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Clinical Sciences |

Phacomatosis Pigmentovascularis of Cesioflammea Type in 7 Patients Combination of Ocular Pigmentation (Melanocytosis or Melanosis) and Nevus Flammeus With Risk for Melanoma FREE

Carol L. Shields, MD; Brad E. Kligman, BS; Mayerling Suriano, MD; Vanessa Viloria; Juan C. Iturralde, MD; Margaret V. Shields; Emil A. T. Say, MD; Jerry A. Shields, MD
[+] Author Affiliations

Author Affiliations: Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania.


Arch Ophthalmol. 2011;129(6):746-750. doi:10.1001/archophthalmol.2011.135.
Text Size: A A A
Published online

Objective  To describe the features of phacomatosis pigmentovascularis (cesioflammea type).

Design  Noninterventional retrospective case series composed of 7 patients.

Results  Nevus flammeus combined with ipsilateral ocular melanocytosis or melanosis was seen in all 7 patients. Additional contralateral nevus flammeus was observed in 3 patients. Nevus flammeus (unilateral in 4 patients and bilateral in 3 patients) was distributed in trigeminal nerves V1 (n = 3), V2 (n = 7), and V3 (n = 5). Related findings included diffuse choroidal hemangioma (n = 1) and glaucoma (n = 1), with no patients having brain hemangioma or seizures. Ocular pigmentary abnormalities (unilateral in all 7 patients) included congenital ocular melanocytosis (n = 6) and conjunctival acquired melanosis (n = 1). Pigmentation was sectorial (partial) in 5 patients and complete in 2 patients. Melanocytosis involved the periocular skin in 1 patient, sclera in 2 patients, iris in 2 patients, and choroid in 4 patients. In 3 of 6 patients, melanocytosis was visible in the choroid only on dilated fundus evaluation. Related tumors included choroidal melanoma (n = 3), optic disc melanocytoma (n = 1), and conjunctival melanoma in situ (primary acquired melanosis) (n = 1). Melanoma metastasis developed in 1 patient.

Conclusions  Phacomatosis pigmentovascularis shows features of nevus flammeus and more serious ocular pigmentary abnormalities (uveoscleral melanocytosis and conjunctival melanosis). Melanocytosis may be detected only by dilated ocular fundus examination, as found in 3 of 6 patients. Furthermore, choroidal melanoma can develop from melanocytosis, as noted in 3 of our 6 patients (50%). All patients with nevus flammeus should be examined for phacomatosis pigmentovascularis by an ophthalmologist because ocular melanocytosis and uveal melanoma may remain hidden within the eye.

Figures in this Article

Phacomatosis pigmentovascularis represents the coexistence of a cutaneous vascular malformation (most often nevus flammeus [port-wine stain]) with melanocytic nevus (most often ocular or dermal melanocytosis or both).1 Since phacomatosis pigmentovascularis was first reported in 1947 by Ota et al,2 there have been few clinical series published on this rare condition. In the dermatology literature, Cordisco et al3 described 25 patients, Vidaurri-de la Cruz et al4 identified 24 patients, and Fernández-Guarino et al5 reported on 15 patients. In the ophthalmology literature, Teekhasaenee and Ritch6 described in 1997 a series of 9 patients with phacomatosis pigmentovascularis, some of whom demonstrated related glaucoma. In 2005, Tran and Zografos7 reported 3 cases of phacomatosis pigmentovascularis that were associated with uveal melanoma.

In 2005, Happle8 proposed a reclassification of phacomatosis pigmentovascularis with emphasis on creating relevant descriptive nomenclature rather than using the prior numerical system. The previous cumbersome classification devised in 1947 by Ota et al2 characterized groups I to V, with a and b subdivisions, whereas the revised classification proposed in 2005 by Happle8 categorized 3 groups descriptively as phacomatosis cesioflammea, phacomatosis spilorosea, and phacomatosis cesiomarmorata (Table 1). Herein, we describe 7 patients with phacomatosis cesioflammea, all diagnosed following ocular consultation.

Table Graphic Jump LocationTable 1. Revised Classification of Phacomatosis Pigmentovascularis (PPV)a

Clinical features of the patients with phacomatosis cesioflammea are summarized in Table 2 (Figures 1, 2, and 3). All cases were diagnosed following our ocular examination.

Place holder to copy figure label and caption
Figure 2.

Phacomatosis pigmentovascularis of cesioflammea type with related melanoma. In case 6, a 77-year-old woman with lifelong facial nevus flammeus (A) developed conjunctival primary acquired melanosis (melanoma in situ) (B). In case 2, a 78-year-old man with lifelong facial nevus flammeus (C) developed choroidal melanoma (D). He demonstrated sectorial scleral melanocytosis in the quadrant of the tumor.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Clinical features of phacomatosis pigmentovascularis of cesioflammea type. Case 3 shows prominent bilateral facial nevus flammeus (A) in a Hispanic girl with obvious episcleral and periocular cutaneous melanocytosis (B). Case 4 shows subtle left-sided facial nevus flammeus (C) of the lower cheek region in a boy of white race/ethnicity, previously treated with laser, and subtle choroidal melanocytosis superiorly (D). There was no episcleral or cutaneous melanocytosis. The left pupil appeared red due to an associated choroidal hemangioma that was treated with external beam radiation therapy.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 1.

Case 7. Ocular melanocytosis may be found only in the choroid and may not be visible externally. Bilateral facial nevus flammeus in an infant (A) and 3 years later after laser treatment (B). At that time, dilated ocular examination disclosed choroidal melanocytosis in the right eye (C) but not in the left eye (D).

Graphic Jump Location
Table Graphic Jump LocationTable 2. Clinical Features of Patients With Phacomatosis Cesioflammea
CASE 1

A 48-year-old woman was referred with choroidal melanoma. Mild ipsilateral iris melanocytosis was observed. Long-standing ipsilateral unilateral congenital cutaneous nevus flammeus was noted. Phacomatosis cesioflammea was diagnosed. Melanoma subsequently metastasized to the liver.

CASE 2

A 78-year-old man was referred with choroidal melanoma and vitreous hemorrhage (Figure 3C and D). Minimal scleral melanocytosis was found. Prominent bilateral congenital cutaneous nevus flammeus was noted. Phacomatosis cesioflammea was diagnosed.

CASE 3

A 15-year-old Hispanic girl with prominent bilateral congenital cutaneous nevus flammeus was referred for evaluation (Figure 1A and B). Unilateral oculodermal melanocytosis was found. Phacomatosis cesioflammea was diagnosed. Ipsilateral optic disc melanocytoma was noted.

CASE 4

A 13-year-old boy with congenital cutaneous nevus flammeus and visual loss from choroidal hemangioma was referred for treatment (Figure 1C and D). Patchy choroidal melanocytosis was found on dilated examination. Phacomatosis cesioflammea was diagnosed. External radiation therapy was delivered to resolve the retinal detachment associated with the choroidal hemangioma.

CASE 5

A 42-year-old woman with choroidal nevus was referred to rule out melanoma. She was found to have choroidal melanocytosis and long-standing ipsilateral unilateral congenital cutaneous nevus flammeus. Phacomatosis cesioflammea was diagnosed. At a 3-year follow-up visit, growth of the melanoma was confirmed and treated.

CASE 6

A 77-year-old woman with lifelong unilateral congenital cutaneous nevus flammeus was found to have ipsilateral ocular pigmentation that proved on examination and subsequent excision to be primary acquired melanosis of the conjunctiva with atypia (melanoma in situ) (Figure 3A and B). Phacomatosis cesioflammea was diagnosed.

CASE 7

A 6-week-old girl had been noted after birth to have bilateral congenital cutaneous nevus flammeus and was treated with dermatologic laser photocoagulation (Figure 2). At age 2 years, the tongue showed mild left hyperemia. Amblyopia in the right eye led to the discovery of subtle epiretinal membrane and prominent diffuse choroidal melanocytosis. Phacomatosis cesioflammea was diagnosed.

Phakos is Greek for birthmark or spot. Phacomatosis (preferred over phakomatosis when a Latin adjective follows8) is a term applied to a group of genetically determined conditions with oculoneurocutaneous findings. According to Happle,8 phacomatosis pigmentovascularis can be divided into 3 distinct types, including phacomatosis cesioflammea, phacomatosis spilorosea, and phacomatosis cesiomarmorata (Table 1). Phacomatosis cesioflammea is characterized by coexistence of a dermal melanocytosis or blue spot and nevus flammeus (port-wine stain). Caesius is Latin for bluish gray, and flammea is Latin for flame or fire. Additional findings in phacomatosis cesioflammea include nevus anemicus, focal alopecia, asymmetric limb length, glaucoma, and hypoplastic nails. Phacomatosis spilorosea is characterized by coexistence of nevus spilus (a speckled lentiginous nevus) and a light pink telangiectatic nevus (different from the darker port-wine stain). Spilo is Latin for spot or speckled, and rosea is Latin for pink. Associated findings include lymphedema, hemiparesis, seizures, and asymmetric limb length. Phacomatosis cesiomarmorata is the association of nevus caesius (blue-gray nevus and mongolian spot) and cutis marmorata telangiectatica congenita. Marmorata is Latin for marblelike. Related defects include asymmetric cerebral hemispheres, leg hyperplasia, and blue sclera.

Fernández-Guarino et al5 reviewed 216 published cases of phacomatosis pigmentovascularis through May 2007 and classified 77% as cesioflammea, 13% as spilorosea, 1% as cesiomarmorata, and 8% as unclassifiable. Almost all information on this topic in the literature emanates from dermatology studies. Few studies exist in the ophthalmology literature. A PubMed survey for the keywords phacomatosis pigmentovascularis and ophthalmology or eye yielded only 9 relevant publications, most of which were case reports. Teekhasaenee and Ritch6 described a series of 9 patients with phacomatosis pigmentovascularis from their glaucoma practice and noted melanocytosis bilaterally in 7 of them. They reported that congenital glaucoma occurred in all 10 eyes with both melanocytosis and episcleral vascular malformations of Sturge-Weber syndrome. Eyes with melanocytosis only or episcleral vascular malformations only did not develop glaucoma, so the authors concluded that the coexistence of these 2 conditions in one eye was a strong indicator of the development of glaucoma. They also advised long-term follow-up of all such patients for secondary glaucoma. Tran and Zografos7 described 3 patients with phacomatosis pigmentovascularis, classified as type IIb in their study but reclassified by us using the new terminology as phacomatosis cesioflammea. Among patients in that study, melanocytosis was unilateral and nevus flammeus was unilateral, but the conditions were contralateral to each other in 2 cases and ipsilateral in 1 case. All 3 patients were initially seen with uveal melanoma in the eye with melanocytosis. These authors advised long-term follow-up for melanoma in affected patients.

In our case series, 6 patients had unilateral melanocytosis, and 1 patient had unilateral conjunctival primary acquired melanosis. Nevus flammeus was ipsilateral in all 7 patients and also contralateral in 3 patients. Among a glaucoma-based practice in the study by Teekhasaenee and Ritch,6 glaucoma was present in 10 eyes, and no patient showed melanoma. Conversely, in our tumor-based practice, glaucoma was observed in no patient, and 4 of 7 patients demonstrated melanoma. Findings similar to ours were reported by Tran and Zografos7 in their tumor-based practice. In fact, none of our patients had been correctly diagnosed as having phacomatosis pigmentovascularis before referral, and the reason for referral was possible melanoma in 5 patients. In our series, case 6 (Table 2) had nevus flammeus and ipsilateral extensive primary acquired melanosis, a relationship that has not been previously described as a classic feature of phacomatosis pigmentovascularis. We included the patient in this series because of the melanocytic derivation of the precancerous melanosis (melanoma in situ) in the background of nevus flammeus.

Dilated ocular examination is critical in establishing the diagnosis of melanocytosis. Most important, ocular melanocytosis was not visible externally in 5 of 6 patients herein and was apparent only with close examination of the sclera, iris, and choroid. In 3 of 6 patients, the pigment was solely in the choroid and was found only after dilated ocular examination. For example, 1 child received frequent laser therapy to a facial nevus flammeus and was finally discovered to have choroidal melanocytosis during our dilated ocular examination several years later. Based on our findings, we concur with Tran and Zografos7 that all patients with phacomatosis pigmentovascularis should receive dilated fundus evaluation for uveal melanoma. Furthermore, we believe that all patients with Sturge-Weber syndrome or cutaneous nevus flammeus should undergo dilated fundus examination for uveal melanocytosis and possible melanoma.

The association of dermal melanocytosis with cutaneous nevus flammeus is believed to result from a twin-spotting phenomenon.9,10Twin spotting is the association of 2 genetically different clones of cells within a region of normal cells, generated by somatic recombination. In other words, twin spotting produces mosaic distribution of lesions, is sporadic and usually without familial occurrence, and affects monozygotic twins discordantly. Moutray et al11 describe monozygotic twins who were discordant for phacomatosis cesioflammea, supporting the twin-spotting theory. In that study, twin 1 had normal findings, and twin 2 had cutaneous nevus flammeus of the arm, maxilla, and periocular region, in addition to mongolian spot and bilateral ocular melanocytosis. The authors concluded that phacomatosis pigmentovascularis resulted from mosaicism related to a postzygotic event.

In summary, we describe 7 patients with phacomatosis pigmentovascularis of cesioflammea type. We observed some new findings in our case series, including epiretinal membrane in 1 patient, primary acquired melanosis (melanoma in situ) in 1 patient, and related choroidal melanoma in 3 patients. In several patients, ocular melanocytosis was not obvious externally, as it involved primarily the choroid. We advise that all patients with nevus flammeus should have a complete ocular evaluation by an ophthalmologist to search for related melanocytosis and possible melanoma, which may not be clinically evident to the nonophthalmologist.

Correspondence: Carol L. Shields, MD, Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, 840 Walnut St, Ste 1440, Philadelphia, PA 19107 (carol.shields@shieldsoncology.com).

Submitted for Publication: July 9, 2010; revision received September 1, 2010; accepted October 7, 2010.

Author Contributions: Dr C. L. Shields had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None reported.

Funding/Support: This study was supported by the Eye Tumor Research Foundation (Dr C. L. Shields).

Role of the Sponsor: The funders had no role in the design or conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript.

Happle  R Neurocutaneous diseases. Freedberg  IMEisen  AZWolf  KAusten  KFGoldsmin  LAKatz  SIFitzpatrick's Dermatology in General Medicine. 6th ed. New York, NY McGraw-Hill2003;1806- 1821
Ota  MKawamura  TIto  N Phakomatosis pigmentovascularis [in Japanese]. Jpn J Dermatol 1947;521- 3
Cordisco  MRCampo  ACastro  C  et al.  Phakomatosis pigmentovascularis: report of 25 cases. Pediatr Dermatol 2001;1870
Vidaurri-de la Cruz  HTamayo-Sánchez  LDurán-McKinster  Cde la Luz Orozco-Covarrubias  MRuiz-Maldonado  R Phakomatosis pigmentovascularis II A and II B: clinical findings in 24 patients. J Dermatol 2003;30 (5) 381- 388
PubMed
Fernández-Guarino  MBoixeda  Pde Las Heras  EAboin  SGarcía-Millán  COlasolo  PJ Phakomatosis pigmentovascularis: clinical findings in 15 patients and review of the literature. J Am Acad Dermatol 2008;58 (1) 88- 93
PubMed Link to Article
Teekhasaenee  CRitch  R Glaucoma in phakomatosis pigmentovascularis. Ophthalmology 1997;104 (1) 150- 157
PubMed Link to Article
Tran  HVZografos  L Primary choroidal melanoma in phakomatosis pigmentovascularis IIa. Ophthalmology 2005;112 (7) 1232- 1235
PubMed Link to Article
Happle  R Phacomatosis pigmentovascularis revisited and reclassified. Arch Dermatol 2005;141 (3) 385- 388
PubMed Link to Article
Suzuki  KIshizaki  HTakahashi  H Phacomatosis pigmentovascularis IIIb associated with porokeratosis, acanthosis nigricans and endocrinopathy in brother and sister [in Japanese, with an English summary]. Skin Res (Hifu) 1990;3265- 70
Danarti  RHapple  R Paradominant inheritance of twin spotting: phacomatosis pigmentovascularis as a further possible example [letter]. Eur J Dermatol 2003;13 (6) 612
PubMed
Moutray  TNapier  MShafiq  AFryer  ARankin  SWilloughby  CE Monozygotic twins discordant for phacomatosis pigmentovascularis: evidence for the concept of twin spotting. Am J Med Genet A 2010;152A (3) 718- 720
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 2.

Phacomatosis pigmentovascularis of cesioflammea type with related melanoma. In case 6, a 77-year-old woman with lifelong facial nevus flammeus (A) developed conjunctival primary acquired melanosis (melanoma in situ) (B). In case 2, a 78-year-old man with lifelong facial nevus flammeus (C) developed choroidal melanoma (D). He demonstrated sectorial scleral melanocytosis in the quadrant of the tumor.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Clinical features of phacomatosis pigmentovascularis of cesioflammea type. Case 3 shows prominent bilateral facial nevus flammeus (A) in a Hispanic girl with obvious episcleral and periocular cutaneous melanocytosis (B). Case 4 shows subtle left-sided facial nevus flammeus (C) of the lower cheek region in a boy of white race/ethnicity, previously treated with laser, and subtle choroidal melanocytosis superiorly (D). There was no episcleral or cutaneous melanocytosis. The left pupil appeared red due to an associated choroidal hemangioma that was treated with external beam radiation therapy.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 1.

Case 7. Ocular melanocytosis may be found only in the choroid and may not be visible externally. Bilateral facial nevus flammeus in an infant (A) and 3 years later after laser treatment (B). At that time, dilated ocular examination disclosed choroidal melanocytosis in the right eye (C) but not in the left eye (D).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Revised Classification of Phacomatosis Pigmentovascularis (PPV)a
Table Graphic Jump LocationTable 2. Clinical Features of Patients With Phacomatosis Cesioflammea

References

Happle  R Neurocutaneous diseases. Freedberg  IMEisen  AZWolf  KAusten  KFGoldsmin  LAKatz  SIFitzpatrick's Dermatology in General Medicine. 6th ed. New York, NY McGraw-Hill2003;1806- 1821
Ota  MKawamura  TIto  N Phakomatosis pigmentovascularis [in Japanese]. Jpn J Dermatol 1947;521- 3
Cordisco  MRCampo  ACastro  C  et al.  Phakomatosis pigmentovascularis: report of 25 cases. Pediatr Dermatol 2001;1870
Vidaurri-de la Cruz  HTamayo-Sánchez  LDurán-McKinster  Cde la Luz Orozco-Covarrubias  MRuiz-Maldonado  R Phakomatosis pigmentovascularis II A and II B: clinical findings in 24 patients. J Dermatol 2003;30 (5) 381- 388
PubMed
Fernández-Guarino  MBoixeda  Pde Las Heras  EAboin  SGarcía-Millán  COlasolo  PJ Phakomatosis pigmentovascularis: clinical findings in 15 patients and review of the literature. J Am Acad Dermatol 2008;58 (1) 88- 93
PubMed Link to Article
Teekhasaenee  CRitch  R Glaucoma in phakomatosis pigmentovascularis. Ophthalmology 1997;104 (1) 150- 157
PubMed Link to Article
Tran  HVZografos  L Primary choroidal melanoma in phakomatosis pigmentovascularis IIa. Ophthalmology 2005;112 (7) 1232- 1235
PubMed Link to Article
Happle  R Phacomatosis pigmentovascularis revisited and reclassified. Arch Dermatol 2005;141 (3) 385- 388
PubMed Link to Article
Suzuki  KIshizaki  HTakahashi  H Phacomatosis pigmentovascularis IIIb associated with porokeratosis, acanthosis nigricans and endocrinopathy in brother and sister [in Japanese, with an English summary]. Skin Res (Hifu) 1990;3265- 70
Danarti  RHapple  R Paradominant inheritance of twin spotting: phacomatosis pigmentovascularis as a further possible example [letter]. Eur J Dermatol 2003;13 (6) 612
PubMed
Moutray  TNapier  MShafiq  AFryer  ARankin  SWilloughby  CE Monozygotic twins discordant for phacomatosis pigmentovascularis: evidence for the concept of twin spotting. Am J Med Genet A 2010;152A (3) 718- 720
PubMed Link to Article

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