Mixed vascular naevus syndrome: report of three children with somatic GNA11 mutation and new systemic associations

Mixed vascular naevus (MVN) is characterized by the co-occurrence of telangiectatic capillary malformation and naevus anaemicus, which can appear as a pure cutaneous phenotype or be combined with systemic manifestations such as brain malformations, neurological abnormalities and musculoskeletal disorders. Recently, GNA11 and GNAQ somatic mutations have been reported in some patients with isolated and syndromic MVN. We report three children with MVN syndrome with generalized cutaneous manifestations and a number of systemic associations not reported to date, including ophthalmological anomalies, musculoskeletal abnormalities such as Sprengel deformity and posterior vertebral fusion anomalies, and septal heart defects. We also confirm a somatic mutation of GNA11 in both telangiectatic naevus and naevus anaemicus in two of our patients and discuss a possible common pathogenic mechanism underlying the different manifestations of the syndrome. Currently, there are no guidelines for the evaluation of patients with MVN syndrome, but according to the different known aspects of the disease, a complete clinical examination should be made, and complementary laboratory and imaging tests should be considered.     

Melanocytic naevi clustered on normal background skin

Several types of maculopapular melanocytic naevi can occur in a multiple form, and be arranged in a nonrandom fashion on the skin. The most frequently reported segmentally grouped naevi are lentigines. Two types of segmentally arranged lentigines probably exist. The first is associated with neurofibromatosis (NF)1 or NF1 signs, features scattered light‐brown lesions and can be considered a type of mosaic NF1. By contrast, non‐NF1 associated lesions are characterized by densely packed, dark lesions, and can be defined as ‘non‐NF1 checkerboard‐arranged lentigines’. Blue naevi, Spitz naevi and common acquired melanocytic naevi can occur, clustered in an agminated (or cannonball) shape. However, if large enough, they always follow a checkerboard pattern. Hence, such mosaic conditions should be termed ‘checkerboard‐arranged blue naevi’, ‘checkerboard‐arranged Spitz naevi’ and ‘checkerboard‐arranged common acquired melanocytic naevi’. Segmentally arranged dysplastic melanocytic naevi probably represent a mosaic form of dysplastic naevus syndrome. Dysplastic melanocytic naevi confined to a cutaneous segment could be defined as ‘isolated segmental dysplastic naevus syndrome’, while segmentally arranged dysplastic melanocytic naevi co‐occurring with widespread, nonsegmental dysplastic melanocytic naevi might configure a ‘superimposed segmental dysplastic naevus syndrome’. Small congenital melanocytic naevi are always grouped along Blaschko lines. The only other instances following Blaschko lines are the so‐called ‘linear lentiginous naevus’ and a unique case of multiple deep penetrating naevi.     

New insights in naevogenesis: number, distribution and dermoscopic patterns of naevi in the elderly

Background/Objectives: It is well recognized that the number and patterns of acquired melanocytic naevi vary with age, but little is known about naevus patterns in the elderly. This is a cross‐sectional study assessing the prevalence, dermoscopic pattern and anatomical distribution of naevus subtypes in a stratified cohort aged between 60 and 89 years. Methods: Fifty‐nine patients who attended the Queensland Institute of Dermatology were recruited randomly and evenly distributed into three age groups: 60–69 years; 70–79 years; and 80–89 years. For each participant, total naevus count and morphological naevus types were recorded with respect to age, sex and anatomical location. Flat (Clark's) naevi were further subclassified according to the dermoscopic pattern as reticular, globular or structureless. Results: Using non‐parametric methods, naevus counts in the elderly decreased due to the disappearance of reticular naevi (P < 0.05). By contrast, structureless and intradermal (Unna's and Miescher's) naevi seemed to persist even into older age. Naevi on the trunk, limbs, head and neck represented 57.6%, 31.0% and 11.3%, respectively. Notably, no reticular naevi were found on the head and neck area. Conclusions: There is a progressive reduction in total naevus counts with advancing age with respect to a cohort aged greater than 60 years.     

On naevi and melanomas in dysplastic naevus syndrome patients

Cutaneous melanoma may occur as isolated, so-called 'sporadic’cases or in association with multiple atypical naevi and in familial clusters, in which case it is referred to as the familial dysplastic naevus syndrome (DNS). In this retrospective study (a) the number and body distribution of naevocytic naevi and (b) the body distribution of malignant melanoma (MM) in individuals with familial DNS were compared in order to study their association. In 45 patients with familial DNS aged 20–39 years naevus counts on trunk and lower extremities were compared with melanoma data and distributions from a second group of 43 patients from the same DNS families aged 12–66 years. Men had significantly more naevi of a size 2 mm or 5 mm on the back than women (P=0.02). Women showed a tendency towards a greater number of naevi on the lower extremities than men, but in women no significant difference in naevi between the lower extremities and the back was found. The total number of naevi on the trunk and lower extremities in familial DNS patients was higher than that in the general population. In conclusion, it was found that predilection sites for melanoma in familial DNS patients of both sexes correspond with the distribution of naevi; in males naevi and melanoma counts and percentage distributions were higher on the back, in females both the back and the lower extremities were affected. These findings strongly suggest an association between naevus distribution and melanoma occurrence and sire in familial DNS, analogous to earlier reports on sporadic melanoma.^1,2     

Familial melanoma

The presence of large numbers of moles, atypical in appearance and distribution typifies the atypical mole syndrome. The syndrome may occur in one individual alone or in an autosomal-dominant fashion in his/her family. The presence of this phenotype indicates an increased risk of melanoma, although the risk varies according to the presence or absence of a family history. The classification devised by Kraemer et al.¹ works well in estimating the risk of melanomas but is, as yet, not fully evaluated. The diagnosis of the syndrome is essentially clinical, necessitating the consideration of various aspects of phenotype such as total mole count, distribution, clinical appearance of the moles, the age of onset, site, and number of melanomas. It is always helpful to screen first-degree and second-degree relatives if there is a family history of moleyness or melanoma. Small numbers of clinically and, sometimes histologically dysplastic naevi may occur in normal individuals. The vast majority of these probably regress as do totally banal naevi, although a low percentage will result in a melanoma.² Those patients should be questioned to establish the existence of a family history of increased numbers of moles and melanoma. They should also be thoroughly examined for the presence of other signs of the syndrome: increased total mole count, iris freckles etc. In the absence of either a family history or these additional clinical features it is unlikely that these individuals have‘the syndrome'. Common sense advice about sun avoidance and self-examination should be given. It is important to distinguish this from the atypical mole syndrome (AMS). Many authors are unhappy about the use of the term‘dysplastic naevus syndrome’for this condition, partly because the histological appearances of the atypical naevi are not dysplastic in the true sense of the word.³ There has also been considerable uncase amongst pathologists about the implications of reporting a naevus as‘dysplastic’. The situation may be improved if it is recognized that dysplastic naevi can occur normally in the general population and that what is important is the recognition of the full phenotype and family history. Some patients from melanoma families do not have‘classically dysplastic’naevi. It is, therefore, probably better to abandon the term dysplastic naevus syndrome in favour of‘atypical mole syndrome’.     

Segmental hypomelanosis and hypermelanosis arranged in a checkerboard pattern are distinct naevi: flag‐like hypomelanotic naevus and flag‐like hypermelanotic naevus

The categorization of congenital hypo‐ or hyperpigmented skin lesions following a segmental pattern has been a long‐lasting matter of debate and have been reported under various and often incorrect terms. To reassess published hypomelanotic and hypermelanotic lesions that did not follow Blaschko lines nor a phylloid pattern of mosaicism, we carried out an extensive and critical review of the worldwide literature. Seventy‐four retrieved cases consisted of lateralized hypomelanotic lesions arranged in a flag‐like pattern or appearing as large patches of grossly oval or angulated shape and sharp, serrated margins. Sometimes lesions harboured maculopapular melanocytic naevi or cooccurred with other segmentally arranged naevi. A probably non‐random association with extracutaneous anomalies was also reported on rare occasions. In 70 cases, lateralized hypermelanotic patches were arranged in a flag‐like pattern that often appeared as large quadrangular patches. Sometimes lesions harboured Spitz naevi. Ten cases belonged to phacomatosis melanorosea, whereas several others were part of so far uncategorized cases of phacomatosis pigmentovascularis. Flag‐like hypomelanosis is a distinct naevus type, for which the term ‘flag‐like hypomelanotic naevus’ is suggested. Its cooccurrence with extracutaneous abnormalities might represent a specific syndrome. Flag‐like hypermelanosis is a distinct naevus type, for which the term ‘flag‐like hypermelanotic naevus’ is suggested. Its co‐occurrence with naevus roseus defines phacomatosis melanorosea. Flag‐like hypermelanotic naevus should be distinguished from the checkerboard‐like areas of darker skin as observed in chimaeras.     

BRAF, NRAS and HRAS mutations in spitzoid tumours and their possible pathogenetic significance

Background The relationships between so‐called spitzoid tumours have proven difficult to understand. Objectives To address three questions: does spitzoid tumour morphological similarity reflect molecular similarity? Does Spitz naevus progress into spitzoid melanoma? Are ambiguous spitzoid tumours genuine entities? Methods BRAF, NRAS and HRAS mutations were analysed using single‐strand conformational polymorphism analysis and sequencing. Results Both Spitz naevi and spitzoid melanoma had a lower combined BRAF and NRAS mutation frequency compared with common acquired naevi (P = 0·0001) and common forms of melanoma (P = 0·0072), respectively. To look for evidence of progression from Spitz naevi to spitzoid melanoma, HRAS was analysed in 21 spitzoid melanomas, with no mutations identified. The binomial probability of this was 0·03 based on an assumption of a 15% mutation frequency in Spitz naevi with unbiased progression. Under these assumptions, HRAS mutations must be rare/absent in spitzoid melanoma. Thus, Spitz naevi seem unlikely to progress into spitzoid melanoma, implying that ambiguous spitzoid tumours cannot be intermediate degrees of progression. In addition, the data suggest that HRAS mutation is a potential marker of benign behaviour, in support of which none of three HRAS mutant spitzoid cases metastasized. Conclusions First, the morphological similarity of spitzoid tumours reflects an underlying molecular similarity, namely a relative lack of dependence on BRAF/NRAS mutations. Second, Spitz naevi do not appear to progress into spitzoid melanoma, and consequently ambiguous spitzoid tumours are likely to be unclassifiable Spitz naevi or spitzoid melanoma rather than genuine entities. Third, HRAS mutation may be a marker of Spitz naevus, raising the possibility that other molecular markers for discriminating Spitz naevi from spitzoid melanoma can be discovered.     

Uncommon vascular naevi associated with focal acantholytic dyskeratosis

Cutis marmorata telangiectatica congenita and vascular twin naevi are rare vascular anomalies in which focal acantholytic dyskeratosis is usually not observed. We describe a 44-year-old-man who presented for evaluation of skin lesions that had been present since birth. Physical examination revealed anaemic macules adjacent to a naevus telangiectaticus on the chest. Naevus anaemicus was also seen on the shoulders, arms, and left leg. There was bluish-reddish reticulate marking of the skin and cutaneous atrophy. Shortening and hypoplasia of the left leg was observed. Histologic examination of two biopsy specimens revealed focal acantholytic dyskeratosis. In vivo confocal laser scanning microscopy showed dilated capillaries and vessels of the upper dermal plexus in the telangiectatic and decreased capillary blood flow in the anaemic skin sites. The findings were consistent with a diagnosis of cutis marmorata telangiectatica congenita, vascular twin naevi, and incidental focal acantholytic dyskeratosis. The particularities of the present case are the following: firstly, the association of two rare vascular anomalies to which the genetic concept of mosaicism can be applied; secondly, the occurrence of incidental focal acantholytic dyskeratosis in sites of vascular naevi.     

Mosaic‐activating FGFR2 mutation in two fetuses with papillomatous pedunculated sebaceous naevus

Papillomatous pedunculated sebaceous naevus (PPSN) has been described as a subtype of sebaceous naevus (SN), typically affecting the scalp and face. In contrast with Schimmelpenning syndrome, no cerebral, ocular or skeletal anomalies have hitherto been reported. We report two unrelated fetuses with PPSN, one with large pink exophytic tumours, the other with minor features but similar microscopic findings. We performed whole‐exome sequencing in affected skin tissue from fetus 1, which identified a postzygotic de novo FGFR2 c.1144T>C (p.Cys382Arg) mutation in 34·6% of reads which was absent in the parents’ blood. Targeted deep sequencing of FGFR2 confirmed its mosaic status in additional affected skin from fetus 1, and identified the same substitution in 26% of reads in affected skin from fetus 2. FGFR2 p.Cys382Arg is a known somatic driver mutation in human cancer, previously reported to result in activation of RAS signalling. A similar paralogous missense mutation in the transmembrane domain of FGFR3 (p.Gly380Arg) has been reported in keratinocytic epidermal naevi. Our findings define a distinct clinical and molecular subgroup of SN, beside HRAS or KRAS‐related SN, and expand the spectrum of mosaic skin conditions associated with receptor tyrosine kinase mutations.     

Dysplastic naevus in non-familial melanoma. A clinicopathological study of 101 cases

In 101 patients with non-familial cutaneous melanoma (CM), melanocytic naevi were counted and classified according to clinical criteria. Only 8% of the patients had very atypical naevi. These atypical naevi were few in number and only one patient exhibited dysplastic naevus syndrome. An histological study was undertaken on the hypothesis that, in a given individual, if the most clinically atypical naevus is not histologically dysplastic it is unlikely that any of the others are. The most clinically atypical naevus in each patient was biopsied. Estimated in this way the prevalence of dysplastic naevi in patients with non-familial CM was only 18%. Comparison of patients with and without dysplastic naevi did not suggest that they constituted two different subsets. An attempt to correlate clinical diagnosis and histological features in this group of patients showed that the diagnosis of dysplastic naevi on the basis of clinical criteria alone is difficult and not reliable.     

Absence of clinical and dermoscopic differences between congenital and noncongenital melanocytic naevi in a cohort of 2-year-old children

Background Congenital melanocytic naevi (CMN) are present at birth. Some naevi, tardive congenital naevi (TCN), become clinically apparent only after birth, during the first years of life. The number of naevi continues to increase due to the appearance of acquired melanocytic naevi (AMN). When AMN begin to appear has not been well defined. Objectives To investigate the clinical and dermoscopic features of the melanocytic naevi present in 2‐year‐old children and to search for and highlight any differences between CMN present at birth (BPN) and naevi appearing after birth during the first 2 years of life (FLN). Methods A nonrandomized observational study was performed. A total of 133 melanocytic naevi in 103 children aged 21–26 months were analysed by clinical and dermoscopic examination. Results Of the subjects, 76% of children had one naevus, 20% had two naevi, 3% had three naevi and 1% had four naevi. Of the naevi, 76 were BPN and 57 were FLN. The naevi with the largest diameters were significantly associated with BPN (P = 0·025). Polycyclic edges (P = 0·0378) were observed with a higher frequency in BPN than in FLN. The predominant dermoscopic patterns were globular (BPN 51%; FLN 58%) and reticular (BPN 28%; FLN 14%). Conclusions The number of naevi present in the first 2 years of life is small, and over half have already appeared at birth. They are distributed widely over the skin. BPN are larger than FLN, but most naevi are small. There was no significant difference in the dermoscopic features between the 133 BPN and FLN. The predominant patterns were globular and reticular. We could not identify defined criteria that allowed us to diagnose CMN with certainty and distinguish them from TCN and AMN.     

Dermoscopic naevus patterns in people at high versus moderate/low melanoma risk in Queensland

Introduction: Dermoscopic understanding of naevus characteristics is essential baseline knowledge for identifying early malignant changes. Method: This cross‐sectional study includes 34 patients (56% female, mean age 48 years) at high risk of melanoma (personal or a first degree family member with history of melanoma) and 31 moderate/low melanoma risk volunteers (55% female, mean age 37 years) recruited at the Princess Alexandra Hospital, Brisbane, between October 2009 and March 2010. Participants received full body and individual dermoscopic imaging of clinically significant naevi (≥2 mm on the back of male/female and lower limbs of female and ≥5 mm at other body sites). Dermoscopic patterns of naevi were compared between people at high versus moderate/low melanoma risk according to age and body site. Results: In both high and moderate/low risk groups, globular naevi predominated on the head/neck and abdomen/chest, reticular and non‐specific naevi on the back, and non‐specific pattern on the upper and lower limbs. Non‐specific naevi were the most common in all age groups. In both risk groups, globular naevi were more frequent in the younger age bracket, and reticular naevi were more frequent in the older age bracket. Mixed naevus patterns were infrequent and were more common in the younger age brackets of both risk groups. Conclusion: Our preliminary data shows that dermoscopic naevus patterns were similar for age and body site in people at different levels of melanoma risk, suggesting high melanoma risk does not influence dermoscopic naevus patterns.     

Epibulbar complex choristoma and hemimegalencephaly in linear sebaceous naevus syndrome

Epidermal naevus syndrome is a group of congenital syndromes comprising epidermal naevi associated with a variety of developmental abnormalities of the ocular, nervous, skeletal, cardiovascular and urogenital systems. We describe a case of an 8‐month‐old boy with a brown alopecic plaque on his face and scalp and a vascularized epibulbar mass involving the entire cornea, which had been present since birth. Histopathological examination identified sebaceous naevus in combination with complex choristoma. Magnetic resonance imaging of the brain showed hemimegalencephaly.     

Immunological associations of the halo naevus with cutaneous malignant melanoma

Antibodies against the cytoplasm of malignant melanoma cells have been found formerly to be circulating in our patients with primary malignant melanoma before metastases had developed. We have found now this same antibody in fifteen patients with resolving halo naevi. It disappears once resolution of the naevus is complete or after a solitary active halo naevus has been excised. However, cytoplasmic antibody has not been detected in the serum of any other patients with cutaneous pigmentary disorders: including fifty-six with various pigmented tumours or naevi, many of them referred to us as suspected malignant melanoma; forty-seven with vitiligo unassociated with halo naevi; and six with benign juvenile melanoma. We postulate that:

• 1 Halo naevus represents an accelerated and successful rejection phase of a pigmented mole developing malignant change.
• 2 There are at least two aetiological types of vitiligo, the common variety and another one associated specifically with halo naevus, perhaps initiated by the same immunological stimulus or its sequelae.
• 3 Juvenile (benign) melanoma is not related immunologically to malignant melanoma.

     

Teaching non-specialist health care professionals how to identify the atypical mole syndrome phenotype: a multinational study

The atypical mole syndrome (AMS) phenotype is the strongest known risk factor for cutaneous melanoma but recognition of the phenotype has been claimed to be problematic and to require specialist assessment. This study determined the ability of previously unskilled doctors and nurses in five countries to recognize the phenotype after brief training. The system used was the AMS scoring system. This incorporates melanocytic naevus counts, clinical atypia of naevi and distribution of naevi. The agreement in scoring between the dermatologist and trained personnel was determined in 986 patients; overall agreement in diagnosis was 94.5% (kappa 0.70, P < 0.0001). The kappa scores in different countries ranged from 0.65 to 0.77 for individual naevus characteristics, indicative of good agreement. Accurate diagnosis of the atypical mole syndrome phenotype is possible by non-specialists. This has implications for collaborative studies of naevi, for screening and for both primary and secondary prevention of melanoma.     

Divided nevus--an embryological experiment of nature

A "divided naevus" (or "kissing naevus") is defined as a congenital melanocytic naevus that occurs on adjacent parts of the upper and lower eyelid and may give the appearance of a single lesion when the eye is closed. We report on four cases of this rare naevus. Two of these were examined histologically and showed the features of compound naevi. The unique occurrence in nature of the divided naevus allows conclusions on the site and time of origin not only of the divided naevus, but possibly also of other congenital melanocytic naevi. The divided naevus must originate at the latest during the period of lid fusion, between the 9th and 20th week of gestation. The fact that the fusion involves only epithelial tissue suggests an epithelial origin of congenital melanocytic naevi, which may later develop secondarily into compound or intradermal naevi by way of "dropping-off".     

Effect of narrowband ultraviolet B phototherapy on melanocytic naevi

Background Melanocytic naevi have been observed to undergo morphological changes following exposure to narrowband ultraviolet (NB‐UV)B radiation. Objectives To analyse changes in naevi exposed to NB‐UVB in a large cohort of patients. Methods Subjects referred for phototherapy had macroscopic and dermoscopic images taken of prominent melanocytic naevi at the following time points: immediately prior to NB‐UVB treatment, after 10 exposures, after 30 exposures or at the end of treatment if earlier, and 3 months after discontinuing treatment. Four dermatologists, by consensus, examined each naevus for specific clinical and dermoscopic features at each time point. The size (area) of each naevus was determined by plenimetry. Results Complete sets of images were taken for 36 out of 51 patients. The most common global dermoscopic patterns in the 440 naevi examined were reticular (50%) and globular (32%). Following NB‐UVB exposure, blurring or merging of lines was observed in 45% of reticular naevi. An increase in colour intensity and in the number of dots or globules was observed in 63% of globular naevi, and 167 naevi (40%) underwent a change in size. Of these, 91/167 (54%) decreased in size, with a median area reduction of 8% (0·9–42%); while 76/167 (46%) increased in size, with a median area increase of 9% (1–76%). Conclusions Around half of naevi exposed to a course of NB‐UVB treatment undergo size or morphological changes. Naevi that enlarged tended to revert to pretreatment size 3 months after discontinuation of phototherapy.     

Frequency and distribution pattern of melanocytic naevi in Estonian children and the influence of atopic dermatitis

BACKGROUND: There is a strong correlation between naevus number and prospective melanoma risk. Melanoma is one of the most rapidly increasing cancers in Estonia and primary prevention programmes for melanoma that target risk behaviour in the sun have so far not been launched. METHODS: The naevus profile was examined in 549/700 9-year-old Estonian children (282 boys and 267 girls) and the presence of active atopic dermatitis (AD) was registered. RESULTS: There was a wide range of naevi (4-121) and a median total body count of 26. There was no difference in naevus count between boys and girls. No dysplastic naevi were found. Thirty-nine of 549 children (7%) had at least one lesion clinically diagnosed as a congenital naevus. Boys had more naevi on the face (median 4) and trunk (median 12) than girls (median 3 and 9, respectively, P < 0.001). Girls had more naevi on the legs compared with boys (median 4 and 3, respectively, P < 0.01). Fifty-four out of 549 (9.8%) had naevi on the palms and 18/549 (3.3%) on the soles. Children with fair skin, freckles and light hair and eye colours had significantly more naevi than those with darker colours. Thirty-one of 549 (6%) children had AD diagnosed on the examination day and they had a lower total naevus count (median 20) compared with children with no AD (median 27, n = 518, P < 0.05). CONCLUSIONS: The naevus situation in Estonian children today might constitute a starting point for evaluating the efficiency of coming preventive measures as a change of naevus number in children might serve as an early marker for a change in melanoma incidence.