Phacomatosis pigmentokeratotica: another epidermal nevus syndrome and a distinctive type of twin spotting

ARTICLE

Epidermal nevi are mosaic lesions reflecting an abnormal ectodermal embryonic development with excess or deficiency of the normal mature cutaneous tissue elements, which are either present at birth or develop in postnatal life [1]. They are named according to the predominant histological constituents (sebaceous, verrucous, follicular, etc.). Their histological classification is important because they may show various components in the same nevus or in different parts of the body, and they may herald different clinical entities (Proteus syndrome, sebaceous nevus syndrome, CHILD syndrome, etc.) [2, 3].

The term "epidermal nevus syndrome" denotes the association of an epidermal nevus with anomalies such as neurological, ophthalmological, and skeletal defects. It was considered one single entity in the past [4], but in recent years it has been generally recognized that there is no such clinical entity as "the epidermal nevus syndrome". In fact, this denomination can be applied to a group of several distinct phenotypes [2, 5]. As most of these syndromes occur sporadically, Happle suggested that they reflect mosaicism produced by lethal genes that survive in a mosaic state only [6]. Based on clinical, histological and genetic criteria Happle considered that the group of epidermal nevus syndromes includes several diseases that differ in genetic origin but share the common feature of mosaicism [2]. To this list he added another one, based on a case described by Tadini et al, and explained it by the genetic mechanism of twin spotting [5, 7, 8].

We here describe three additional cases of phacomatosis pigmentokeratotica.

Case 1

A 9-year-old boy presented with numerous pigmented nevi that had increased in size and number since birth. He was born at term by spontaneous delivery after an uneventful pregnancy, from healthy unrelated parents.

Physical examination disclosed, on the left side of his body, verrucous lesions of a sebaceous nevus following the Blaschko lines in a type Ib pattern of rather broad bands. The sebaceous component was prominent on the left half of the scalp and face, whereas rather verrucous lesions were noted on the left side of the trunk and the left arm (Figs. 1, 2, 3). In addition, a large speckled lentiginous nevus involved the left dorsal area, the left half of the abdomen, and the left arm. This nevus was arranged in a type II mosaic pattern (checkerboard pattern) (Figs. 1, 2). Moreover the boy presented two collagen nevi localized on the chin and in the right lumbar area (Fig. 3). In the left scapular area, a telangiectatic nevoid area intermingling the speckled lentiginous nevus was noted. Additionally, a patch of excessive hyperhidrosis was clinically evident in the lumbar area on the left side. This anomaly was confirmed by means of an iodine-starch test.

A biopsy obtained from the verrucous nevus involving the neck showed orthohyperkeratosis, acanthosis with a rather broad granular layer, and papillomatosis. A biopsy of one of the papular lesions of the speckled lentiginous nevus disclosed a compound melanocytic nevus. Histopathological examination of the collagen nevus involving the lumbar area showed homogenization and increased amounts of mature collagen in the upper dermis.

During the follow up the patient presented a generalized ichthyosiform eruption that was treated with a lactic acid cream and cleared within a few weeks.

On general examination hemiatrophy of the left body side was recognized. Neurological examination revealed no abnormalities. The psychomotor development was according to his age. Ophthalmological examination yielded normal results. Endocrinological evaluation, performed because of increased body weight, disclosed slight hypothyroidism.

At age 11, the number of small heavily pigmented nevi had increased within the café-au-lait macula, and the already present melanocytic nevi had increased in size but did not show clinical or dermatoscopic features of melanocytic dysplasia. No other physical or developmental anomalies were noted, with the exception of slight hyperalgesia of the hyperpigmented areas.

Case 2

A 9-year-old boy showed macular and hyperkeratotic lesions present since birth on his face and trunk. He was born at term after an uncomplicated pregnancy. His parents were non-consanguineous and his family history was non contributory.

The hyperkeratotic lesions were light brown on the face and followed the Blaschko lines on the left side from the parietal and frontal region to the nose, the cheek, the upper lip, and the neck. The oral mucosa including the palate of the same side were likewise affected, resulting in an anomalous dentition on this side. The ocular conjunctiva and the iris of the left eye were involved by this nevus to such a degree that this eye was blind. On the neck, a medial linear dark-brown, hyperkeratotic lesion was noted
(Figs. 4, 5).

Histopathological examination of the lesions on the face and the neck revealed an organoid epidermal nevus with sebaceous differentiation.

A surgical approach to remove part of the facial lesion resulted in a hypertrophic scar.

On the left shoulder and the ipsilateral part of the pre-sternal region, a macular light pigmented lesion was present. This lesion extended to the right side of the body and was arranged in a checkerboard pattern. Within this macular area numerous pigmented melanocytic nevi were noted.

The remaining physical examination revealed left-sided scoliosis. Gastritis with the presence of Helicobacter pylori was also found.

Case 3

A 4 year-old boy presented with a systematized organoid nevus with sebaceous differentiation and a speckled lentiginous nevus. He also had fragile X syndrome. He was born at term from nonconsanguineous parents, and his sister had fragile X syndrome.

The organoid nevus involved the scalp, the neck, the right extremities and the right side of the trunk, stopping at the midline and following the Blaschko lines (Fig. 6).

The speckled lentiginous nevus consisting of a large pigmented macule with scattered dark brown macules and papules involving both sides of the trunk in a checkerboard pattern (Fig. 6).

A biopsy specimen from the occipital region showed an organoid nevus with sebaceous differentiation.

The boy had a mild intellectual deficit. His karyotype showed a fragile X chromosome.

Discussion

The term phacomatosis pigmentokeratotica was proposed by R. Happle [5] to delineate a distinct type of epidermal nevus syndrome characterized by the presence of an organoid epidermal nevus and a speckled lentiginous nevus of the papular type. In most cases so far, the two different nevi were localized on both sides of the body. Two of the present cases, however, showed an ipsilateral involvement.

Happle explained this type of epidermal nevus syndrome by the genetic mechanism of twin spotting [6].

Twin spotting is a well recognized mechanism extensively studied in plants and animals and used to test chemicals for their mutagenic or recombinogenic activity [5, 9-12], and recently proposed as also occurring in human skin
[6, 13]. The twin-spotting phenomenon requires an organism heterozygous for two different recessive mutations. These genes may be localized at different regions on either of a pair of homologous chromosomes. The segments bearing these loci are exchanged by somatic recombination at an early stage of development giving rise to two homozygous daughter cells, representing the stem cells of two different cell populations that generate two mosaic patches [6, 7, 13, 14]. Therefore, twin spots can be defined as paired patches of mutant tissue that differ from each other and from the background tissue [5]. The aforementioned hypothesis would explain not only the vascular twin nevi [13] but also the co-occurrence of an epidermal organoid nevus and a specked lentiginous nevus of the papular type, as well as other nevoid skin lesions that occur close together (unilateral nevoid telangiectasia and ipsilateral Becker's nevus, unilateral eruptive psoriasis and contralateral lichen striatus) [5, 6, 13-16].

In two of the present cases the twinned nevi involved the same side of the body, and this may be best explained by the assumption that the underlying event of somatic crossing-over occurred in a somewhat later stage of embryogenesis. All of the cases of phacomatosis pigmentokeratotica observed so far have been sporadic and, therefore, at least one of the two underlying genes might represent a lethal mutation surviving by mosaicism [5, 8, 23]. In the third case the specked-lentiginous nevus involved both sides of the body, but the organoid epidermal nevus was found on one side only. In all of these cases, as well as in previously reported ones, the organoid nevus followed the Blaschko lines and the speckled lentiginous nevus was arranged in a checkerboard pattern [7, 8].

The co-occurrence of an epidermal nevus of the non-epidermolytic, organoid type and a speckled lentiginous nevus of the papular type in the same patient has been described previously under various names [7, 17-22]. The term phacomatosis pigmentokeratotica, coined by Happle in analogy to phacomatosis pigmentovascularis, indicates a twin-spotting phenomenon comprising an organoid epidermal nevus and a speckled lentiginous nevus of the papular type.

The presence of a vascular spot, as in the first and second cases, has been previously mentioned by Tadini et al [7]; in the first case two collagenous nevi were likewise present. A diffuse ichthyosiform hyperkeratosis symmetrically affecting the entire body was described by Tadini et al [7]. In our first case a similar ichthyosiform condition was noted as a temporary phenomenon only present at one of the first visits.

Neurological, ophthalmological and skeletal abnormalities were previously described in this syndrome [7, 8, 17, 20-22]. The most consistently reported anomaly was hemiatrophy. In our first case, bony asymmetry caused by ipsilateral hemiatrophy was observed. The second child showed ocular involvement by the organoid nevus. In the third case, the presence of fragile X syndrome should be taken as an incidental finding.

In summary, these distinctive cases provide further evidence that paired mosaic lesions in human skin could represent a human twin spot phenomenon. This concept helps us understand other nevoid skin lesions that occur close together. In particular, the delineation of phacomatosis pigmentokeratotica lends support to the notion that the epidermal syndromes represent different mosaic phenotypes originating from different genetic mechanisms. The follow-up of a patient with phacomatosis pigmentokeratotica is important because of a possible later onset of neurological alterations; we must also bear in mind the possibility of cancer development in these patients.

Article accepted on 20/12/99

CONCLUSION

Acknowledgement

We appreciate the assistance of Dr. Rudolf Happle who helped us to better understand this new entity.

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