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 Table of Contents  
CASE REPORT
Year : 2020  |  Volume : 7  |  Issue : 2  |  Page : 92-95

Cutaneous angiofibroma: A clinching evidence for diagnostic workup of tuberous sclerosis complex


1 Department of Pathology, B.K.L. Walawalkar Rural Medical College, Shree-Kshetra Dervan, Ratnagiri, Maharashtra, India
2 Department of Radiology, B.K.L. Walawalkar Rural Medical College, Shree-Kshetra Dervan, Ratnagiri, Maharashtra, India

Date of Submission11-Jun-2020
Date of Decision24-Jun-2020
Date of Acceptance26-Jun-2020
Date of Web Publication22-Dec-2020

Correspondence Address:
Dr. Bhagyashree P Mundhe
Department of Pathology, B.K.L. Walawalkar Rural Medical College, Shree-Kshetra Dervan, Chiplun, Ratnagiri - 415 606, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdpdd.ijdpdd_54_20

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  Abstract 


Tuberous sclerosis complex (TSC) or Bourneville's disease is a genetic multisystem disorder of multisite hamartomas. Majority of TSC cases are sporadic. TSC typically presents in the first decade of life and has a reported incidence of 1:6000–12,000, with intracranial involvement in the form of cortical tubers or subependymal nodules. Tubers (potato-like nodules) are triangular-shaped lesions centered at the cortex/juxtacortical, with apex oriented “inward” toward the ventricles, on magnetic resonance imaging (MRI) of the brain. Tubers represent cortical glioneuronal hamartomas and consist of focal distortions in the cellular organization and morphology, which extend into the underlying (subcortical) white matter. Skin lesions with a history of seizures can be an eye-opener to diagnose angiofibromas and its variant, which can lead to further effective workup such as ophthalmoscopy and MRI of the brain to diagnose TSC, just like in our case.

Keywords: Angiofibroma, face, tuberous sclerosis complex


How to cite this article:
Warpe BM, Mundhe BP, Joshi-Warpe S, Kulkarni A. Cutaneous angiofibroma: A clinching evidence for diagnostic workup of tuberous sclerosis complex. Indian J Dermatopathol Diagn Dermatol 2020;7:92-5

How to cite this URL:
Warpe BM, Mundhe BP, Joshi-Warpe S, Kulkarni A. Cutaneous angiofibroma: A clinching evidence for diagnostic workup of tuberous sclerosis complex. Indian J Dermatopathol Diagn Dermatol [serial online] 2020 [cited 2021 Jan 20];7:92-5. Available from: https://www.ijdpdd.com/text.asp?2020/7/2/92/304340




  Introduction Top


Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome characterized by the development of multiple hamartomas distributed at various body sites, such as brain, skin, retina, kidney, heart, and lungs.[1] Majority of TSC cases (approximately two-third) are sporadic due to new mutations in the genes, TSC1 and TSC2.[2] An autosomal dominant (AD) inheritance pattern has been demonstrated in the remainder of one-third of TSC cases.[2]

Seizures, mental retardation, and cutaneous angiofibromas comprise a classic triad seen in TSC. In spite of variable presentation, 29% of patients have all three of them and about 6% of patients do not have any of the three symptoms.[3] More than 90% of the patients with TSC have ≥1 skin lesions which usually develop early in their life and often go ignored by the patient. The recognition of TSC-related skin lesions can facilitate further workup for early implementation of treatment.[4]


  Case Report Top


An 8-year-old child was brought by parents with complaints of multiple hyperpigmented dome-shaped skin lesions over both cheeks, single-raised hyperpigmented plaque seen on the right forehead, and single pale hypopigmented macule seen just above the left eyebrow.

His history had three episodes of partial seizures about 1 year back, for which he is currently on tablet carbamazepine 100 mg BD. There was no significant family history. He lacked mental retardation.

On examination, his general condition was within normal limits (WNLs) with normal cardiovascular, per-abdominal, respiratory, and central nervous system examinations.

On dermatologic examination, face revealed many skin lesions [Figure 1]a. Multiple hyperpigmented dome-shaped, tiny skin lesions were seen distributed symmetrically over both cheeks [Figure 1]b and [Figure 1]c. A single-raised hyperpigmented irregular plaque was seen over the right forehead measuring 1 cm × 1 cm [Figure 1]d. Furthermore, single hypomelanotic lesion was seen over the left eyebrow measuring 3 cm × 1 cm [Figure 1]e. His complete blood counts, urine examination, liver function tests, kidney function tests, and chest X-ray were WNL.
Figure 1: (a) Clinical photograph showing entire face. (b and c) Clinical photograph showing dome shaped tiny cheek lesions. (d) Clinical photograph is showing single raised hyperpigmented plaque on the right forehead. (e) Clinical photograph is showing single pale hypopigmented macule just above the left eyebrow

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Histopathological examination of the skin biopsy from facial lesion over cheek revealed the presence of angiofibroma of the skin It showed dome shaped lesion with epidermal thinning with dermis [Figure 2]a. Dermis showed dense fibrocollagenous tissue with spindled, stellate cells and dilated blood vessels [Figure 2]b.
Figure 2: (a) Microphotograph of dome shaped (left top: H and E, ×40) skin biopsy from facial lesion over the cheeks is revealing epidermal thinning with dermis. (b) Dermis is showing dense fibrocollagenous tissue with spindled, stellate cells and dilated blood vessels (right top: H and E, ×400). (c) Microphotograph of hyperpigmented plaque over the right forehead is revealing increased melanocytes in the basal epidermis and melanin incontinence within the dermal tissue. Dermal tissue again showed dense collagenous tissue with spindled, stellate cells and dilated, telangiectatic blood vessels (bottom: H and E, ×400)

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Another biopsy (fibrous cephalic plaque [FCP]) from hyperpigmented plaque over the right forehead revealed acanthosis with increased melanocytes in the basal epidermis and melanin incontinence within the dermal tissue. Dermal tissue again showed dense collagenous tissue with spindled, stellate cells and dilated, telangiectatic blood vessels [Figure 2]c.

Hence, considering the presence of angiofibroma of the skin and previous history of convulsions, a suspicion of tuberous sclerosis was made. To support the diagnosis of TSC, series of investigations were done. Ultrasonographic examination of the abdomen and pelvis revealed no abnormality.

Due to the history of seizures, magnetic resonance imaging (MRI) of the brain was done which showed multiple hyperintense lesions (cortical tubers) in the right and left parietal lobes [Figure 3]a and left occipital lobe [Figure 3]b. Calcified hamartomas were seen as areas of signal void that protruded into lumens of both lateral ventricles . On ophthalmoscopic examination, pale mulberry-like opacities were seen around the retinal vessels. Thus, TSC was the final diagnosis.
Figure 3: (a) Magnetic resonance imaging brain: Cortical tubers (arrows) noted as multiple hyperintense lesions in the right and left parietal lobes on T2-weighted image and fluid-attenuated inversion recovery. (b) Magnetic resonance imaging brain: Cortical tubers (arrow) noted as hyperintense lesion in the left occipital lobe on T2-weighted image and fluid-attenuated inversion recovery

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  Discussion Top


Bourneville's disease (TSC) is a genetic disorder of hamartoma formation in many organs, particularly skin, brain, eye, kidney, and heart. TSC has an AD inheritance, but up to 70% of cases are because of new mutations.[5] Two tumor-suppressor genes for TSC have been identified: TSC1 on chromosome 9 and TSC2 on chromosome 16.[3] The proteins hamartin encoded by TSC1 and tuberin encoded by TSC2 form a heterodimer that suppresses the mTOR pathway, which coordinates various functions such as cell growth, metabolism, and proliferation. Overactivation of mTOR pathway results for the development of various tumors in different organs.[6]

TSC is highly variable in clinical presentation and findings. Disease manifestations continue to develop over the lifetime of an affected individual. Accurate diagnosis is fundamental for the implementation of appropriate medical treatment.[7]

The clinical diagnostic criteria as per the recommendations of the 2012 International TSC Consensus Conference include a total of 11 major criteria and 6 minor criteria.[4],[7]

Major criteria include (1) hypomelanotic papules (≥3 with at least 5 mm in diameter), (2) angiofibromas (≥3 in number) or FCP, (3) ungal fibromas (≥2 in number), (4) Shagreen patch, (5) multiple retinal hamartomas, (6) cortical dysplasia including cortical tubers, (7) subependymal nodules, (8) subependymal giant cell astrocytoma, (9) cardiac rhabdomyoma, (10) lymphangioleiomyomatosis, and (11) angiomyolipomas (≥2 in number).

Minor criteria include (1) confetti skin lesions, (2) dental enamel pits (≥3), (3) intraoral fibromas, (4) retinal achromic patch, (5) multiple renal cysts, and (6) nonrenal hamartomas.

For a definite diagnosis of TSC, at least two major or one major with ≥2 minor criteria are to be fulfilled. For a possible diagnosis of TSC, either one major or ≥2 minor features are to be fulfilled.[7]

DNA testing is useful for diagnosis and determining the causative mutation. However, approximately 30% of patients with TSC have negative results for TSC1 and TSC2 mutations.[1] Due to cost restraints, it was not done in our case.

Therefore, a careful skin examination is the easiest, earliest, and most accessible method to establish a TSC diagnosis. The common skin lesions are ash-leaf macule, forehead plaques, Shagreen patch, and facial angiofibromas. The presence of facial angiofibromas is a major criterion and is nearly pathognomic of TSC.[1]

The facial angiofibromas are popular lesions that primarily affect the nasolabial folds, cheeks, and chin bilaterally and symmetrically or as mosaic pattern unilaterally.[8] Microscopically, angiofibromas are typical well-circumscribed dome-shaped lesions. The main proliferating element is the spindle cells with a cytologically bland, oval-to-fusiform nucleus and a scanty amount of lightly eosinophilic cytoplasm with ill-defined margins. The vascular component is composed of numerous small-to-medium–sized vessels distributed uniformly throughout the lesion.[8] Our patient had skin lesions over the cheeks bilaterally which were confirmed as angiofibroma on biopsy.

FCPs are histologically similar and represent a larger variant of angiofibromas.[8] They are raised, firm plaques, usually located on the forehead or scalp and have tan to yellow-brown color. FCP can occur at any age, can vary in size and shape, and can grow to several centimeters in diameter.[8] Our patient had skin lesion over the right forehead which was confirmed as FCP on biopsy.

A single hypomelanotic, pale lesion over the left eyebrow was noted clinically which was not biopsied. As it was a single lesion, it did not fit into the TSC major criterion.

Our patient had a history of convulsions without mental retardation apart from the present skin lesions diagnosed on histopathology. These two findings are part of the classical triad of TSC. On further investigations, the presence of cortical tubers on MRI of the brain and pale retinal hamartoma on ophthalmoscopic examination confirmed the case as TSC. All these findings together fulfilled three major criteria (angiofibroma of skin with its FCP variant, cortical tubers, and retinal hamartomas), which support the final diagnosis of TSC as per the 2012 recommendations.[4],[7]


  Conclusion Top


Facial angiofibroma is one of the major criteria and is a pathognomic, earliest, and easiest finding that helps to clinch the diagnosis of TSC. Our workup on this case with skin lesions led to the diagnosis of cortical tubers and retinal hamartomas. Systematic approach helped in early diagnosis of this variably presenting neurocutaneous syndrome involving multiple organ systems and helped plan further follow-up and management.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient's parent has given his consent for images and other clinical information to be reported in the journal. The patient's parent understands that his names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Hake S. Cutaneous manifestations of tuberous sclerosis. The Ochner J 2010;10:200-04.  Back to cited text no. 1
    
2.
Krueger DA, Northrup H, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus conference. Pediatr Neurol 2013;49:255-65.  Back to cited text no. 2
    
3.
Schwartz RA, Fernández G, Kotulska K, Jóźwiak S. Tuberous sclerosis complex: Advances in diagnosis, genetics, and management. J Am Acad Dermatol 2007;57:189-202.  Back to cited text no. 3
    
4.
Cardis MA, DeKlotz CM. Cutaneous manifestations of tuberous sclerosis complex and the paediatrician's role. Arch Dis Child 2017;102:858-63.  Back to cited text no. 4
    
5.
Goel A, Patel DK, Agrawal A, Dalal B, Lakhani KK, Agrawal SB. Tuberous sclerosis. JIACM 2004;5:75-8.  Back to cited text no. 5
    
6.
Słowińska M, Jóźwiak S, Peron A, Borkowska J, Chmielewski D, Sadowski K, et al. Early diagnosis of tuberous sclerosis complex: A race against time. How to make the diagnosis before seizures? Orphanet J Rare Dis 2018;13:25.  Back to cited text no. 6
    
7.
Northrup H, Krueger DA, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus conference. Pediatr Neurol 2013;49:243-54.  Back to cited text no. 7
    
8.
Garcia NG, de Carli ML, Oliveira DT, Soares CT, Ribeiro Júnior NV, Sperandio FF, et al. Tuberous sclerosis with severe cutaneous manifestation and multiples facial angiofibromas. Head Neck Pathol 2016;10:542-6.  Back to cited text no. 8
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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