Tuberous sclerosis (TS) is a hamartomatous, multisystem disorder first recognized more than 100 years ago.1 The classical triad consists of seizures, mental deficiency, and facial angiofibromas.2 Incomplete forms occur where only one element of the classical triad is present.3 Primary diagnostic criteria include facial and ungual fibromas, angiofibromas, cortical and subependymal astrocytomas, multiple retinal astrocytomas, and the presence of a fibrous plaque on the forehead. The occurrence of one of the primary diagnostic criteria is sufficient to diagnose TS. Although no full agreement on secondary criteria exist, these generally include infantile spasms, hypopigmented macules ("ash leaf spots"), shagreen patches on the skin, a single retinal hamartoma, renal angiomyolipoma, cardiac rhabdomyoma, and the existence of first-degree relatives with a diagnosis of TS.2-3
Many of the clinical findings described are not present early in infancy, and the presentation of a patient with limited signs and symptoms may make differential diagnosis difficult. We report two infants referred to King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia, with a tentative diagnosis of retinoblastoma who later were proven to have TS.
Case Report 1
A 5-month-old Saudi girl was referred with left leukocoria that was first noticed when the child was 3 days old. The child was the product of a normal pregnancy and delivery. Her nine siblings were healthy. A vague history of seizure-like activity was given. She viewed objects in a central, steady, and well-maintained manner with the right eye but did not fixate with the left eye at all. The right pupil was regular and reactive whereas the left pupil was irregular and poorly reactive. The anterior segment of the right eye was normal; the left eye was microphthalmic (corneal diameter 9,0 mm) and posterior synechiae were present. A left anterior polar cataract was associated with mild cortical and posterior subcapsular changes. A large, creamy-white lesion was present in the left posterior pole obscuring the optic nerve head; this mass extended medially to the ora serrata and was seeding into the vitreous anteriorly.
Fig 1: The right fundus in patient 1 showing retinal hamartoma (arrow).
An indented fundus examination under anesthesia (EUA) revealed no other abnormalities in the left eye, but four translucent round gray lesions were noted in the right posterior pole. Three of these were located on the vascular arcades close to the disc (Fig 1). Their sizes varied from 4.0 mmX2.0 mmx2.00 mm to 0.4 ramxO.4 mmxO.5 mm. A fifth, small, fleck-like lesion was noted in the right superior nasal quadrant. This measured about 0.2 mm and resembled a gliotic tuft. Intravenous fluorescein angiography in the right fundus showed a hypointense reaction in the early phase followed by staining on the late phase consistent with astrocytic hamartomas.
B-scan ultrasonography detected focal calcification in the left-sided mass that was of medium reflectivity. The maximum height of this lesion was 3.5 mm. The left optic nerve was thickened, measuring anteriorly 3.7 mm and posteriorly 4.2 mm. The visual evoked response was present but reduced in the left and normal in the right eye. Because of this large, calcified, seeding mass, the diagnosis at this stage was felt to be bilateral retinoblastoma, Computed tomographic (CT) scanning revealed left relative microphthalmos with a minimally calcified mass filling about 20% of the medial aspect of the globe (Fig 2). A thin optic nerve was surrounded by a saccular dilation of the subarachnoid space. In the brain at the supratentorial level, multiple, disseminated, high-density periventricular lesions were present, including one sited at the foramen of Monro. On noncontrast CT scan, these lesions were seen to be calcified. This radiologie appearance alerted us to the possibility of TS.
Fig 2: Computed tamographic scan of the orbits in patient 1. A large mass lesion is present in the left globe (arrow).
Magnetic resonance imaging (MRI) confirmed the CT findings in that the calcified periventricular lesions were seen as slightly hypointense on T2, indicating calcification on MBL A careful cutaneous examination revealed a number of hypopigmented macules ("ash leaf spots") typical of TS. Renal ultrasound was negative and both parental fundi were normal. Radiologie examination revealed no bony sclerosis in the legs or arms. The child's electrocardiograph and echocardiogram were normal. Based on the radiologie findings, a tentative diagnosis of TS was made. Intervention was delayed and the child's clinical course was followed closely. On subsequent examinations, the clinical picture remains essentially unchanged. A slight enlargement (0.4 mm) of the small superior nasal tuft, in the right side, has been noted. In the left eye an area of fundus depigmentation was seen adjacent to the large but unchanged hamartoma. A seizure episode was observed and confirmed. The child has been referred to a neurologist. This child has been followed for 11 months without any clinical change.
Case Report 2
An 8-day-old infant was referred with a tentative diagnosis of buateral retinoblastoma. Apart from a borderline low head circumference, the infant was normal. CT scan of the orbits and brain revealed scattered high density foci in the subependymal region of both lateral ventricles and anterior to the trigone of the lateral ventricle. These were felt to be consistent with calcifications resulting from intrauterine viral infection. Cytogenetic analysis disclosed a normal female karyotype (46 xx).
EUA disclosed two small retinal lesions, each 1 mm in size, in the posterior pole of the right eye. The ReeseEllsworth classification was Ib; the right eye was otherwise normal with a horizontal corneal diameter of 10 mm. The lesions in the right eye were treated with cryotherapy and argon photocoagulation and appeared to regress. The left eye was microphthalmic with a horizontal corneal diameter of 7 mm and had an inferonasal iris and ciliochoroidal coloboma involving the optic disc and macula. A 1-mm lesion was seen in the retina straddling the superonasal aspect of the coloboma. The Reese-Ellsworth staging was Ia. The left eye was treated with external beam radiation, 4000 cGy in fractionated doses. This was considered the only modality that could treat this lesion effectively because of its position.
A second EUA 1 month later revealed a single new lesion measuring approximately 0.4 mmxO.2 mmX0.2 mm in the right eye. No treatment was instituted at this time. The parents stated that the child was having one or two generalized seizures a week. The child was referred to a neurologist and commenced on 24 mg of phenobarbitone nightly. These seizures were assumed to be secondary to parenchyma! damage wrought by the intrauterine viral infection. Despite the phenobarbitone, the frequency of the seizures increased.
At EUA 2 months later, another small tumor was noted in the right superonasal retina. Both the new and the previously discovered lesion (which was unchanged) were treated with argon photocoagulation. Previously treated original lesions in the right eye appeared to be quiescent. The small tumor previously seen in the left eye straddling the coloboma had regressed totally. Six weeks later, a new 0.1-mm sized lesion was seen in the right nasal retina and treated with cryotherapy.
The next EUA was not performed for 5 months because the patient's seizure problem precluded general anesthesia. An electroencephalogram recorded modified hypsarrhythmia. Electrocardiography showed sinus rhythm with frequent premature atrial contractions and right ventricular hypertrophy. Echocardiography revealed a dilated right ventricle with a large hamartoma and a second-degree atrial septal defect. Renal echography showed a moderate number of simple cystic defects. When the retina was examined, six new translucent gray lesions were found scattered throughout the right nasal and superior retina. A similar new lesion was observed in the left eye. All the lesions measured between 0.2 mm to 0.4 mm in size. At this point, diagnosis other than retinoblastoma was entertained. A review of the MRI scan of the brain showed periventricular subependymal lesions more consistent with TS than with the sequelae of intrauterine viral infection. A subependymal tumor was noted at the foramen of Monro that was typical of TS. Careful examination of the child's skin revealed hypopigmented areas, further reinforcing the diagnosis of TS. This child's fundus appearance remains unchanged for 8 months since his last EUA.
Retinal tumors have been found in 53% of patients with TS.4 Three types of retinal hamartomas are described.5,6 The commonest seen are relatively small, smooth, gray, translucent lesions that often are located superficial to a retinal vessel. The second type of retinal manifestation is that of a multinodular lesion containing material of a similar appearance to tapioca; this type is considered the classical hamartoma of TS but is not as common as the smaller gray lesions.6 In a third form, a combination of the described hamartomas is seen with a nodular center and a clear periphery.
A greater degree of hamartomatous variation was noted in these two cases. In Case 2, most of the lesions were small gliotic-like flecks 0.2 mm to 0.4 mm in size. The right fundus of Case 1 had four gray lesions corresponding to the first type described. Case 1 also manifested a single gliotic fleck in the right superior nasal retina that appeared to enlarge gradually. These flecks may mature gradually to the classically described hamartoma stage- small, smooth, gray, translucent lesions. The left eye of Case 1 showed a large pedunculated mass arising from the posterior pole and growing forward to reach the ora serrata. This mass does not correspond to any of the three classically described types. This single pedunculated lesion may be another type of hamartomatous manifestation of TS.
Similar large lesions have been described in three patients who underwent enucleation for possible retinoblastoma.6,7,8 In infancy, these large masses can be confused with retinoblastoma. The associated vitreous seeding adds to the diagnostic difficulty. Vitreous seeding has been reported and is thought to be due to cystic degeneration within the tumor.9 Vitreous traction resulting from posterior vitreous detachment also has been implicated.9 The presence of posterior synechìae in the eye harboring the seeding hamartoma points to recurrent episodes of intraocular inflammation. Echographically, the lesion in Case 1 was of medium to high reflectivity. On CT scan, calcification was noted, as was some hypointensity on the MRI T2 image display. Clinically, echographically and radiologically this lesion was entirely consistent with endophytic retinoblastoma.
Other ocular lesions reported in TS include iris sector and fundus depigmentation,10 subconjunctival nodules and angiofibromata of the lid,5 and ocular coloboma».3,4,11,13 Bilateral microphtualmos has been noted in TS,4-T and notably, one eye of each of our children was microphthalmic.
The differences in disease progression between OUT two cases were interesting. Except for one lesion, relative stability was observed in Case 1. Previous long-term observations have suggested either absent or very slow rates of change.14"16 Zimmer-Galler et al documented a new hamartoma arising from a previously documented normal area of the retina." In our second patient, every EUA revealed new fleck-like lesions. This would appear to be a previously unreported phenomenon. These flecks appeared imperceptibly to enlarge slowly and gain substance. In both previously reported cases of infantile TS, the retinal hamartomas were clinically stable.15,16 Hamartomatous development may have occurred in utero in Case 1, whereas this occurred in the postnatal era in Case 2.
Retinoblastoma is the most important entity in the differential diagnosis. A number of reports exist where eyes thought to have retinoblastoma were found to harbor a hamartoma.5,7,8 The opposite circumstance where TS was diagnosed for retinoblastoma (and necessary enucleation delayed) also has been described.6 In another instance, an eye thought to have an intraocular melanoma was found to harbor a glial nodule when enucleated.17 In a large series of 500 patients presenting with putative retinoblastoma, none was found to have TS.18 These reports illustrate the diagnostic difficulty that these hamartomas pose. Conversely, when a large intraocular hamartoma presents with intralesional calcification and vitreous seeding excluding retinoblastoma may be difficult.
In a very young child, nascent hamartomas may be similar to early retinoblastoma, as in our Case 2. The diagnosis of TS for both our cases was achieved because of the characteristic subependymal calcification on CT and MRI. A calcified lesion also was seen in Case 1 at the left foramen of Monro. These subependymal hamartomas are pathognomonic for TS and should be looked for in children with leukocoria. Other diseases in the differential diagnosis include choroiditis, Coats' disease, myelinated nerve fibers, and retinal detachment. These entities are easier to distinguish from TS than is retinoblastoma.
Systemic manifestations of TS may aid in the diagnosis. Hypomelanotic macules are the earliest and commonest skin lesions. They may be present at birth. A Wood's ultraviolet light may aid in their detection in infancy. These ash leaf spots, however, are variably present in 15% to 50% of children.5 Shagreen patches and periungual and subungual fibromas often appear at puberty. Radiologie examination may reveal cyst-like formations in the phalanges of 65% of patients.2 Irregular new bone formation may be seen on the metatarsal and metacarpal shafts.2 Renal cyst and angiomyolipoma formation increases with age. Cardiac rhabdomyomas are seen in some 30% of patients. Many of these findings may not be present in infancy, making the diagnosis of TS more difficult. Neuroimaging is reported as having 67% yield in this age group.2
On summary, we report two different clinical presentations of TS in infancy. In the youngest child, serial examinations revealed new fleck-like lesions that appeared to enlarge gradually and imperceptibly. The older child manifested three different types of hamartoma, two of which did not correspond with those classically described. In the left eye, a large calcified lesion seeding in the vitreous resembled retinoblastoma. In the patient's right eye, a small, initially fleck-like lesion gradually enlarged and gained substance along with four classical, gray-translucent hamartomas in the posterior pole of this eye. Based on clinical examinations, both cases were thought to represent retinoblastoma. In both cases, radiologie evidence of characteristic subependymal hamartomas suggested the diagnosis of TS. Although rare, TS should be considered in the differential diagnosis of retinoblastoma, and we stress the importance of intracranial radiologie findings in this regard.
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