outreach support group30 or the Nävus-Netzwerk registry.31

In none of these reports the patients were born to consanguineous parents; sporadic

GCMN from consanguineous parents however has been reported by Goodman et al.32

In addition, there are three reports on twins with GMCN; all were discordant same-sex

monozygotic twins. 12-14 Reports on chromosome abnormalities in GCMNs are infrequent.

Dessars et al.20 found two balanced translocations involving the BRAF gene and one

deletion of the long arm of chromosome 6 out of 27 GCMNs. Heimann et al.33 analyzed

a single GCMN and found 22% of mitoses to be polyploid and 4% with chromosome

rearrangements involving 1p, 12q and 19p. Finally, Bastian et al.34 found no chromosomal

aberrations in eight GCMN without foci of proliferation.

In addition to the previously mentioned neurocutaneous melanosis, a variety of co-occurring

disorders has been associated with GMCN, including structural brain abnormalities (Dandy-

Walker malformation,35,36 hemimegalencephalopathy,35,37 meningohydroencephalocele,36

Table 1: Summary of reported familial clustering of giant congenital melanocytic naevi.

Author Familial relation Patient 1 Patient 2 Nevi in family

Hecht (1981)7 Double first cousins Male; hairy naevus covering half of the scalp

Female; hairy naevus covering half of the scalp

None

Voigtländer (1974)8 Siblings Male; hairy naevus encircling the wrist

Female; hairy naevus covering abdomen, buttocks and thigh. Multiple satellite nevi

Parents < 10 small hairless naevi

Beck (1921)9 Grandson/grandmother

Male; ‘tierfell’ Female; similar distribution

Parents unaffected

Gould (1896)10 Siblings Male; hairy naevus covering the trunk and thighs. Hundreds of satellite naevi

Female; hairy naevus covering the entire back. Hundreds of satellite naevi

Unknown

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lissencephaly38 and microcephaly39) spina bifida occulta,24 polydactlyly,39 linear epidermal

naevus syndrome,40 segmental neurofibromatosis,24,41-43 encephalocraniocutaneous

lipomatosis,37 general lipomatosis,32 placental nevomelanocytosis,44-46 Hirschsprung

disease47 and hypotrophy of the underlying bone48 or subcutaneous fat.49,50

Discussion

Out of 120 patients, two cases of familial clustering and one chromosomal aberration

were identified. The results from the literature search underscribe that, albeit rare,

familial clustering of GCMN does occur and leads to suggest that some inheritable factor

is implicated. In order to discuss inheritance, first the embryology and proliferation of

melanocytes and GCMN will be briefly reviewed.

Embryology

Melanoblasts are derived from the neural crest and proliferation, differentiation

and migration is regulated by a complex network of interacting genes, such as the

microphthalmia-associated transcription factor gene (Mitf)51 and the c-kit proto-

oncogene.52 Mutations in this network may deregulate the pigmentary system during

embryogenesis, resulting in various congenital pigmentation disorders. This mechanism

is thought to explain the deposition of melanocytes in the leptomeninges53 and

placenta44-46 of GCMN patients, and possibly also the co-occurrence of structural

brain abnormalities,38 spina bifida, neurofibromatosis,24 encephalocraniocutaneous

lipomatosis54 and Hirschsprung disease.47

Of interest, it has been hypothesized that as the c-met / hepatocyte growth factor scatter

factor (HGF/SF) signaling pathway influences melanoblast proliferation and migration,13

a morphogenic error of this pathway with overexpression of either factor may result in

abnormal distribution of melanocytes and formation of GCMN or NCM.15,16,55

The rare occurrence of divided naevi sheds some light on the time of congenital

melanocytic nevus formation. These naevi are seen at adjacent parts of the body that

were fused at some point during embryogenesis, such as the eyelids56-58 or the glans

penis and prepuce.59-61 The current hypothesis is that, after melanoblast migration to

the epidermis in the 7th week of gestation,62 a single nevus was formed in the period of

embryological fusion, which is between the 9th and 20th week for the eyelids and the 11th

and 14th week for the penis. After embryological division, proliferation continues as two

separate naevi.

An other explanation might be that a propensity to develop GCMN is present in all body

cells, and gives rise to an increased chance to obtain a second mutation that will lead to

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Familial clustering of GCMN

the GCMN itself. This may be compared to a likely similar mechanism in Klippel-Trenaunay

syndrome, in which often an upper and a lower limb are affected but not the trunk in

between, indicating these to be separate events in the limbs.63 This hypothesis does not

necessarily exclude the former hypothesis.

Proliferation

The proliferation of melanocytes is partially controlled by the RAS-RAF-MAPK pathway,

which induces proliferation and melanogenesis in response to UVB radiation and the

binding of α-melanocyte stimulation hormone (α-MSH) to the melanocortin-1 receptor

(MC1R).64 Various activating mutations in this pathway with a higher kinase activity have

been identified.

The somatic BRAFV600E mutation65 has been shown common in both melanoma and

different types of melanocytic naevi66-69 suggesting it is an early event in melanocytic

neoplasia. Germline mutations of the BRAF-gene have not been found in melanoma or

naevus patients;70,71 however chromosomal translocation was identified as a mechanism

of BRAF activation in GCMNs.20,72 On the other hand, germline mutations of the BRAF-

gene and several other components of the RAS-RAF-MAPK pathway have been identified

in cardio-facio-cutaneous syndrome,73,74 which is associated with skin hyperpigmentation

and frequent naevi.75 This substantiates the relationship between these mutations and

inherited pigmentation disorders.

There is some evidence that somatic NRAS mutations in codon 61, which have also been

implicated in melanocytic neoplasia,76,77 are correlated with congenital melanocytic

naevi: Bauer et al.17 identified the NRAS mutation in 26 out of 32 congenital naevi, Ichii-

Nakato et al.19 in 9 out of 20 medium-sized congential naevi and Dessars et al.20 in 18 out

of 24 GCMNs. However, the absence of congenital pigmentary abnormalities in patients

with germ-line NRAS mutations suggest these findings to be secondary phenomena.

In contrast to previous reports66,67 very few BRAF mutations were identified in these

studies or a study by de Raeve et al.,18 who detected no BRAF mutations in 19 GCMNs.

Bauer et al.18 suggested the previous observations might be due to use of a different

definition of ‘congenital’ such as occurring within the first two years of life or based on

histological criteria, thereby essentially falsely designating these as truly congenital.

The final component of the RAS-RAF-MAPK pathway that has been implicated in

melanoma is the polymorphic germline mutation of MC1R.78 Papp et al.76 identified MC1R

variants in 3 out of 17 CMN, but other germline mutations associated with melanoma

and dysplastic naevi79 such as CDKN2A and CDK4 were not found.

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Inheritance

Based on the occurrence of multiple or medium-sized naevi in the relatives of GCMN

patients,32 autosomal dominant transmission with variable expression was suggested as

a possible explanation for the familial occurrence. However, in the present cases and

other reports on familial clustering,7-10 no significantly increased number of naevi was

observed in the relatives, arguing against such a mode of inheritance.

An autosomal recessive trait is also unlikely, as there is a lack of reports on GCMN patients

born to consanguineous parents, and the incidence of familial cases does not fit this

model.

Among the discordant and familial cases reported in the literature and those reported

here, there was no obvious sex predilection (male:female=5:8 for the familial cases and

male:female=2:1 for the discordant cases) and there is also no known difference in

severity between affected males and females, making X-linked inheritance less likely.

The occurrence of monozygotic twins discordant for GCMN argues against any

Mendelian pattern of inheritance (although this does not rule it out completely), and

suggests a postzygotic event might be involved, producing a genetic mosaic in which

the disease manifests. For several autosomal dominant skin disorders80-82 a segmental

pattern of involvement due to cutaneous mosaicism resulting from a postzygotic loss of

heterozygosity22 has been proved.

As GCMN are likely to be neither dominant nor recessive, the concept of ‘paradominant

inheritance’ was introduced. This offers an explanation for the occasional familial

occurrence of otherwise sporadic conditions, and also for the discordance in monozygotic

twins.21 A paradominant trait does not manifest in a heterozygous individual and can thus

be transmitted unperceived in families. It is only when a postzygotic mutation causes

loss of heterozygosity that the disease manifests in the ensuing mosaic (Fig. 8). This

mechanism has also been suggested for other conditions.83

One can speculate mutations disturbing neural crest development are involved, because

of their function in melanocyte depositions and the nature of co-occurring disorders.

Possibly mutations in genes with different functions are involved, giving rise to polygenic

paradominant inheritance:84 one or more mutations or polymorphisms segregate on

either side of a patients family and each in themselves do not cause GCMN; it is only

when a second postzygotic mutation in another gene occurs that a GCMN develops. In

this context, the observed somatic mutations of melanocyte proliferation could confer an

increased viability to a cell carrying the mutations or polymorphisms.

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Familial clustering of GCMN

Conclusion

The multitude of factors implicated in the embryology and proliferation of melanocytes

illustrates the plethora of possibilities that might lead to GCMN formation. GCMNs

generally occur isolated, but the two familial occurrences described here and the

infrequent occurrence reported in literature raise suspicion that an inheritable factor is

implicated. The discordance in monozygotic twins and the segmental pattern in which

the disease manifests suggest a postzygotic mutation. A polygenic, paradominant

inheritance can explain the clinically observed transmission pattern. Possibly mutation(s)

in gene(s) influencing neural crest development will play a role. However, the exact

etiology remains to be elucidated.

Figure 8: Paradominant inheritance. The allele highlighted in red is paradominant; the corresponding normal allele is grey. The trait only manifests when a postzygous mutation in the developing embryo gives rise to loss of heterozygosity, forming two genetically and phenotypically different populations.

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