Tuberous sclerosis and its oral manifestations. A clinical case

LÓPEZ-LÓPEZ J, RODRÍGUEZ DE RIVERA-CAMPILLO E, MARQUES-SOARES M S, FINESTRES-ZUBELDIA F, CHIMENOS-KÜSTNER E, ROSELLÓ-LLABRÉS X. TUBEROUS SCLEROSIS AND ITS ORAL MANIFESTATIONS. A CLINICAL CASE. MED ORAL 2004;9:216-23.

ABSTRACT

Tuberous sclerosis (TS) is a congenital anomaly in the development of the embryo which is transmitted through the autosomal dominant gene. It has various forms of clinical expression. It is classified as one of what are known as Phacomatoses (phakos stain and oma tumour), which are development anomalies that can originate tumours and/or hamartomas in the nervous system. Lesions in the nervous system are nearly always accompanied by cutaneous anomalies. In this study we introduce the case of a woman patient aged 55, diagnosed several years earlier with Tuberous Sclerosis, who attended for intraoral lesions which were clinically compatible with fibromata. These lesions of fibrous appearance occurred above all on the lower lip and in both cheeks' mucous membra-nes, little mentioned in the literature as a site for such a manifestation of TS. The pathological anatomy suggested lesions compatible with Angiomyolipoma.
In addition, the data referring to TS are reviewed; its implications for the mouth are described; and histopathological results are used to examine the significance of the word Angiomyolipoma.

Key words: Tuberous sclerosis / Angiomyolipoma / fibromata

INTRODUCTION

Tuberous sclerosis (TS) (Bourneville's or Bourneville-Pringle's disease, ICD-DA 759.5) is a congenital anomaly in the development of the embryo. It is transmitted through the autosomal dominant gene, with high but not full penetrability, and has various forms of clinical expression. It is classified as one of what are known as Phacomatoses (phakos stain and oma tumour) (1), a word coined in 1923 by Van der Hoeve. These are genetically determined development anomalies with varying possibilities of evolution, but able to cause tumours and/or hamartomas in the nervous system. It should be noted that lesions to the nervous system are nearly always accompanied by cutaneous anomalies, which gives rise to other names such as neurocutaneous syndromes, neuroectodermal dysplasia or neurocrinopathies.

The classic triad described by Vogt in 1908 comprises epilepsy, mental deficiency and facial angiofibromas (these are telangiec-tases or small yellow nodules, often distributed around the nose, cheek and chin and often shaped like butterfly wings) (2-5). Other classic authors who contributed to the development of the initial criteria were Von Recklinghausen (who defined the disease in 1863), Bourneville and Pringle (6).

Authors differ in their view of the degree of incidence of TS, both because of the varying clinical manifestations it presents and its genetic penetrability (estimated at 50-60%). Thus, while some authors give as a reliable figure of occurrence 1:100,000 individuals (1), others talk in terms of 1:5-15,000 (7).

Currently, the classic triad is found in less than a third of patients and as many as 6% of patients show none of these symptoms. Today certain diagnostic criteria, which group together definitive and supposed criteria (see Table 1), are accepted (1,8,9). The recommendation made by Marshall in 1959 is also still valid. This suggested that we should suspect the disease when faced by a patient with epileptic crises linked to skin disorders or progressive dementia (10).

 

Table 1. Diagnostic criteria for Tuberous Sclerosis. Taken from (1).

AETIOPATHOGENY

Although the disease's aetiology is unknown, the mechanism that favours its development appears to respond to a disorder in the Cellular Adhesion Molecules (CAM). Some studies suggest that the Neurological Cellular Adhesion Molecules (NCAM), genetically located in the region 11q23, are responsible for the tissue disorder present in TS. Other authors believe it could be caused by a mutant gene located in the long arm of chromosome 9 (9q34) (TSC1) or 16 (16p13.3) (TSC2) (1,5,11).

CLINICAL MANIFESTATIONS

The disease is usually diagnosed in the first years of life, due to the presence of epileptic patterns or to deterioration in the locomotor system, which leads to the search for stains on the skin. Sometimes the diagnosis is later, when comitial patterns, intracraneal calcification or facial "sebaceous adenomas" appear. Up to a third of the cases may occur with few or no symptoms, so that recognition of patterns in progenitors may be key to diagnosis as well as to subsequent genetic counselling on the disease (1). As such, it is important to understand the variety of its clinical manifestations (1,4,12,13).

-1) NEUROLOGICAL ASPECTS

Although epilepsy and mental disorders are characteristic of the disease, up to a third of patients may present no psycho-neurological disorder, especially in the case of late diagnoses. Epilepsy occurs in 80-90% of cases, usually appears before the second year of life and is normally the reason for consultation. The earlier it presents, the more serious it is. It usually occurs in the form of West's or the Lennox-Gastaut syndrome. Epileptic patterns associated with colourless stains direct physicians towards the diagnosis of the disease. Remember that epilepsy which is hard to control will unfailingly imply mental deficiency (1).

-Mental disorders present to a varying degree (60-80%) and may occur alongside behaviour and personality disorders, but above all psychotic disorders. Autism is extremely high in some series. Intracraneal Hypertension is found on occasion, due mainly to a benign tumour (1, 5).

-2) DERMATOLOGICAL MANIFESTATIONS

Cutaneous manifestations are pertinent to the diagnosis of this disease, especially if they are associated with neurological patterns. Low-colour or colourless stains are white leaf-shaped macules.

Facial angiofibromas are erroneously called Sebaceous Adenomas of Pringle, as the sebaceous glands are only passive partners to the lesion. These are small rounded tumours incrusted in the skin, between a pin-head and pea in size, reddish-coloured and normally spread out symmetrically in the shape of butterfly wings (nasogenian folds) around the nose, cheeks and chin (1).

The "orange skin" appearance refers to zones of the skin, in general dorsal or lumbar, with an irregular surface comparable to orange skin. Koenen's tumours or ungual angiofibromas, located on hands or feet, may be sub- or peri-ungual. In histological terms they are hamartomas, with Hyperkeratosis, vascular proliferation and collagen (1).

-3) OTHER MANIFESTATIONS

Retinal hamartomas can be observed in the eye, sometimes on a routine back-of-eye examination (1,5). Renal Angiomyolipo-mas are the most typical of the manifestations inside the body. They are usually multiple, bilateral and associated with cysts. They are responsible, along with the epileptic patterns and the pulmonary, cardiac and vascular manifestations, for the disease's poor prognosis (1,14).

Cardiac involvement is usually Rhabdomyoma, which is normally only diagnosed at autopsy. The most prevalent pulmonary manifestation is usually more or less extensive polycystic disease. Osseous lesions are usually pseudo-cystic, metacarpal and metatarsal or phalangeal geodes measuring 1 to 3 mm, or areas of Hyperostosis. Among the vascular manifes-tations, dysplasias of the vascular walls are found. In the brain, aneurysms, sometimes responsible for subarachnoid haemorrhages, or giant aneurysms which can become calcified have been described (1,3,5).

-4) ORAL MANIFESTATIONS

Oral lesions are especially important in TS, as up to 15% of patients present them (15). These lesions are collected in the first series on the disease, especially in its most common manifestation: "fibrous plates" located on the gums, lips and tongue (6,16). Currently most authors group oral lesions, which vary in their incidence according to different authors, in several groups: dental lesions, mucous lesions, skeletal lesions and other lesions (4,6,17-19).

4.1. Dental disorders.

Hypoplasia of the enamel in the form of holes or pitting is very significant in this illness, even more so than in other mental disorders such as cerebral paralysis, Down's syndrome or Phenylketonuria (17). High prevalence figures are quoted (40-60%) and Mlynarczyk, in a study of 50 patients, gives a mean of 90% for the entire group, with variations between 76 and 100%, depending on the age interval considered (19).

4.2. Mucous lesions.

The presence of mucous nodules (both scarce and abundant) is described classically. Their prevalence is calculated at around 11-15% (6,15), though Lygidakis, in a study of 39 patients, quotes prevalence of 56% (20). The lesion consists of red-yellowish or mucous-coloured angiofibrous nodules of variable size. They mainly occur on the front part of the gum, but cannot be discounted on the lips, cheek, tongue or palate. These nodules [gingival fibrous nodules or gingival nodules such as Giunta describes (21)] are in histological terms composed of normal tissue similar to gums, with little parakeratosic flaky epithelia, with thick layers of connective fibres and various degrees of interdigitation. These fibrous nodules must be distinguished, in clinical-pathological examinations, from fibromata, papillomas, focal epithelial Hyperplasia, hamartomas, gingival cysts and Exostosis (21,22). Gingival Hyperplasia has been linked in particular to anti-convulsion therapy and poor oral hygiene (18,23).

4.3. Skeletal lesions.

Cleft palates, hare-lips and alveolar Hyperostosis are described, with occurrence running at 45-60%, depending on the authors (16, 18).

4.4. Other lesions.

A wide variety of lesions linked to the illness have been described, in particular: calcified odontogenic tumour, desmoplastic fibroma, mucous and/ or intraosseous heman-gioma, odontogenic myxoma (4), facial asymmetry, bifid uvula, delayed eruption and diastemata, inter al.

DIAGNOSIS

CT (computed tomography) is particularly useful, as it enables calcium deposits (mainly accumulating in the subependymal nodules or white substance) to be detected and thus the anomaly in the CNS to be identified early. These calcifications can be detected in the first months of life and even at birth. CT also detects periventricular nodules or subependymal astrocytomas (present in 7-15% of all cases). However, only MR (Magnetic Resonance) enables clear identification of cortical tubers. These two examinations are complementary (24). MR is also used for antenatal diagnosis of the disease.

EVOLUTION AND PROGNOSIS

The course and prognosis of the condition depend on the type of epileptic crises and on the depth of the intellectual deterioration of the patients. Cardiac Rhabdomyomas can cause rhythm disorders. Pulmonary cyst disease may occur alongside Pneumothorax, pulmonary Hypertension and even cor-pulmonale. Renal cysts may set off arterial Hypertension and Angio-myolipoma may occur alongside Haematuria, retroperitoneal haemorrhage or progressive renal failure, thought by many authors to be one of the main causes of mortality (1,5,24).

TREATMENT

Treatment will be specific to each of the various clinical manifestations that the patient presents. This runs from medical treatment for epileptic fits (Valproic acid, ACTH, Clonazepam, Phenytoin, Phenobarbital or Carbamazepine, depending on the kind of attack) or for cardiac complications (anti-arrhythmia or pressure-lowering drugs etc.), to surgical treatment in cases of Rhabdomyomas, giant subependymal tumours or Angiomyoli-pomas (5,24).

Therapeutic Advice

When a child is diagnosed with the disease, members of its family must undergo the following tests: a) dermatological examination; b) back-of-eye examination; c) brain CT and MR scan; and d) heart and kidney echograph. It will also be necessary to find out if there is mental handicap or epilepsy in the family. If one of the parents is found to be affected, the possibility of transmitting the disease is estimated at 50% (1). If the parents are undamaged, the possibility of transmission is slight, but it is not impossible. Further procreation should be advised against if a child has the disease.

CLINICAL CASE

Woman of 55 attending the clinic for a buccal review. In her family and personal background, there was a medical history compatible with Tuberous Sclerosis (compatible calcifications in CT and facial angiofibromas). She had no other pertinent medical history. The patient presented multiple facial lesions, previously diagnosed as "Sebaceous Adenomas" (Fig. 1). In the buccal examination multiple lesions, some 3-6mm across at their greatest width and spread round the jugal mucous membrane and inner lip, were appreciated (Fig. 2, A y B). Some of the lesions had exophytic, sessile growth and normal colouring of the mucous membrane; others were nodules, whose appearance was compatible with accumulation of mucous material. The patient had not consulted before about these lesions, which were asymptomatic, and did not remember how long she had had them. She presented no other intraoral lesion and had advanced loss of teeth, according to the patient due to a history of slow caries.

 

Fig. 1. Facial lesions diagnosed as sebaceous adenomas.
Lesiones faciales diagnosticadas de adenomas sebáceos.

 

Fig. 2. Lesions on the lip (A,B).
Lesiones en el labio (A,B).

A diagnosis of suspected multiple Fibromatosis associated with the underlying disease (TS) was made and two samples, from the inside lip and left jugal mucous membrane, were taken for histopathological study. The histological result of the two lesions, through a Haematoxylin-eosin stain, was Angio-myolipoma (Fig. 3). An immunohistochemical test for HMB-45 and m-actin was also run, but both turned out negative.

Fig. 3. Histopathological images. HE stain.
Imágenes histopatológicas. Tinción con HE.

 

As the lesions and the anatomo-pathologic findings were asymptomatic, she was advised to have periodic check-ups, the same as she did for other signs of the disease.

DISCUSSION

Data on fibrous nodules, mainly located on the gums but also present on the palate and tongue among other sites in the buccal mucous membrane, in patients with TS are found in the literature (5,20-22). Nevertheless, the clinical appearance of the lesions of our patient fitted perfectly into what Giunta (21) describes as gingival nodules. The location did not seem very common, as most studies, in particular Shafer (25) and Giunta (21), state that the lesions are basically at a gingival location. Lygiadakis (20), in a series of 48 patients, with oral Fibromatosis in 56%, found lesions on gums, palate and tongue, but did not describe any on jugal mucous membrane or lips.

In histological terms, fibrous lesions associated with TS are defined as normal tissue similar to gum tissue, with little keratinised epithelium and variable degrees of collagen fibre or papillary interdigitation, which can be classified as small fibromata (22).

Angiomyolipoma, first described by Albrecht in 1904 and given its current name by Morgan in 1951, is defined as an unusual renal tumour developing from a hamartoma. Generally considered benign, it contains a large amount of smooth muscle, adipose tissue and blood vessels. The proportion of these three elements varies. In 40% of cases it is associated with Tuberous Sclerosis and on these occasions may be bilateral and multiple (26). Among presentations not associated with Tuberous Sclerosis are cases occurring on the trunk and extremities, though very rarely in the head or neck area (27).

Of the 10 cases of intraoral presentation that we found in the literature, all occur singly. In some of these cases no histochemical tests additional to the Haemotoxylin-Eosin stain were conducted to complete the diagnosis (Table 2) (28-36). None of the cases recorded had a multiple presentation, associated or otherwise with TS. In those cases in which no immunohistochemical tests were conducted, the diagnosis should be considered differential with Angiolipoma, of which the literature contains nine intraoral cases (37-40), or with Angioleiomyoma, Lipoma, Angiomyoma or fibrolipomatous Hyperplasia.

Table 2. List of cases of intraoral Angiomyolipoma found in the literature.
(*) F= female; M= male; S= Size in cm; TS= Tuberous Sclerosis YES or NO; I= Immunohistochemical 
test run, YES or NO; -- = data unknown.

Tabla 2. Relación de casos de angiomiolipoma de presentación intraoral recogidos de la literatura.
(*) H= hembra; V= varón; T= Tamaño en cm; ET= Esclerosis Tuberosa SÍ o NO; I= Inmunohistoquímica 
realizada SÍ o NO; - = desconocemos el dato

 

In conclusion, the above leads us to think that the few described cases of oral Angiomyolipoma associated with TS refer to a single tumour. Although the case of our patient satisfies the indicated criteria in relation to the Haemotoxylin-Eosin stain, it should also be positive for the antigen associated with melanoma (HMB-45) and, at the very least, for m-actin. Our case was negative to these antigens. In addition, the patient had multiple fibromata which were clinically compatible with fibromata associated with TS, mostly described as being on the gums. As such, we believe this case showed a pattern of multiple labial and jugal fibromata, associated with the underlying disease (TS), in a fairly uncommon location and with an unusual fat, vessels and muscle content.

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