Bourneville-Pringle Disease Treated with Electrocauterization and

Topical Tacrolimus 0.1%: A 1 Year Observation

of Severity and Recurrence

Intan Nurmawati Putri

*, Yoga Hadi

, Holy Ametati

, Diah Adriani Malik

, Meira D. K. A.

Department of Dermatovenereology, Medical Faculty of Diponegoro University/Dr. Kariadi General Hospital.

Departement of Anatomic Pathology, Medical Faculty of Diponegoro University/Dr. Kariadi General Hospital.

Corresponding auhor

Keywords: BPD, angiofibroma, electrocauterization, topical tacrolimus, FASI score.

Abstract: Bourneville-Pringle Disease (BPD) also known as tuberous sclerosis complex (TSC) is a rare autosomal

dominant genodermatosis, which incidence varies from 1/12.000 to 1/14.000 live births. The genes implied

to be mutated in this disease are tuberous sclerosis 1 (TSC1) and tuberous sclerosis 2 (TSC2). Diagnosis is

made with two or more significant features or one major plus two or more minor features of the disorder.

Management of BPD is supportive and symptomatic. Prognosis depends on systemic involvement. We

reported an 11-year-old boy with various size firm tumors on his face, hypomelanotic macule on his back and

slightly elevated skin-colored patch on his right lateral thigh. History of neurological manifestation and

systemic complaint were adverse. Histopathological examination was following angiofibroma in BPD.

Electrocauterization with general anesthesia combined with topical tacrolimus, 0.1% were performed for the

angiofibromas in this patient. The prognosis was qua ad vitam dubia ad bonam, quo ad sanationam, and quo

ad cosmeticam dubia ad malam. In this case, diagnose BPD was based on anamnesis, clinical features (three

significant symptoms; angiofibroma, ash leaf macule, shagreen patch), and histopathological examination.

The aim of angiofibroma therapy is for cosmetic purpose. Electrocauterization and topical tacrolimus 0.1%

yielded a satisfactory result for the angiofibroma. Angiofibromas never worsen. There was an improvement

in his FASI (Facial Angiofibroma Severity Index) score from severe to mild. Inhibitor mammalian of target

rapamycin (mTOR) pathway might be considered. A proper therapy will improve a patient's quality of life.

1 INTRODUCTION

Bourneville-Pringle disease (BPD) also known as

tuberous sclerosis complex (TSC) is a multisystem

genetic disease with varied phenotypic expression

characterized by the formation of benign tumor that

very rarely develop into a metastatic lesion, on

various organs like brain, lungs, skin, heart, and

kidney (Darling , 2012).

BPD can affect all race and ethnic groups,

regardless of gender. BPD is a genodermatosis that

rarely happens with its incidence rate around

1/12,000 to 1/14,000 live births. The pathogenesis of

this disease is that a mutation causes it in TSC1 or

TSC2 genes lead to overactivation of mammalian

target of rapamycin (mTOR) pathway, which will

lead to uncontrolled cell growth (Darling, 2012;

Osborne, 2011).

Definite diagnosis of BPD is made when an

individual has two significant symptoms or one

primary symptom with two minor symptoms

(Osborne, 2011; James et al, 2011). The symptoms

may vary among individuals, from mild to severe

symptoms. Severe symptoms are a neurological

manifestation, cardiac rhabdomyoma. Mild

symptoms may include skin abnormalities such as

angiofibroma, periungual fibroma, shagreen patch.

Angiofibromas shows prominent vascular component

owing to increased expression of angiogenic factors

like vascular endothelial growth factors (VEGF) and

mTOR overactivation that promotes angiogenesis.

Facial angiofibromas appearance of facial papules.

The diagnosis of this disease is made by taking a

medical history and physical examination to form a

temporary initial diagnosis (Darling, 2012; Tsao et al,

2012; Northrup et al, 2013).

460

Bourneville-Pringle Disease Treated with Electrocauterization and Topical Tacrolimus 0.1 .

DOI: 10.5220/0009991504600464

In Proceedings of the 2nd International Conference on Tropical Medicine and Infectious Disease (ICTROMI 2019), pages 460-464

ISBN: 978-989-758-469-5

Treatment is done depending on several

conditions. Some individuals with mild disease may

not require treatment. Current treatment modalities

include vascular laser, ablative laser and other

destructive techniques such as shave excision,

cryosurgery, dermabrasion, photodynamic therapy,

and electrodesiccation, but that repetitive invasive

techniques can cause permanent sequelae, scarring,

cheloid, psychological trauma, and outcomes are

often less than satisfactory (Osborne, 2011; Aoud et

al, 2017; Ruano et al, 2014).

The use of new topical

formulations such as mTOR inhibitor and calcineurin

inhibitor has recently opened up a new therapeutic

perspective in the treatment of facial angiofibromas.

This disease has a long-lasting effect. Even after

treatment, a routine check-up is required. Children

may need mental and behavioral development

assessment. Early prevention can help children to

grow and develop effectively (Gutreund et al, 2013;

Tanaka et al, 2011).

This case aims to learn about the recent update on

the diagnosis and management of BPD to improve

patients' quality of life (Darling, 2012; Tsao et

al,2012; Tanaka et al, 2011).

2 CASE

An 11-year-old boy patient presented to dermatology

and venereology clinic of Kariadi General Hospital

Semarang with lumps on his face with various size,

between 0.5-2 cm in diameter, since the last six years.

The lumps felt itchy occasionally, although painless

and didn't bleed easily. The lumps were increasing in

number and size. He also presented with a skin-

colored plaque on his right thigh, 3x5 cm in size, and

a painless, itchless white patch on his back, 2x3 cm in

size. Now, the patient is in 1st grade of junior high

class and without ever failing a grade. The patient had

never undergone any treatment for his disease.

History of seizure, epilepsy, and other systemic

disorder was denied by the patient. The patient was

delivered usually by a midwife, and there were no

developmental abnormalities. History of an allergic

reaction to any food or medicine was denied. History

of vitiligo and cheloid was denied. However, the

history of cheloid in his father was positive. Family

history of the same disease was denied.

= Healthy male

= Healthy female

= Deceased

= Sick male

Physical examination from general state: proper,

compos mentis, dermatological status of patient

showed: hypopigmented macule with discrete border

(ash leaf macule) on his back, 2x3 cm in size (Figure

1.A), skin-colored plaque (shagreen patch) on his

right thigh, 3x5 cm in size (Figure 1.B), multiple

hyperpigmented papules and nodules on his face and

nose (angiofibroma) in varying diameters, around

0.5-2 cm, FASI score 9 (severe) (Figure 2.A),

Laboratory result was standard.

Figure 1. A. Ash leaf macule. B. Shagreen patch.

Pedigree

Bourneville-Pringle Disease Treated with Electrocauterization and Topical Tacrolimus 0.1

461

Consultation with pediatric department showed

no systemic disorder. Consultation with pediatric

psychology department showed an IQ test result of 95

(within standard limit). There was no systemic

involvement, therefore unnecessarily EEG, MRI,

ECG, USG examination.

Histopathological examination showed;

angiofibroma, which is one of the many

manifestations of tuberous sclerosis on the skin

(Figure 2C, 2D).

Electrocauterization was done under general

anesthesia. On seventh day post-surgery, we found

skin erosion, excoriation, and crust on the wound. The

patient was educated to apply sunscreen and wear a

mask when going out. In the next follow-up, 30th-day

post-surgery, we found hypopigmented macule on the

surgical area. In the follow-up, 180th-day post-

surgery, we did not find any hypopigmented macule.

After one year observation, angiofibromas on his face

grew up in the form of papules, then we applied

tacrolimus ointment 0.1% twice daily, educated to

wear sunscreen, and educated burning sensation as a

side effect of tacrolimus. After one month therapy

with topical tacrolimus; erythema reduced and the

angiofibroma never worsen. In this case, FASI score

after therapy was 3 (Mild) (Figure 2B). Prognosis in

this patient was quo ad vitam dubia ad bonam, quo ad

sanationam, and quo ad cosmeticam dubia ad malam.

Figure 2. A. Before therapy, FASI Score 9 (severe) B. After therapy, FASI Score 3 (mild) C. 100x magnification, Epidermis;

Pigmented, keratinized, stratified squamous, Dermis; Hair follicle pressed by swollen fibro collagenous connective tissue

stroma D. 400x magnification, Ploriferation blood vessels coated by endothelium with lumen fulfilled by erythrocyte

3 DISCUSSION

The diagnosis of BPD, in this case, was based on

medical history, physical examination, and

histopathological examination. This patient met the

criteria for BPD with three significant symptoms:

angiofibroma, shagreen patch, and ash leaf macule.

Based on US National Tuberous Sclerosis

Association alliance consensus published in 2012, the

diagnostic criteria of BPD consists of two significant

symptoms; or one primary symptom and two minor

symptoms is met (Table 1). (Northrup et al, 2013).

Mental retardation is found in 60-70% BPD cases but

if brain development during childhood is usual,

mental disorder is rarely found in later life. In this

patient, history of seizure was denied. The patient

never failed a grade, and his IQ test result was 95

(within standard limit). (Darling, 2012;Northrup et al,

2013). Histopathological examination showed skin

tissue covered by epidermis with subepithelial

hyperkeratosis, fibro collagenous connective tissue

stroma in which there were dilatating blood vessels,

and atrophic sebaceous glands. (Tsao et al, 2012)

Malignant feature wasn’t found; this description fits

angiofibroma found in BPD.

Differential diagnosis of trichoepithelioma can be

eliminated because trichoepithelioma astarts showing

in adolescence, the lesion is located on nasolabial

crease, nose, forehead, upper lip, and eyelid,

sometimes occurs with telangiectasis, and its peculiar

histopathological feature is horn cysts. Differential

diagnosis of sebaceous adenoma (SA) can be

eliminated because SA usually happens in elderly,

and the lesion is located on the face, head, and eyelid,

histopathological examination shows irregular-

shaped tumor with discrete margin, consists of

lobules formed by sebaceous gland cells and basaloid.

(Tsao et al, 2012)

Hair follicle

Erythrocyte

462

Table 1.

major symptoms minor symptoms

Angiofibroma Dental enamel pits (3 or more)

Periungual fibroma (2 or more) Intraoral fibromas (2 or more)

Hypomelanotic macules (3 or more, with the smallest

diameter 5 mm)

non-renal hamartomas

Shagreen patch Retinal achromic patch

Multiple retinal nodular hamartomas 'Confetti' skin lesions

Cortical dysplasias Multiple renal cysts

Subependymal nodule

Subependymal giant cell astrocytoma

Cardiac rhabdomyoma

Lymphangioleiomyomatosis (LAM)

Angiomyolipomas (2 or more)

(Reference: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference)

BPD management requires a multidisciplinary

approach. Generally, angiofibroma can be treated

with excision, curettage, chemical peeling,

cryosurgery, dermabrasion, electrosurgery, and laser.

Complications that may arise from surgical treatment

are an infection, hypertrophic scar, post-

inflammatory hyperpigmentation, and

hypopigmentation. Angiofibroma in this patient was

treated by electrocauterization, curettage under

general anesthesia, combined with tacrolimus 0.1%.

Electrosurgery combined with topical mTOR

inhibitor (sirolimus) might be a better choice to

prevent recurrence of angiofibromas (Tanaka et al,

2011;Amin et al,2017) The mechanism of sirolimus

binds to mTORC1 (mTORComplex1) thereby

inhibiting its downstream pathway, but sirolimus is

not included in the national formulary, the cost of

therapy which is prohibitively expensive. We applied

topical tacrolimus 0.1% in this case, mechanism of

action tacrolimus is binds to a nuclear factor of

activated-T cells (NFAT) to activation of genes

encoding cytokines, thereby inhibiting cell cycle. We

used topical tacrolimus 0.1% because it is more

effective compared to the 0.03% formulation.

There

was an improvement of FASI score from severe to

mild (Table 2)

Table 2.

Before therapy After therapy

Erythema Dark red/purple: 3 Skin color : 0

Size Confluent : 3 <5mm : 1

Extension ˃50% cheek surface: 3 ˂50% cheek surface: 2

Total

9 3

(Reference: 2014 British Association of Dermatologists)

FASI score is reliability assessment of new tool

developed to measure severity and responsiveness to

therapy in BPD-associated facial fibroma. The use of

antibiotic cream was meant to prevent infection on

the surgical wound. Sunscreen use when the patient

went out of the house was in order to avoid direct sun

exposure. (Northrup et al, 2013)

Prognosis depends on the clinical picture of the

disease. Some individuals may have an average life

span with few medical complications. Prognosis of

this patient was qua ad vitam dubia ad bonam, quo ad

sanationam and quo ad cosmeticam dubia ad malam

(Darling, 2012; Osborne, 2011; James et al, 2011;

Tsao et al, 2012;Amin et al,2017)

4 CONCLUSION

The diagnosis of BPD, in this case, was formed based

on a patient's history, clinical picture, and

histopathological examination. Clinical

manifestations found in the patient were three major

criteria: facial angiofibroma, hypomelanotic macule

(ash leaf macule), and shagreen patch without

systemic involvement. Electrocauterization

combined with mTOR inhibitor (sirolimus) appears

to be a promising and effective way of treating facial

angiofibromas which is cosmetically disfiguring in

patients with BPD. The major disadvantages are the

cost of Topical Sirolimus (TS) which is prohibitively

Bourneville-Pringle Disease Treated with Electrocauterization and Topical Tacrolimus 0.1

463

expensive, drug preparation is not included in the

national formulary, for the reason of drugs

inavailability in Indonesia, we weren't able

necessarily to provide topical sirolimus to the patient.

Electrosurgery and Topical Tacrolimus (TT) 0.1%

become the other alternatives to reduce FASI score.

TT can replaces invasive procedure for angiofibroma

due to tue recurrence, included in the national

formulary and also cheaper than TS. TT 0.1% more

effective compared to the 0.03% formulation. The

severity of BPD depends on systemic involvement,

while the possibility for recurrence is very high

caused by TSC1 and TSC2 mutation. Therefore

prognosis for this patient is qua ad vitam dubia ad

bonam, quo ad sanationam, and quo ad cosmeticam

dubia ad malam. Continuing observation by the

doctor is important. By having proper medical

management, most individuals who live with BPD

can hope for a normal quality of life.

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