Phakomatosis Pigmentovascularis: A Clinical Profile of 11 Indian Patients.

INTRODUCTION: Phakomatosis pigmentovascularis (PPV) is a rare congenital syndrome characterized by the simultaneous presence of capillary malformation and pigmentary nevi. The objective of our study was to describe the clinical characteristics of a series of Indian patients presenting with this rare entity.
MATERIALS AND METHODS: It was a record-based descriptive case series.
RESULTS: A total of 11 patients with PPV (9 females, 2 males, age range: 7 days to 45 years; mean 11.6 years) were studied. Port wine stain was present in 10 (91%) patients and one patient (9%) had cutis marmorata telangiectatica congenita. Isolated nevi of Ota and Mongolian spots were seen in 4 (36%) patients each. Simultaneous presence of both Mongolian spots and nevus of Ota was present in 1 (9%) patient. The combination of Mongolian spots and bilateral palatal hyper-melanosis was noticed in 2 (18%) patients. Café au lait macule was present in one patient. Bilateral ocular melanosis was found in 3 (27%) patients. Unilateral ocular melanosis was noticed in 4 (36%) patients. Two patients (18%) had history of seizure disorder and intracranial vascular anomalies on MRI imaging. Two patients (18%) had features of Klippel-Trenaunay syndrome. According to the traditional classification, three patients had PPV type 2b, one patient had PPV type 5b, and seven patients had PPV type 2a. According to the Happle's classification, 10 patients had PPV of cesio flammea type, and one patient had PPV of cesio marmorata type. LIMITATIONS: We could not perform genetic study of the patients.
CONCLUSION: Our findings emphasize the importance of detailed systemic evaluation including ocular examination and brain imaging in every patient of PPV.

Introduction

Phakomatosis pigmentovascularis (PPV) is a congenital syndrome characterized mainly by the concurrent presence of capillary malformation and pigmentary nevi.[12] This rare condition was first described by Ota et al. in 1947.[123] From the clinical features, it was traditionally classified into five types.[134] Recently, Happle has re-designated this syndrome into four newer types [Table 1].[5] The relative frequency of PPV at the National Institute of Pediatrics of Mexico city was 5.8 per 100,000 pediatric patients and 0.634 per 100,000 dermatological patients.[6]

Table 1

Classification of PPV

Traditional classification	Happle’s classification	Vascular lesion	Cutaneous lesion
PPV I	-----------------	Nevus flammeus	Epidermal nevus
PPV II	Phakomatosis cesio flammea	Nevus flammeus±Nevus anemicus	Dermal melanocytosis
PPV III	Phakomatosis spilorosea	Nevus flammeus±Nevus anemicus	Nevus spilus
PPV IV	Unclassified	Nevus flammeus±Nevus anemicus	Dermal melanocytosis±Nevus spilus
PPV V	Phakomatosis cesio marmorata	Cutis marmorata telangiectatica congenita (CMTC)	Dermal melanocytosis

Although there are several sporadic case reports, very few descriptive case series have been published.[26789] The objective of the present study was to document the different cutaneous as well as systemic features associated with the PPV in a series of Indian patients.

Materials and Methods

This descriptive study was carried out by analyzing the detailed case records of consecutive patients with a diagnosis PPV seen over a period of 7 years (From 2010 March to 2017 February) at a tertiary care hospital in eastern India. The study was approved by Institutional Ethics Committee. We extracted data from our structured case-record forms pertaining to findings of detailed history, thorough clinical examination, routine biochemical tests, and appropriate radiological imaging studies that were done in every patient.

Case definition

PPV was recognized by the simultaneous presence of capillary malformation and pigmentary nevi.[1]

Klippel-Trenaunay syndrome (KTS) was defined as the presence of superficial vascular stain of the skin, varicose veins, and soft tissue/bony hypertrophy.[10] Cutis marmorata telangiectatica congenita (CMTC) was defined as the congenital vascular anomaly with a persistent reticular pattern with a marble bluish or deep purple appearance.[11]

A statistical analysis was performed using GraphPad Prism version 5 (GraphPad Software Inc., San Diego, CA, USA; 2007) software and Microsoft Excel.

Results and Analysis

Demography

A total of 11 patients [Table 2] (age range: 7 days to 45 years; mean 11.60 year; SD: 15.58) were seen [Figures 1–5]. Out of them, two were male and nine female with a male to female ratio 1:4.5.

Table 2

Profile of patients with phacomatosis pigmentovascularis

Age	Gender	Vascular lesion		Cutaneous pigmentation		Ocular lesion	Systemic feature	Diagnosis (Traditional)	Diagnosis (Happle)
		Type	Distribution	Type	Distribution
35 year	F	Port wine stain	Face; bilateral	Nevus of Ota	Bilateral	Bilateral ocular melanosis	Nil	PPV TYPE IIA	Phakomatosis Cesio flammea
2 year	F	Port wine stain	Face, sole; bilateral	Mongolian spotsPalatal hypermelanosisCafé aulait macule	Trunk (Bilateral)Lower abdomen, thigh	Bilateralocular melanosis	Seizure Intracranial vascular anomalies	PPV type II B	Phakomatosis cesio flammea
45 year	F	Port wine stain	Left eye brow, left side of neck	Nevus of Ota	Left side Extending onto the forehead	Left sided ocular melanosis	Nil	PPV TYPE IIA	Phakomatosis cesio flammea
23 year	F	Port wine stain	Back	Nevus of Ota	Bilateral	Bilateral ocular melanosis;	Nil	PPV TYPE IIA	Phakomatosis cesio flammea
4 year	F	Port wine stain	Left side of face	Nevus of Ota	Bilateral	Left sided Ocular melanosis	Nil	PPV TYPE IIA	Phakomatosis cesio flammea
3 month	F	Port wine stain	Face, upper chest, left upper limbs, genitalia	Mongolian spots	Trunk, upper limbs	Nil	Nil	PPV TYPE IIA	Phakomatosis cesio flammea
7 year	F	Port wine stain	Face, palms	Nevus of Ota Mongolian spot	Trunk	Bilateral ocular melanosis	Klippel -Trenaunay syndrome	PPV type II A	Phakomatosis cesio flammea
5 month	M	Port wine stain	Face	Mongolian spot	Trunk	NIL	NIL	PPV II A	Phakomatosiscesioflammea
7 day	M	CMTC	Limbs	Mongolian spot	Trunk	Right -sided ocular melanosis	Seizure intracranial vascular anomalies	PPV VB	Phakomatosis cesiomarmorata
5 year	F	Port wine stain	Right side of face, right forearm	Mongolian spot	Right side of abdomen	Nil	Nil	PPV IIA	Phakomatosis cesio flammea
6 year	F	Port wine stain	Right side of face Right forearm	Mongolian spot Palatal hypermelanosis	Back Bilateral	Right sided ocular melanosis	Klippel -Trenaunay syndrome	PPV II A	Phakomatosis cesio flammea

Figure 1

(a) Port wine stain over both the upper limbs and chest (b) Bilateral ocular melanosis with port wine stain (c) Palatal hypermelanosis

Figure 5

Magnetic resonance angiography of brain reveals abnormal tortuous vessels in relation to P2 segment of right postero-cerebral artery anomaly

(a) Extensive port wine stain and Mongolian spots involving the face, trunk, limbs, and genitalia (b) Extensive port wine stain and Mongolian spots over the head, neck, and back

(a) Cutis marmorata telangiectatica over the lower limb (b) Magnetic resonance angiography of brain reveals a few abnormal dilated vessels in right parietal lobe

(a) Ocular melanosis and facial port wine stain (b) port wine stain over the soles (c) Coexistence of café au lait macules and Mongolian spots (d) Mongolian spots (marked by *) and port wine stains (marked by arrows) over the back

Cutaneous lesions

Port wine stain was present in 10 (91%) patients. In 9 patients (90%), it was distributed over the face. The back, upper part of the chest, left upper extremity, palm and sole, and genitalia were involved in one (9%) patient. One patient (9%) had CMTC distributed over the lower extremities. Isolated nevus of Ota was seen in 4 (36%) patients, among them 3 patients had bilateral involvement and one patient had left sided unilateral affection. Mongolian spots, seen in 4 (36%) patients, were distributed over the trunk in 3 patients and over the right side of abdomen in one patient. Simultaneous presence of both Mongolian spots and nevus of Ota was observed in 1 (9%) patient. The combination of Mongolian spot and bilateral palatal hypermelanosis was noticed in 2 (18%) patients. Café au lait macule was present in one patient.

Ocular features

Bilateral ocular melanosis was found in 3 (27%) patients. Unilateral ocular melanosis was noticed in 4 (36%) patients.

Systemic involvement

Two patients (18%) had history of seizure disorders. Magnetic resonance angiography of brain of the patient having CMTC and Mongolian spots revealed a few abnormal dilated vessels in right parietal lobe. This patient reported recurrent episodes of seizure on subsequent follow-up. The other patient had port wine stain and Mongolian spot. Magnetic resonance angiography of brain of this patient revealed abnormal tortuous vessels in relation to P2 segment of right posterior cerebral artery draining in torcula suggestive of arterio-venous malformation of right parieto-occipital lobe. In addition, two other patients (18%) had features of Klippel-Trenaunay syndrome.

Final diagnosis

According to the traditional classification, 3 patients had PPV type 2b, one patient had PPV type 5b, and 7 patients had PPV type 2a. According to the Happle's classification, 10 patients had PPV of ceisio flammea type, and one patient has PPV of cesio marmorata type.

Discussion

PPV is a rare distinctive syndrome characterized by the coexistence of a pigmentary nevus and vascular malformation.[1] The diagnosis of this condition is essentially clinical.[2] PPV was traditionally classified into the following 4 types according to the associated pigmented lesions[14] namely, type 1 (nevus flammeus and verrucous epidermal nevus), type 2 (nevus flammeus and Mongolian spot with or without nevus anemicus), type 3 (nevus flammeus, nevus spilus with or without nevus anemicus), and type 4 (nevus flammeus, Mongolian spot, nevus spilus with or without nevus anemicus).[13] A fifth type with cutis CMTC and dermal melanocytosis was described later.[6] Each of these types was further divided into: a) if only cutaneous signs were present; and b) if there were also extracutaneous signs.[24]

The old classification of PPV by numbering and lettering has the disadvantage of being difficult to memorize.[511] Happle has proposed a relatively simplified classification for PPVs.[5] It divides PPVs into four subtypes namely, phakomatosis cesio flammea (associates blue spots to nevus flammeus), phakomatosis spilorosea (characterized by the coexistence of nevus spilus and a pale-pink nevus), phakomatosis cesio marmorata (the association of a blue spot with CMTC and a fourth group of unclassifiable PPV).[512] The inclusion of type I PPV was debated according to the argument that a linear epidermal nevus does not originate from pigmentary cells.[2]

According to Happle, a categorical separation between cases showing solely cutaneous changes and those characterized by additional extracutaneous anomalies seems improper because of a number of reasons. First of all, in other genetic disorders such as incontinentia pigmenti, CMTC or neurofibromatosis type 1, no such distinction prevails. Furthermore, a supposed type “a” may later turn out to be a case of type “b.” Moreover, the additional letter “b” does not contain any information concerning which particular extracutaneous abnormality is present. Therefore, it seems preferable to give an exact description, if necessary, of the associated extracutaneous defect.[5] Since its initial description, there have been a few clinical series published on this rare syndrome.[678910] Most reported cases were sporadic ones and were from Japan, Mexico, or Argentina. The most commonly reported type was type IIb, followed by the type IIa.[2]

The pathogenesis of PPV is poorly understood. It has been suggested that genetic aberrations in vasomotor nerve cells and melanocytes, both derived from common neuro-ectodermal precursor cells, may be responsible for the association of vascular and pigmented nevi.

Another view suggests that the twin-spot theory can explain the coexistence of vascular and pigmented lesions.[21213] The gene/s responsible for PPV is/are yet to be identified definitely.

The demographic data of our patients showed that their age ranged between 7 days to 45 years. A variable age range have been reported by Fernández-Guarino et al. (1 year to 50 year),[2] Vidaurri-de la Cruz et al. (6 month to 16 year),[6] Ruiz-Maldonado et al. (2 month to 3 year),[7] and Shields et al. (2 to 78 year) [Table 3].[8] In concordance with the previous case series of Fernández-Guarino et al.,[2] Vidaurri-de la Cruz et al.,[6] Nanda et al.,[9] Ruiz-Maldonado et al.,[7] and Shields et al.,[8] a female preponderance was noted in the present study.

Table 3

Comparison of different studies on PPV

Study/Reference/Year	Number of cases studied	Gender	Age range	Vascular lesion	Cutaneous pigmentation	Ocular lesion	Systemic features	Diagnosis (Traditional)	Diagnosis (Happle)
Fernández -Guarino et al.[2]/2008	15	Female=11 Male=4	1 –50 years	Nevus flammeus=14 CMTC=1	Nevus of Ota-10 Mongolian spot=1 Nevus of Ota+Mongolian spot=3	Melanosis=10 Glaucoma=1	Present=4	PPV IIa-9 PPV IIb-4 PPV Vb-1 PPV IV a-1	Phacomatosis cesio flammea=13, Phacomatosis cesio marmorata=1 Unclassified=1
Nanda A et al.[9]/(2016)	4	All female	1.5 month– 1.5 year	Nevus flammeus=3 CMTC=1	Diffuse dermal melanosis=3 Mongolian spot=1	Bilateral glaucoma=2	Present=3	PPV IIb-2 PPVIIa-1 PPV Vb-1	Phacomatosis cesio flammea=3 Phacomatosis cesio marmorata=1
Vidaurride la Cruz et al.[6]/2003	24	Female=13 Male=11	6month - 16 year	Nevus flammeus=24	---------	Ocular melanosis=12 Glaucoma=11	Present=18	PPV IIa-6 PPV IIb-18	Phacomatosis cesio flammea=24
Ruiz-Maldonado et al.[7]/1987	4	Female=4	2 month–3 year	Nevus flammeus=4	A slate-gray cutaneous pigmentation=4	Ocular melanosis=4	Seizure=3	PPV type 2b=3 2a=1	--------------
Shields et al.[8]/2011	7	Female=5 Male=2	2–78 year	Nevus flammeus=7	Dermal melanosis=1	Ocular melanosis=7	None	-----------	Phacomatosis cesio flammea=7
Present study	11	Female=9 Male=2	7 day -45 year	Nevus flammeus=10 CMTC=1	Nevus of Ota=4 Mongolian spot=4 Mongolian spot+nevus of Ota=1 Mongolian spot + palatal melanosis=2	Bilateral melanosis=4 Unilateral Ocular melanosis=4	Intracanial vascular anomaly=2 Klippel -Trenaunay syndrome=2	PPVIIa-7 PPV IIb-3 PPV Vb-1	Phacomatosis cesio flammea=10 Phacomatosis cesio marmorata=1

PPV: Phakomatosis pigmentovascularis; CMTC: Cutis marmorata telangiectatica congenita

In the present series, 91% presented with nevus flammeus and 9% patient had CMTC. Previous studies also showed that nevus flammeus was the most common vascular malformation found among PPV patients.[2] Nevus flammeus was found in 100% patient in the study of Vidaurri-de la Cruz et al.,[6] Ruiz-Maldonado et al.,[7] and Shields et al.,[8] whereas, it was noticed in 73% and 75% of the patients in the study of Fernández-Guarino et al.[2] and Nanda A et al.,[9] respectively.

In the present series, 36% patient had nevus of Ota. In comparison, nevus of Ota was found in 66% of the patients in the study of Fernández-Guarino et al.[2]

Thirty-six percent of the patients in the present series presented with only Mongolian spot in contrast to that of 6.7% in the study of Fernández-Guarino et al.[2] and 25% in the series of Nanda et al.[9] In the present series, 9% of the patients presented with Mongolian spot and nevus of Ota. Similar combination of the pigmentary changes have been reported in 20% of the patients by Fernández-Guarino et al.[2] Palatal hypermelanosis was found in 18% of the patients in the current series, a hitherto unreported occurrence. In the present series, 18% patients had KTS, whereas in the studies of Fernández-Guarino et al.[2] and Vidaurri-de la Cruz et al.,[6] the occurrence were 6.7% and 8.3%, respectively. Café au lait macule was present in one of our patient with PPV type 2b (phacomatosis cesio flammea), which is rarely reported in case of PPV.[14]

Ocular melanosis seen in 63% of our patients was the only ocular finding in our series. Fernández-Guarino et al.[2] have found that 67% of the patients had ocular melanosis, whereas Vidaurri-de la Cruz et al.[6] had reported that 50% of their patients had ocular melanosis. There was no case with glaucoma in our series in contrast to a previous study by Vidaurri-de la Cruz et al.,[6] where 45% of the patients had glaucoma.

A large number of diseases have been reported to be associated with PPV. These include Sturge-Weber syndrome, colonic polyposis, KTS, right kidney agenesis, leg-length discrepancy, multiple renal angiomatosis, scoliosis, subglottic stenosis, epilepsy, hypoplastic larynx, cerebral atrophy, multiple granular cell tumors, hypoplasia of portal veins, iris mamillations, hypoplasia of inferior vena cava, iliac and femoral veins, iris hamartomas, glaucoma, and congenital triangular alopecia.[813]

Eighteen percent of our patients had history of seizure disorder and MR angiogram showed presence of intracranial vascular anomaly in both of them.

In the study of Ruiz-Maldonado et al.,[7] three out of the four patients had episodes of seizure. The presence of systemic features were also reported by Fernández-Guarino, (26% of the patients)[2] and Vidaurri-de la Cruz et al. (75% of the patients).[6] However, no systemic feature was reported by Shields et al.[8] There was no case of Sturge-Weber syndrome in our patients in contrast to the previous study of Vidaurri-de la Cruz et al.,[6] where Sturge-Weber syndrome was seen in 25% of patients, and it was documented in 13% of patients by Fernández-Guarino et al.[2]

According to traditional classification, 63.6% patients of the current study had PPV-2a. This was in agreement with the previous study of Fernandez-Guarnio et al.,[2] where it was found in 60% of patients. However, Vidaurri-de la Cruz et al. had found PPV 2a type in only 25% of their patients.[6] PPV 2b was diagnosed in 27.3% of our patients, a finding similar to that of Fernández-Guarino et al.[2] who had reported this finding in 26% of the patients. Vidaurri-de la Cruz et al.,[6] however, have reported that 75% of their patients had PPV 2b. According to the Happle's classification,[5] 91% patients of the present series had phacomatosis cesio flammea and 9% had phacomatosis cesio marmorata. Vidaurri-de la Cruz et al.[6] had reported that 100% of their patients had PPV of cesio flammea type, and the occurrence of phacomatosis cesio flammea was 86% and 75% in the studies of Fernández-Guarino[2] and Nanda et al.,[9] respectively.

The cutaneous changes of PPV are essentially cosmetic and their management is often problematic. Q-switched ruby laser irradiation to the site of dermal melanosis and pulsed dye laser irradiation to the port-wine stain has anecdotally showed marked improvement of PPV type 2a.[15] The combined laser therapy using Q-switched alexandrite and long-pulsed dye lasers has also shown significant improvement in patients with type 2 PPV.[16]

The removal of a good portion of cutaneous and vascular lesions using combined multiple laser approach using Q-switched ruby laser, the Q-switched Alexandrite laser, and the flash lamp pumped pulsed-dye laser was also reported.[17] CMTC without atrophy can be expected to improve on its own.[16]

Limitations

Because of institutional non-availability, we could not perform genetic analysis of the patients in the present series.

Conclusion

We emphasize the importance of detailed systemic evaluation including ocular examination and brain imaging in every patient of PPV.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.