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Romanian Journal of Morphology and Embryology 2009, 50(1):119–124

CASE REPORTS

Tuberous sclerosis complex: report of two intrafamilial cases, both in mother and daughter

DANIELA DUMITRESCU1), E. F. GEORGESCU2), MIHAELA NICULESCU3), CRISTIANA IULIA DUMITRESCU4), S. S. MOGOANTĂ5), IULIANA GEORGESCU6)

1)Department of Radiology and Medical Imaging 2)Department of Internal Medicine 3)Department of Pathology, “Filantropia” University Hospital 4)Department of Pharmacology 5)Department of Surgery University of Medicine and Pharmacy of Craiova 6)Division of Dermatology, Mediplus Diagnostica Clinical Center, Craiova

Abstract Tuberous sclerosis complex (TSC) is a multisystem syndrome characterized by neurological symptoms and tumors in multiple organs including , brain, skin, eyes, and . Kidney and brain are the two most frequently affected organs in TSC. TSC is an autosomal disorder with extensive clinical variability. We described TSC in a family at a mother and her daughter. We emphasized the importance of Computed Tomography in the discovery of some asymptomatic organic involvement as bilateral renal angiolipoma in the mother. Keywords: tuberous sclerosis, , .

 Introduction  Patients and Methods Tuberous sclerosis complex (TSC) is an inherited We will describe two cases of patients belonging to neurocutaneous disorder characterized by the potential the same family, a mother (case no. 1), aged 34-year-old for the presence of in almost every and her daughter (case no. 2), aged 4, both displaying organ, most notably in the skin, brain, kidney, heart cutaneous TSC – suggesting lesions on their faces. and eyes [1]. The condition was described by Moreover, the woman told us that her daughter has been von Recklinghausen in 1862 [2]. suffering from infantile spasms since she was 3-year-old. In 1880, Bourneville described the pathologic She consulted many specialists and was recommended a features of the sclerotic tubers found post mortem CT examination. Apart from this, the girl is in patients with and mental retardation and welldeveloped physically and intellectually, according coined the term “sclerose tubereuse” [1]. to her age. The woman is apparently in complete health The term “tuberous sclerosis” refers specifically to condition, without any subjective signs of neurological, the presence of multiple sclerotic masses scattered renal, pulmonary or digestive affections. The family throughout the cerebrum. The diagnosis of TSC is based history shows that all the other family members are on the identification of hamartomas in more than one apparently healthy, with normal intellect. Both cases organ system. A hamartoma is a were highly examined clinically and paraclinically. composed of an overgrowth of mature cells and tissues There were drawn fragments from the cutaneous lesions that normally occur in the affected tissue, but often with and histopathologically examined. Cutaneous fragments one predominating element. The hamartoma formation were fixed in 10% formalin paraffin-embedded and is most notable in the skin, brain, kidneys, heart and routinely stained with Hematoxylin–Eosin. Imagistic eyes [1]. tests were used to discover organic affections without The kidney and brain are two of the most frequently any clinical expression, and in this case CT was preferred. affected organs in TSC [3]. CT scanning was performed with a 5 mm slice thick- The disease is an autosomal disorder with extensive ness and interval native, after intravenous administra- clinical variability. The presence of hamartomas in two tion by bolus injection of nonionic contrast material at different organ systems is considered by some clinicians rate of 1 mL/s, on a CT Philips Aura. A CT-scan to be sufficient for the diagnosis [4]. indicated clear pointed nodular calcifications.

120 Daniela Dumitrescu et al.  Results no. 1 (the mother) (Figure 2). Besides, the woman had some small pulpous bud-like proliferations emerging General clinical examination was performed within from peri- folds (Figure 3) at fingers and toes normal limits for both the mother (case no. 1) and her and numerous confetti, hypopigmented macules on daughter (case no. 2). During dermatologic examination, the trunk and lower extremities. At the ophthalmologic both mother and daughter presented pink to red small examination, the woman’s diagnosis was “optic nodules of 1–5 mm diameter symmetrically distributed primitive atrophy, whitish juxta-papillar placard of the in the nasolabial folds, cheeks and nose. Most of the left eye and thin arteries with whitish striations in the nodules were yellowish and firm, others were right eye”. Histopathologically, in both cases the images telangiectasic and soft, with a glossy smooth surface are typical for angiofibroma (misnamed adenoma (Figures 1 and 2). The lesions were conspicuous in case sebaceum).

Figure 1 – Pink to red small Figure 2 – Pink to red, yellowish Figure 3 – Periungual nodules symmetrically distribu- and teleangiectayic small nodules (Könen tumors); smoat buds flesh ted in the nasolabial folds, of 1–5 mm diameter, with glossy -colored at the base of nail and cheeks and nose. smooth surface symmetrically periungual with partial disrupt of distributed in the nasolabial folds, the nail. cheeks and nose.

In the second case, the epithelium presents minimum elements in superficial derma, with marked atrophy of acanthosis with hyperkeratosis and parakeratosis, sebaceous glands, typical changes of an angiofibroma associated with fibroblastic proliferation of capillary (Figure 4, a and b).

(a) (b) (c)

(d) (e) (f) Figure 4 – (a) Squamous epithelium fragment with minimum acanthosis and parakeratosis (HE stain, ob. 10×); (b) Fibrovascular proliferation with atrophy of sebaceous gland (HE stain, ob. 20×); (c) Squamous epithelium fragment with marked acanthosis, parakeratosis and papillomatosis (HE stain, ob. 10×); (d) Derma–perivascular fibromatous proliferation (HE stain, ob. 20×); (e) Diffuse and perivascular sclerofibrous proliferation with dilatation of sebaceous glands (HE stain, ob. 10×); (f) Periglandular sclerofibrous proliferation (HE stain, ob. 20×).

Tuberous sclerosis complex: report of two intrafamilial cases, both in mother and daughter 121

In the first case, covering epithelium shows marked ▪ white macules localized on the trunk containing papillomatosis, acanthosis, hyperkeratosis and abnormal melanocytes. parakeratosis. In subjacent derma, histopathological Computed tomography shows: examination shows dense fibrous and ▪ at the daughter: calcified subependymal perivascular proliferation with marked atrophy of periventricular – IVth (Figure 5a), and along sebaceous glands (Figure 4, c and d), which alternates the lateral border of temporal horn of right lateral with diffuse fibrous sclerosis and also periglandular ventricle; -like lesions in the white matter and fibrous proliferation, with circumferential arrangement. punctate calcifications conglomerated in left cerebellar Intraglandular eosinophilic content (Figure 4, e and f) it hemisphere with serpiginous enhancement (Figure 5b), is an argument for . Both described and smaller calcified nodules in the subependymal forms – angiofibroma and sebaceous adenoma – are region of both lateral ventricles and in the cortex of the characterized by a marked fibroblastic proliferation with parietal region (Figure 5c); pericapillar and periglandular sclerohyaline dystrophy. ▪ at the mother: subependymal calcified nodules in Histopathological examination of the other the typical sites, along the lateral walls of the body of cutaneous lesions at mother shows: the lateral ventricles (Figure 6a); multiple angiomyo- ▪ only vascular fibrous tissue in periungual tumor; at left kidney (Figure 6b), and right kidney ▪ excessive collagen in lumbar lesion; (Figure 6, c and d).

(a) (b) (c) Figure 5 – (a) Calcified subependymal nodule periventricular (IVth ventricle); (b) Punctate calcifications conglomera- ted in left cerebellar hemisphere and serpiginous enhancement. Large calcified cerebellar tuber. Calcified subependymal nodule along the lateral border of temporal horn of right lateral ventricle. Cyst-like lesions in the white matter with 1 cm diameter; (c) Smaller calcified nodules in the subependymal region of both lateral ventricles and in the cortex of the parietal region.

Figure 6 – (a) Subepen- dymal calcified nodules in the typical sites, along the lateral walls of the body of the lateral ventricles; (b) Left kidney: multiple angio- (a) (b) myolipoma with diame- ters between 5 and 35 mm; (c, d) Bilaterally renal .

(c) (d)

122 Daniela Dumitrescu et al.

 Discussion may have smaller satellite lesions around [11]. The shagreen patch is found in 20% to 30% of patients with Tuberous Sclerosis Complex (TSC) is an autosomal TSC [13]. dominant disorder characterized by hamartomas in 4. Periungual and ungual fibromas (Köenen tumors) many organs [5]. It is an inherited disease with almost are found in approximately 20% of unselected patients complete but variable [6, 7]. with TSC and are more common in adolescents and Two-thirds (65%) of cases are sporadic and are thought adults than in young children [13]. These tumors appear to represent new [5, 8, 9]. Two as smooth buds at the base of the nail or subungually associated with TSC have been cloned: TSC1 located on and may reach a size sufficient to disrupt the nail bed the long arm of (9q34) and TSC2 located [11]. They are flesh-colored, usually multiple, and may on the short arm of (16p 13.3). TSC 1 affect fingers and toes. The nails of toes are more com- encodes hamartin and TSC2 encodes the tuberin. monly involved than those of the fingers [12, 14]. These TSC is caused by affecting either of the lesions occasionally develop subsequent to trauma [13]. presumed tumor suppressor genes, TSC1 and TSC 2. Other less lesions are multiple skin Both appear to function as tumor suppressors, because tags of the neck and axillae, “café au lait” spots in up somatic loss or intragenic mutation of the corresponding 30% of patients with TSC [6], confetti lesions (stippled wild-type allele is seen in the associated hamartomas hypopigmentation), polyosis (a white patch or forelock) [5]. The expressivity is not determined by the specific and thumbprint macules [13, 15]. Neurological manife- mutation, because different manifestations can stations are often the presenting feature and major cause develop in affected members of the same family [10]. of morbidity/mortality. Symptoms of cortical tubers This disorder affects about 1 per 100 000 individuals in may include , mental retardation, learning the USA and Western Europe. It has a worldwide disabilities, and abnormal behavior. Seizures have a distribution and involves both sexes. focal or multifocal origin, this clinical feature depending Clinical presentation on the localization of the cortical tubers [16]. The most common types of seizures are infantile spasm, partial The disease has protean manifestations and affects motor seizures, and generalized tonic clonic seizures every organ, even though the classic features are mental [15, 16]. Infantile spasms are most common during deficiency, epilepsy and adenoma sebaceum. infancy. Epilepsy associated with TSC is often Four types of skin lesions are pathognomonic: intractable, but control has benefited from the 1. Adenoma sebaceum (Pringle) or facial angiofibro- introduction of the new antiepileptic drugs. Mental ma is rarely present at birth but usually appears around retardation occurs in approximately 50% of patients the age of 5 to 6-year-old. The lesions increase in size with TSC. Almost all mentally retarded children will and number until puberty and remain stationary there- have seizures. Conversely, many patients with TSC after. They are pink to red nodules with a smooth, have seizures, but not mental retardation [15]. glistening surface [11], symmetrically distributed in the In general, the earlier the onset of the seizures is nasolabial folds, cheeks, and nose in a butterfly pattern. particularly infantile spasms, the greater the risk of The upper lip is notably spared [11]. The chin, ears, mental retardation, cognitive impairment, and behavioral forehead, and eyelids may be involved. The lesions are disorders [18, 20]. The intracranial abnormalities usually discrete, but occasionally they may coalesce. include tubers, subependymal nodules and subependy- Facial are comprised of vascular and mal giant cell [21]. No correlation was connective tissue elements and are found in approxima- found between the number of subependymal lesions and tely 75% of patients with TSC [6]. Forehead plaque, a the clinical severity of TSC. Computed tomography variant of angiofibroma, is seen in approximately 20% of (CT) and magnetic resonance (MR) features of the brain patients with TSC [6, 12]. These lesions appear in early lesions in patients TSC were an important support for childhood, grow very slowly, and present as firm, eleva- diagnostic. CT clearly demonstrates calcified subepen- ted plaques that are yellow-brown to flesh-colored [6]. dymal nodules. MR imaging more clearly demonstrates 2. Hypomelanotic macules or “ash leaf spots” named cortical and white matter lesions than CT, since MR after the European mountain ash tree [12] are usually imaging provides an excellent image. Contrast between present at birth and almost all lesions are evident within various normal structures and high sensitivity in the first two years of life [6]. Typically, the macules are detecting pathological states due to intrinsic differences rounded at one end and tapered of the other. These in proton density and in particular, in proton relaxation macules are found in more than 90% of patients with times of tissues [22]. Renal manifestations of TSC are a TSC [6]. In fair-skinned individuals, Wood’s light helps very significant cause of morbidity and mortality [23]. in their detection [11]. They may be the only cutaneous Three types of tumors occur in TSC kidneys: (1) sign of tuberous sclerosis and that is why they are of , which are benign tumors composed great diagnostic importance. of , and vessels; (2) epithelial ; 3. The shagreen or “leather” patch is an irregularly and (3) malignant tumors [3]. Angiomyolipomas are the shaped plaque of thickened skin, slightly elevated, with most common renal lesions. They are found in as many a “peau d’orange” surface. Characteristically, the patch as 75–80% of the affected children older than 10 years is in lumbosacral region and is the result of an [13] and must be distinguished from multiple renal cysts accumulation of collagen. Occasionally, a central patch that occur less commonly. Females are more often affe-

Tuberous sclerosis complex: report of two intrafamilial cases, both in mother and daughter 123 cted, in a female to male ratio of 3 to 4:1 [24]. The facts macroglossia, thickening of the alveolar bone and that they are rarely diagnosed before puberty in patient pseudocystic lesions of the mandible [1, 32]. Pulmonary without tuberous sclerosis, that large ones are more involvement is uncommon and its symptoms include common in women that men and that they occasionally dyspnea, hemoptysis, and recurrent spontaneous pneu- grow rapidly during pregnancy suggest that hormones mothorax [11]. The classic pulmonary lesion is lymph- may play a role in stimulating the growth of angiomyo- angioleiomyomatosis, a progressive lung disease [10]. [25]. Angiomyolipomas are benign tumors Bone involvements is evident in 80% of patients with composed of blood vessels with thickened walls, imma- tuberous sclerosis and include bone cysts found mainly ture smooth muscle cells, and adipose tissue [7]. The in the phalanges of the hands and feet, sclerotic lesions, lesions are often multiple and bilateral and grow in size and periosteal new bone formation [33]. Gastrointestinal and number with age [7, 13]. Typical angiomyolipomas manifestations may also be present. Hamartomatous are benign but may have alarming properties: nuclear polyps in the gastrointestinal tract, especially in the pleomorphism and mitotic activity, extension in the rectum, usually asymptomatic, are common [12]. Papill- vena cava, and spread to regional lymph nodes, without omas in the gastrointestinal tract were also reported [2]. malignant progression [25]. Smaller angiomyolipomas According to National Institute of Health (NIH) Conse- usually do not cause symptoms, but lesions larger than nsus Conference, a permanent diagnosis of TSC can be 4 cm in diameter are associated to an increased risk of made when two major features or one major feature plus serious hemorrhage [7, 13]. Epithelioid angiomyolipo- two minor characteristics are demonstrated (Table 1) ma is a recognized variant with malignant potential. [34]. Additional diagnostic categories include probable The second most frequent renal manifestation is a TSC when one major feature plus one minor one are . The tubule cysts in this disease are lined by a present, and possible TSC when either one major feature distinct, perhaps unique epithelium of marked hypertro- or two or more minor characteristics are present [34]. phic and hyperplastic cells with prominent eosinophilic Table 1 – Diagnostic criteria of TSC*,**,*** cytoplasm, bearing some resemblance to that of proxi- Major features Minor features mal tubule [26]. The combination of cystic kidneys and ▪ Facial angiofibromas or forehead ▪ Multiple randomly angiolipomas has been said to be virtually pathognomo- plaque; distributed pits in nic for tuberous sclerosis [13]. The cysts may be large ▪ Nontraumatic ungual or periungual dental enamel; and renal impairment, although relatively uncommon, ; ▪ Hamartomatous ▪ Hypomelanotic macules – more than rectal polyps; may occur before other evidence of the syndrome [27– three; ▪ Bone cysts; 29]. Renal cysts are identified in children younger than ▪ Shagreen patch (connective tissue ▪ Cerebral white-matter those with present angiomyolipomas [30]. Cysts greater ); “migration tracts”; than 4 cm in diameter are more likely to be symptomatic ▪ Cortical tuber; ▪ Gingival fibromas; ▪ Subependymal nodule; ▪ Nonrenal hamartoma; and might present with flank pain or gross or ▪ Subependymal giant cell ; ▪ Retinal achromic as a tender mass [24]. Hypertension is also a major ▪ Multiple retinal nodular hamartomas; patch; manifestation of the renal abnormality. ADPKD will ▪ Cardiac , single or ▪ “Confetti” skin develop in patients with a contiguous deletion of PKDi multiple; lesions; ▪ Lymphangiomyomatosis; ▪ Multiple renal cysts. gene, which is associated with flank pain, hypertension, ▪ Renal angiomyolipomas. pyelonephritis and progressive renal failure [31]. Renal *Definite TSC – either two major features or one major feature plus carcinomas are rare and tend to grow more slowly in two minor features; **Probable TSC – one major and one minor patients with TSC than in those found in the general features; ***Possible TSC – either one major feature or two or more minor features. population. The average age in patients with TSC is of 28-year-old, compared to 53-year-old in patients witt In the two cases of patients, belonging to the same renal carcinomas in the general population [7]. Ultraso- family whom we presented above, we can find out two nography, CT and arteriography are important in disting- major criteria necessary for TSC diagnosis. However, uishing multiple renal cysts from the more common we must underline the importance of their imagistic angiomyolipomas in this disease. Other organs are also investigations, respectively CT, to discover any organic involved. Cardiac are present in two alteration, which most of the time evolves asymptomati- thirds of newborn infants with TSC and are usually cally during long periods, but undergoes major compli- multiple [13] and asymptomatic [15]. They frequently cations. In case no. 1 (the woman’s case), following develop between 22 to 26 weeks of gestation, are of imagistic investigations, there was discovered a signific- maximal size, and cause the most clinical symptomato- ant renal affectation – the presence of angiomyolipoma. logy during intrauterine life or early infancy [31]. The They are generally benign, but may lead to serious com- lesions often regress over the first few years of life [13]. plications. On the other hand, a cranial affection was Retinal hamartomas occur in 40% to 50% of patients discovered at the woman’s daughter. Children seem to with TSC and are bilateral in a third of cases [30, 31]. develop subependymal giant cell astrocytomas, possibly Most lesions are asymptomatic. Three types of retinal more frequently than adults do. These tumors are histo- lesions have been described including classic “mulberry” logically benign but are locally invasive and may cause lesions adjacent to optic disc, plaque-like hamartomas, because of their typical occurrence in the and “punched-out” areas of retinal hypopigmentation anterior lateral ventricle. Early identification of an enla- [13]. Oral manifestations include enamel pitting in the rging giant cell tumor enables it to be removed before permanent teeth [31], fibrous hyperplasia, , symptoms development and before it becomes locally bifid uvula, cleft lip and palate, high-arched palate, invasive, probably reducing the likelihood of tumor

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Corresponding author Daniela Dumitrescu, Associate Professor, MD, PhD, Department of Radiology and Medical Imaging, University of Medicine and Pharmacy of Craiova, No. 1 Emergency County Hospital, 60 1st May Avenue, 200322 Craiova, Romania; Phone +40251–502 263, e-mail: [email protected]

Received: November 15th, 2008

Accepted: January 27th, 2009