Phacomatosis Pigmentokeratotica: a Further Case Without Extracutaneous Anomalies and Review of the Condition

Pediatric Dermatology Vol. 28 No. 6 715–719, 2011

Phacomatosis Pigmentokeratotica: A Further Case without Extracutaneous Anomalies and Review of the Condition

Rattanavalai Chantorn, M.D.,*, and Tor Shwayder, M.D.

*Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok Thailand, Department of Dermatology, Henry Ford Hospital, Detroit, Michigan

Abstract: Epidermal nevus syndrome is the term for the association of an epidermal nevus and extracutaneous anomalies, including neurologic, ophthalmic, and skeletal defects. Epidermal nevus syndromes include different disorders that share the feature of mosaicism. Phacomatosis pigmentokeratotica (PPK) is a distinctive new epidermal nevus syndrome ﬁrst described in 1996 characterized by the presence of multiple organoid nevi with sebaceous differentiation, a speckled lentiginous nevus, and skeletal and neurologic abnormalities. Only a handful of cases of PPK without extracutaneous manifestations have been reported. We report here an individual with PPK with only cutaneous signs and conﬁrm this distinctive syndrome has two subtypes according to the presence or absence of extracutaneous involvement.

Happle et al (1) first proposed the term ‘‘phacoma- reported. Approximately 30 cases of PPK have been tosis pigmentokeratotica’’ (PPK), which is characterized reported. Seven of all reported cases have no systemic by the cooccurrence of organoid nevus with sebaceous abnormalities described (5–8). We report an 18-year-old differentiation arranged along Blaschko’s lines, and woman with unilateral papular nevus spilus with Spit- speckled lentiginous nevus (SLN) of the papular type zoid features associated with ipsilateral congenital nevus (papular nevus spilus) arranged in a checkerboard pat- sebaceous and contralateral linear epidermal nevus. tern (2). Phacomatosis pigmentokeratotica is divided There have not been extracutaneous anomalies or into two subgroups according to the presence or absence malignant transformation detected during our 18-year of extracutaneous involvements. Happle (3) explained follow-up of this patient. that this syndrome represented an example of the genetic mechanism didymosis, or twin spotting. The two com- CASE REPORT ponents of this twin spot phenomenon have been iden- tified as Schimmelpennning syndrome and SLN A healthy 18-year-old white woman was born with a syndrome. The occurrence of a neoplasm arising in nevus giant yellow–orange plaque involving the left side of her sebaceous such as basal cell carcinoma (4) and papular scalp and face extending to the ear and posterior neck nevus spilus such as malignant melanoma (4) has been (Fig. 1), along with involvement of the right side of her

Address correspondence to Tor Shwayder, M.D., Director, Department of Dermatology, Henry Ford Hospital, Detroit MI 48202, or e-mail: [email protected].

DOI: 10.1111/j.1525-1470.2011.01655.x

2011 Wiley Periodicals, Inc. 715 716 Pediatric Dermatology Vol. 28 No. 6 November ⁄ December 2011 tongue (Fig. 2). Biopsy of the occiput at age 26 days compatible with epidermal nevus with sebaceous differ- demonstrated compact hyperkeratosis, mild acanthosis, entiation. She also had a few spots of brownish papules and spongiosis in epidermis. The underlying dermis on her left shoulder noted when she was 2 years old. She showed scattered small but mature-appearing sebaceous has had numerous operations involving staged excisions lobules. These findings were consistent with nevus seba- of nevus sebaceous on her scalp as well as tissue ceous. At 15 months of age, biopsies of the scalp, fore- expanders over the first few years of life. This patient was head, preauricular area, and neck (from an outside lost to follow-up and return to the dermatology clinic dermatologist) revealed epidermal verrucous hyperplasia when she was 13 years old. Over the past several years, with acanthosis and papillomatosis; focal hyperplasia of numerous scattered asymptomatic spots have developed the sebaceous glands was also noted. These biopsies were over her left upper back, shoulder, arm, and dorsal hand. These spots have been in different in size and color. She has been otherwise healthy. No systemic involvement has been detected so far. Physical examination disclosed a large confluent brown verrucous plaque with waxy filiform projections on the entire surface of the left ear and in the postauric- ular area and upper neck region (Fig. 3A and B). In a confluent distribution involving the left upper midback all the way down her left shoulder and her left arm and dorsal hand are multiple well-circumscribed, scattered brown macules and papules, together with some scattered pink–red and blue papules (Fig. 4A and B). Under a Wood’s lamp, examination of the left upper back revealed a subtle hyperpigmented background with over- lying speckled brown and black dots clinically consistent with a SLN of the papular type. These are ipsilateral to the nevus sebaceous. Extending to the midline on the patient’s chest is a linear cluster of brown verrucous Figure 1. The patient at 6 months old. Note giant yellow– orange plaque involving the left side of her scalp and face papules. On the right side of the tongue, there are irreg- extending to the ear and posterior neck. ularplaquesthesamecolorashertonguethatend directly at the midline. Ocular, skeletal, and neurologic examinations are all normal. At the follow-up visits, biopsies were done on some different morphologic pigmented lesions (red papule, red–blue papule, and blue papule) diagnosed as Spitz nevus and compound and intradermal nevus with Spit- zoid features (Fig. 5). Basically for aesthetic reasons the patient underwent surgery of multiple sites. The scalp had multiple staged excisions which was complicated by wound separation and scar formation. The plastic sur- geons also tried Candela V-beam laser treatment of the epidermal nevus with some improvement. She has been monitored for extracutaneous manifestations and malignant transformation of the remaining nevus sebaceous and SLN.

DISCUSSION The association of a SLN and nevus sebaceous is a diagnostic clue tp PPK (9). This distinctive syndrome hasbeenhypothesizedtobeduetoso-calleddidymosis, also known as the twin spot phenomenon. Half of PPK Figure 2. Irregular plaque on the right side of her tongue. would be Schimmelpenning syndrome, and the other Chantorn et al: PPK without Extracutaneous Anomalies 717

Figure 3. (A) Fourteen years old. Note nevus sebaceous around the ear, epidermal nevus along the sternum, and multiple acquired and Spitz nevi on pigmented base on the left shoulder and arm. (B) Eighteen years old. Note the remaining epidermal nevus with sebaceous differentiation and papular nevus spilus.

A B

Figure 4. (A) Fourteen years old. Multiple scattered brown, pink–red, and blue macules and papules over the left shoulder and upper midback. (B) Eighteen years old. Note marked increase in number of unusual nevi.

half would be SLN syndrome. The twin-spotting phenomenon is a well-known mechanism extensively studied in plants and animals and recently proposed to occur in human skin. It has been hypothesized that cooccurrence of the two different nevi represents this twin spotting. These twin spots are paired patches of mutant tissue that are dissimilar from each other and from the background tissue (1). To impute ‘‘twin spotting,’’ it is necessary for the two different recessive mutations to be located on the same chromosome. The chromosomes bearing these loci would then be exchanged through somatic crossing over in the early stages of embryo- genesis, giving rise to two different homologous daughter cells that evolve into two different mosaic lesions (3). In addition to PPK, this phenomenon is hypothesized to be a genetic mechanism in vascular Figure 5. Biopsy from left arm papule at 13 showing sym- twin nevi and phacomatosis pigmentovascularis. metric nests of vertically oriented melanocytic cells with minimal atypia in the epidermis and superficial dermis con- Schimmelpenning syndrome is defined as the asso- sistent with compound nevus with Spitzoid features. ciation of the linear nevus sebaceous arranged along the 718 Pediatric Dermatology Vol. 28 No. 6 November ⁄ December 2011

Blaschko lines and extracutaneous involvement. This logram, and hypophosphatemic vitamin D–resistant syndrome can be variable in symptoms and extracuta- rickets (1,2,6,9). Happle et al reported the significant neous manifestations. The common extracutaneous associations between PPK and urologic, renal, and vas- features include skeletal defects, neurologic defects such cular defects (12). Three cases of PPK have been reported as hemimegalencephaly with contralateral motor dis- associated with arterial hypertension (12–14). Extrinsic ease, and ocular abnormalities, including coloboma and compression of the renal artery by a spinal root tumor epibulbar lipodermoid (9). Skeletal defects in this syn- caused one (13), one resulted from aortic stenosis and drome include bone cysts, kyphosis and scoliosis, foot renal artery stenosis (14), and the other one is from and hand deformities, craniofacial defects, dislocation spindly renal artery (12). Skin and internal malignancies of hip hemihypertrophy, and vitamin D–resistant are considered a risk in PPK. These often occur on the rickets (9,10). Ocular anomalies include coloboma, skin and included basal cell carcinoma and malignant lipodermoid of the conjunctiva, nystagmus, corneal melanoma (4,5), although extracutaneous neoplasms opacity, defects of the optic nerve, and cortical blindness have been described, such as subcutaneous rhabdo- (9,10). Additional neurologic features are mental and myosarcoma (15) and pheochromocytoma (12). In cognitive deficiency; seizure; hydrocephalus; Dandy- addition, urologic and renal abnormalities have been Walker malformation; dysplasia of brain vessels; agen- reported, including rhabdomyosarcoma of the bladder esis of the corpus callosum; cerebral heterotropia; and and nephroblastoma (12). cortical agyria, microgyria, or pachygyria (9,10). One difference between PPK and Schimmelpenning Happle (10) has recently described sSLN syndrome, syndrome, is that coloboma and epibulbar lipodermoid which is defined as a SLN and ipsilateral neurological are observed in Schimmelpenning syndrome and not in defects. SLN, or nevus spilus, consists of a cafe´-au-lait PPK (9). The epidermal nevi with sebaceous differenti- macule with multiple dark brown or black dots that ation in PPK have greater potential to develop true basal represent macular or papular proliferations of melano- cell carcinoma than in Schimmelpenning syndrome (9). cytes superimposed (10). It has been proposed that it be Furthermore, PPK cases appear to develop hypophos- further categorized into two subtypes: macular and phatemic vitamin D–resistant rickets at a higher rate papular (11). Papular SLN may occur as an isolated than observed in Schimmelpenning syndrome (9). lesion or as a component of PPK, whereas macular SLN In summary, we have reported another case of a rare may occur as an isolated birthmark or as a component distinct epidermal nevus syndrome,calledPPK,andwe of phacomatosis pigmentovascularis type III (phaco- hope that other physicians will recognize this unusual matosis spilorosea). Neurologic abnormalities associated syndrome. Our patient thus far had no extracutaneous with SLN syndrome are hyperhidrosis, muscular weak- features or malignant degeneration, however, extracu- ness, dysesthesia, sensory and motor neuropathy, nerve taneous involvements reported in the literature indicate palsy with thinning of nerves, and spinal muscular that we should monitor such patients carefully. Because atrophy with fasciculation (10). of significant association of neurologic, renal, and vas- Phacomatosis pigmentokeratotica is a distinct type of cular abnormalities in PPK, complete physical exami- epidermal nevus syndrome. Because most of these syn- nation including blood pressure monitoring and dromes occur sporadically, Happle suggested that they neurologic examinations should be done, and investiga- reflect mosaicism generated by lethal genes that survive tions performed if further abnormalities are detected. in a mosaic state only (3). PPK is limited to the skin or associated with extracutaneous abnormalities. The REFERENCES pattern of extracutaneous anomalies reported in PPK represents the variable features of Schimmelpenning 1. Happle R, Hoffmann R, Restano L et al. Phacomatosis syndrome SLN syndrome. In particular, neurologic de- pigmentokeratotica: a melanocytic-epidermal twin nevus syndrome. Am J Med Genet 1996;65:363–365. fects appear to be a typical component of this syndrome, 2. Tadini G, Restano L, Gonzales-Perez R et al. Phacoma- and can in some cases develop later in life. The major tosis pigmentokeratotica: report of new cases and further neurologic abnormalities in PPK are mental deficiency, delineation of the syndrome. Arch Dermatol 1998;134: seizures, hemiparesis, hyperhidrosis, cutaneous 333–337. dysesthesia, muscular weakness, sensory neuropathy, 3. Happle R. Mosaicism in human skin. Understanding the patterns and mechanisms. Arch Dermatol 1993;129:1460– and motor neuropathy. Additional extracutaneous 1470. presentations have been reported in the literature, such as 4. Martinez-Menchon T, Mahiques Santos L, Vilata Corell JJ ptosis, strabismus, congenital glaucoma, esotropia, et al. Phacomatosis pigmentokeratotica: a 20-year follow- conductive hearing loss, facial dysmorphism, hemiatro- up with malignant degeneration of both nevus compo- phy, kyphosis and scoliosis, abnormal electroencepha- nents. Pediatr Dermatol 2005;22:44–47. Chantorn et al: PPK without Extracutaneous Anomalies 719

5. Hermes B, Cremer B, Happle R et al. Phacomatosis 11. Vidaurri-de la Cruz H, Happle R. Two distinct types of pigmentokeratotica: a patient with the rare melanocytic- speckled lentiginous nevi characterized by macular versus epidermal twin nevus syndrome. Dermatology 1997;194: papular speckles. Dermatology 2006;212:53–58. 77–79. 12. Jacobelli S, Leclerc-Mercier S, Salomon R et al. Phacoma- 6. Wollenberg A, Butnaru C, Oppel T. Phacomatosis pig- tosis pigmentokeratotica with nephroblastoma and juve- mentokeratotica (Happle) in a 23-year-old man. Acta nile hypertension. Acta Derm Venereol 2010;90:279–282. Derm Venereol 2002;82:55–57. 13. Okada E, Tamura A, Ishikawa O. Phacomatosis pigmen- 7. Kinoshita K, Shinkai H, Utani A. Phacomatosis pigmentokeratotica complicated with juvenile onset hypertension. tokeratotica without extracutaneous abnormalities. Der- Acta Derm Venereol 2004;84:397–398. matology 2003;207:415–416. 14. Boente Mdel C, Asial RA, Happle R. Phacomatosis 8. Polat M, Yalcin B, Ustun H et al. Phacomatosis pigmen- pigmentokeratotica: a follow-up report documenting addi- tokeratotica without extracutaneous abnormailities. Eur J tional cutaneous and extracutaneous anomalies. Pediatr Dermatol 2008;18:363–364. Dermatol 2008;25:76–80. 9. Happle R. The group of epidermal nevus syndromes Part I. 15. Gruson LM, Orlow SJ, Schaﬀer JV. Phacomatosis pig- Well deﬁned phenotypes. J Am Acad Dermatol 2010;63:1– mentokeratotica associated with hemihypertrophy and a 22; quiz 3–4. rhabdomyosarcoma of the abdominal wall. J Am Acad 10. Happle R. Speckled lentiginous nevus syndrome: delinea- Dermatol 2006;55(2 Suppl):S16–S20. tion of a new distinct neurocutaneous phenotype. Eur J Dermatol 2002;12:133–135.