To define the spectrum of pigmentary mosaicism more accurately and to map the correlation with extracutaneous manifestations, we retrospectively reviewed literature detailing 651 patients with pigmentary mosaicism. Importantly, we found that the clinical picture of pigmentary mosaicism and the medical terms used to describe it are variable. In the literature, including recent articles, a wide range of terms, e.g. LWNH, HI, incontinentia pigmenti achromians, nevus depigmentosus, achromic nevus, and segmental pigmentation disorder are used, and these multiple terms foster unnecessary confusion and ambiguity, as they in fact all describe the same clinically heterogeneous condition. Therefore, as Happle et al. states, these expressions should be avoided since they erroneously indicate nosological entities [
5]. Adding to further confusion, the definitions of these terms seem to vary depending on the author. Patients with coexisting hyper- and hypopigmented skin may be referred to as cutis tricolor, a term introduced by Happle et al. [
84]. Lipsker et al. suggested the term cutis bicolor in patients with two shades of colour [
73], but as this term does not indicate the type of pigmentation anomaly, we recommend using the more specific terms hyperpigmentation and hypopigmentation.
Cases
The gender composition in our study was almost equal: 46% were male and 54% were female. Similar results have been observed in other studies [
86].
Forty-three percent exhibited hyperpigmentation, 50% exhibited hypopigmentation, and 7% exhibited a combination of hyper- and hypopigmentation. The low percentage of patients exhibiting both hyper- and hypopigmentation was expected, as this requires three pigmentarily different cell lines, as opposed to only two in patients exhibiting either hyper- or hypopigmentation.
The distribution of the dyspigmentation was primarily Blaschkoid (79%) and occurred on all parts of the body. In practice, the patterns can be difficult to distinguish, as reported by Hansen et al. [
32]. We must keep in mind that different authors might classify a given pigmentation pattern differently, and based on this, biased results are possible. In most cases however, the pigmentation pattern is clear and the classification is straightforward. Furthermore, in doubtful cases it was possible to verify the classification by the clinical photos provided in most articles.
Our study showed that the abnormal pigmentation was noted within the first year of life in 282 (75%) of the patients. However, this percentage might not be accurate, as it can be difficult to determine the exact time of presentation of the dyspigmentation, e.g. in very light skinned Caucasians where a hypopigmented anomaly can go unnoticed in the first years of life. Additionally, in many studies the dermatologists saw the patients later in life, where parents reported the age at onset based on their memory.
Most frequently, pigmentary mosaicism appears sporadically, but a family history of the condition was described in 4% of the reported cases. A rare case of two paternal half-brothers with pigmentary mosaicism of the hyperpigmented type was reported [
26]. A chromosomal mosaicism with a partial duplication of chromosome 3p was demonstrated in two different tissues from one patient, whereas the lymphocytes of the other patient did not show the chromosomal anomaly and therefore no common cause for the pigmentary mosaicism was found. A family with LWNH in three successive generations has also been reported: a 12-year-old girl, the 45-year-old mother, and the 65-year-old grandmother [
19]. Only chromosome analysis was performed and here again, no possible common genetic cause was identified.
In this review a strikingly high frequency of extracutaneous manifestations (55%) was seen in comparison with other individual reviews, where extracutaneous manifestations were reported in 0, 8 and 30% of the patients [
87‐
89]. Our review revealed a presence of extracutaneous manifestations in 32% of patients with hyperpigmentation, 73% of patients with hypopigmentation, and 83% of patients with combined hyperpigmentation and hypopigmentation. These results differ from findings in previous reviews, where hypopigmentation and hyperpigmentation are found to be associated with extracutaneous manifestations to an equal extent [
87,
90].
The most frequently reported extracutaneous anomalies were skeletal deformities, seizures, mental retardation, dysmorphic facial features, and developmental delay. Regarding these features it is important to bear in mind that the groups of different anomalies should be considered heterogeneous collections of disorders indicating numerous different underlying mosaic states, and not distinct groups of pheno- or genotypes [
5].
Cytogenetic analyses
In this review, cytogenetic analysis was performed in 66% (241 patients) of patients with extracutaneous manifestations and by comparison in only 8% (22 patients) of patients without extracutaneous manifestations. Thirty-two percent of patients without extracutaneous manifestations and 43% of patients with extracutaneous manifestations were found to have abnormal karyotypes. On the basis of the available data, it is not possible to detect significant differences in the presence of chromosomal abnormalities in the two groups (p = 0.320). The remarkable difference in proportion of cytogenetically tested patients depicts a need to change daily practice when handling patients with suspected pigmentary mosaicism. It is also important to test patients without extracutaneous manifestations, as the frequency of abnormal karyotype seems comparable to patients with extracutaneous manifestations. The data represent procedures performed over a period of more than 30 years, and the relevance of the results to the recent dermatologic community can therefore be questioned. However, the tendency to test primarily when extracutaneous manifestations are observed is also seen in more recent studies, which confirms the need for standardization of future handling.
Sixteen percent of the cytogenetically tested patients exhibited non-mosaic structural or numerical abnormalities, and in most of these cases the detected aberration does not in itself explain the pigmentary mosaic. However, in six cases a chromosomal translocation involving chromosome X was seen, and differences in gene expression after X-inactivation of either the normal or the translocated X may explain the pigmentary mosaicism.
The chromosomes involved in the investigated cases of pigmentary mosaicism were: 2, 3, 4, 5, 7, 9, 10, 12, 13, 14, 15, 16, 18, 20, 21, 22, and the sex chromosomes. The wide range of this result confirms the earlier mentioned and important point, that the etiology of pigmentary mosaicism is heterogeneous and complex and should not be considered distinct syndromes despite similarities in the clinical picture.
Based on the literature review, we recommend that fibroblasts obtained from light and dark skin are analysed as well as peripheral blood lymphocytes. Despite following this procedure, failure to detect a chromosomal mosaicism may persist, if the mosaic state is present in neither lymphocytes nor fibroblasts. Taibjee et al. studied 10 patients with pigmentary mosaicism in whom previous karyotyping was negative, and were only able to show cytogenetic abnormalities in keratinocytes in 1 of them [
67]. Apart from the abovementioned reason, another explanation is that the genetic change responsible for the pigmentary mosaicism cannot be visualized at the chromosomal level, but may be anything from a point mutation to a copy number variation too small to detect by standard chromosome analysis [
91]. Finally, the differences in pigmentation may be caused by epigenetic mechanisms.
For therapeutic reasons, it is important to differentiate pigmentary mosaicism from other diagnoses with abnormal pigmentary findings such as incontinentia pigmenti, McCune-Albright syndrome, vitiligo, neurofibromatosis Recklinghausen, piebaldism, and tuberous sclerosis. This, in addition to earlier mentioned reasons, reinforces our recommendation to perform cytogenetic evaluation of peripheral blood lymphocytes and skin fibroblasts in all patients with suspected pigmentary mosaicism. When performing chromosome analysis, a significant number of metaphases from both normal and affected skin should be investigated to ensure detection of even small percentages of abnormal cells and to detect possible cytogenetic variations between the two differently coloured skin types. Though more expensive, a contemporary approach is to perform chromosome micro array analysis on uncultured cells [
4]. When cell culturing is avoided, the selection bias, which is usually in favour of the normal clone, is minimized [
92]. Another strength of this method is the capacity to detect even small deletions or duplications, which cannot be detected by standard chromosome analysis [
93]. On the other hand only abnormal clones of a certain size (usually above 5–10%) can be detected by chromosome micro array. The two approaches have different advantages and may be combined to improve the detection rate of cytogenetic abnormalities in cases of pigmentary mosaicism. Finally, next-generation sequencing (NGS) of the exome or even the genome may be added as the method of choice in the near future [
94], as it gives the ability to detect monogenic causes even in a mosaic state. When further improved, the NGS techniques may even replace chromosome micro array and banding techniques for detection of copy number variations and chromosomal rearrangements.