Familial cutis tricolor: a possible example of paradominant inheritance

ARTICLE

Auteur(s) : Mete BABA¹, Deniz SEÇKIN², Cenk AKÇALI¹, Rudolf HAPPLE³

¹ Başkent University Faculty of Medicine, Department of Dermatology, Adana Hospital, 01250 Adana, Turkey.
² Başkent University Faculty of Medicine, Department of Dermatology, Ankara Hospital, 06490 Ankara, Turkey.
³ University of Marburg Faculty of Medicine, Department of Dermatology, Deutschhausstrasse 9, D-35033, Marburg, Germany

Article accepted on 17/4/2003

In 1997, Happle et al. [1] proposed the term ‘cutis tricolor’ for the presence of congenital hyper- and hypopigmented macules on a background of normal skin. In addition to three different degrees of skin pigmentation, the sporadic case described by these authors was associated with multiple extracutaneous birth defects. Subsequently reported cases of cutis color further expanded the clinical spectrum of this phenomenon [2-4]. This three-color pigmentation most likely represents an example of allelic twin spotting [1, 5].
We report two sisters with cutis tricolor. One of them had in addition a unilateral hypoplasia of the breast, whereas the other lacked any associated abnormalities. To our knowledge, familial cutis tricolor has not been reported previously. Moreover, this is a first report of an association with mammary hypoplasia.

Case report

Case 1

A 15-year-old girl presented with changes in skin color on her trunk and neck which had been present since birth but later became more visible. She was born at term after an uneventful pregnancy to nonconsanguineous healthy parents. Her sister had similar skin changes (see case 2). Her mental and physical development was normal except for left mammary hypoplasia. On physical examination, she had widespread hyper- and hypopigmented macules in close proximity to each other, forming streaks in a bilateral arrangement along the lines of Blaschko with a V-shaped or fountain-like pattern on the back and an S-shaped and partly whorled pattern on the anterior and lateral aspects of the trunk and neck. The remaining skin had an intermediate degree of pigmentation. In addition, she had a marked hypoplasia of the left breast (Fig. 1). There were no other cutaneous or extracutaneous pathological findings.
Biopsies were obtained from hypo- and hyperpigmented areas as well as from an area with intermediate pigmentation. Histopathological examination of sections stained according to Masson-Fontana showed a decreased number of epidermal melanocytes in the hypopigmented area, whereas in the dermis of the hyperpigmented area pigment incontinence and macrophages laden with melanin were noted. No pathological findings were observed in the area with an intermediate pigmentation.
Mammary ultrasonography confirmed pronounced hypoplasia of the left breast.

Case 2

The 12-year-old sister of case 1 had similar congenital changes of skin color. On physical examination, linear hyper- and hypopigmented macules adjacent to each other involved the right side of her back and extended to the abdomen in a pattern following the lines of Blaschko, with a sharp demarcation at the anterior midline (Fig. 2). The remaining skin had an intermediate degree of pigmentation. No other abnormalities were noted.

Discussion

The two cases were categorized as examples of cutis tricolor because of the presence of congenital hyper-and hypopigmented macules on a background of normal skin.
The term ‘cutis tricolor’ was first proposed by Happle et al. [1] to describe a sporadic case of hypo- and hyperpigmented skin segments adjacent to each other and associated with normally pigmented areas, resulting in three different colors. In their patient, the pigmentary anomalies were associated with other birth defects such as dysmorphic facial appearance, severe kyphoscoliosis, delayed motor development, epileptic seizures, and mental retardation. Subsequently, some additional cases of cutis tricolor with or without additional features have been reported. In one of these cases, paired melanotic and achromic macules were part of phacomatosis pigmentovascularis [2]. Ruggieri [3] described cutis tricolor in two children, aged 6 and 11 years. One of them was otherwise healthy, whereas the other one had psychomotor delay, dysmorphic features, musculoskeletal abnormalities and white matter lesions. Furthermore, the phenomenon of cutis tricolor was reported in a case of ataxia-telangiectasia [4]. This case was unusual because of the presence of pigmentary changes in the absence of telangiectasias. In one of our cases, unilateral hypoplasia of breast was present. This association has not been reported in previous cases of cutis tricolor.
Cutis tricolor has tentatively been explained by the mechanism of didymosis or twin spotting [1, 5, 6]. During embryogenesis, two different clones of mutant cells originate from a somatic recombination occurring in a doubly heterozygous embryo. Phenotypically this leads to two different lesions in close proximity to each other on a background of normal skin. The extent of lesions depends on the time of the somatic crossing-over, that is to say, the earlier the event, the larger the area involved. We think that the unusual combination of three different degrees of pigmentation in combination with unilateral hypoplasia of breast in one of our patients reflects genomic mosaicism. Because simple postzygotic de novo mutations alone cannot explain a familial occurrence of cutis tricolor, we hypothesize that our cases may represent an example of paradominant inheritance. Such nonmendelian form of inheritance may imitate an autosomal dominant mode of transmission which is why the term “paradominant” was chosen [7]. Heterozygous individuals are phenotypically normal, and the mutation can therefore be transmitted unperceived through many generations. The trait only becomes manifest when a somatic mutation occurs at an early developmental stage, giving rise to loss of heterozygosity and forming a homozygous or hemizygous population of cells [5, 7]. As a result, the embyo will become a mosaic. Exceptional cases of familial aggregation observed in various mosaic phenotypes that usually occur sporadically have tentatively been explained by paradominant transmission [8-12]. In the present case of familial cutis tricolor, we assume that both of the sisters were doubly heterozygous at the underlying gene locus, and that postzygotic recombination involving this locus occurred in both of them at an early stage of embryogenesis.
Most likely, the unilateral hypoplasia of breast noted in one of these sisters is causally related to her pigmentary disorder. Cutis tricolor apparently does not constitute a clinicogenetic entity but represents a cutaneous phenomenon that may occur in several different states of mosaicism. Until now, a comprehensive inventory of syndromes associated with cutis tricolor is not available because the number of case reports is so far limited. < 

References

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