Introduction

The oculoneurocutaneous syndromes (ONCS) are a group of disorders characterized by systemic hamartomas and/or choristomas of the eye, brain, skin, and sometimes the viscera.1–38 The term ‘phakomatoses’, previously used to designate these entities, is nonspecific and is used less often in the literature. As a result, we have chosen to group these entities under the rubric ONCS, which more accurately reflects their true nature. However, we realize that other terminology may be adopted in the future when the genetics of these conditions is better understood. The syndromes described include tuberous sclerosis complex (TSC), neurofibromatosis (NF), von Hippel–Lindau (VHL) syndrome, Sturge–Weber (SW) syndrome, WyburnMason (WM) syndrome, oculoneurocutaneous cavernous hemangiomatosis, and organoid nevus syndrome. This chapter covers these syndromes with emphasis on their ocular manifestations. The authors also discuss and illustrate the clinical and histopathologic features of these syndromes in more detail in recent textbooks.1–3

Genetics

Most of the ONCS have an autosomal dominant (AD) mode of inheritance, often with incomplete penetrance. Specific chromosomal abnormalities are continually being recognized in association with these entities. Notable exceptions are SW, WM, and organoid nevus syndrome, in which heredity does not appear to play a role and genetic abnormalities are not yet clearly delineated.3

Malignant potential

The tumors that develop in the ONCS are generally benign.1–3 Some of these syndromes, however, can be associated with malignant neoplasms. Examples include the increased incidence of malignant schwannomas of the peripheral nerves in patients with NF. Hypernephroma and pheochromocytoma occur with greater frequency in patients with VHL.3

Formes frustes

Patients with the ONCS may manifest only some of the clinical features of a particular syndrome, referred to as a forme fruste.3 Furthermore, patients can occasionally exhibit lesions characteristic of one entity and other lesions characteristic of another, referred to as the crossover phenomenon. One example, among several, is the café au lait spots seen in patients with NF that can occasionally be seen in patients with TSC.

Tuberous sclerosis complex

(Bourneville’s syndrome)

DEFINITION/OVERVIEW AND ETIOLOGY

Tuberous sclerosis complex (TSC) is characterized by retinal astrocytic hamartomas, cutaneous abnormalities, central nervous system (CNS) astrocytomas, and internal tumors such as cardiac rhabdomyoma, renal angiomyolipoma, and other tumors1–9 (Table 18). It is best known for producing a triad of adenoma sebaceum (cutaneous angiofibromas), seizures, and mental deficiency.

The incidence of TSC is about one in 10,000.5 Although TSC usually is diagnosed during the first few years of life, it has occasionally been recognized in patients as young as 1 month of age or as old as 50 years. This syndrome has been identified in all races and there is no predilection for gender.

Most evidence suggests that TSC is transmitted by an AD mode with incomplete penetrance. In many cases, the family history is unremarkable and examination of family members is normal. In such patients, the disease is considered to be due to sporadic mutations. About half of the families show linkage of chromosome 9q34 and about half to chromosome 16p13.1

CLINICAL PRESENTATION

The retinal astrocytic hamartoma is the characteristic fundus lesion of TSC (253, 254).1–3 However, an identical lesion is occasionally found in patients who have no other clinical or genetic evidence for TSC. In either case, a small noncalcified tumor can be extremely

Table 18 Clinical features of tuberous sclerosis complex

Eyelid

Angiofibroma (adenoma sebaceum), depigmented macules (ash leaf sign)

Retina

Astrocytic hamartoma, peripheral depigmented areas, atypical coloboma, optic trophy

Brain

Astrocytic hamartoma

Skin

Angiofibroma (adenoma sebaceum), ash leaf macules, shagreen patches, ungual/subungual fibromas

Liver, thyroid, pancreas, testes, and other organs can develop hamartomas

253

253 Tuberous sclerosis complex.Noncalcified retinal astrocytic hamartoma.

254

254 Tuberous sclerosis complex.Calcified retinal astrocytic hamartoma.

sessile or dome-shaped retinal mass with acoustic solidity and orbital shadowing if there is calcification in the lesion.

The uveal tract is rarely affected in TSC. A depigmented iris sector, seen in some patients with TSC, is believed to be the equivalent of the depigmented cutaneous lesions.6 Irregular areas of atrophy of the retinal pigment epithelium (RPE) are occasionally seen with TSC.

The differential diagnosis of retinal astrocytic hamartoma includes retinoblastoma, hemangioblastoma, retinal granuloma, focal or massive gliosis of the retina, myelinated retinal nerve fibers, and optic disc drusen. Retinoblastoma is perhaps the most difficult and important tumor to differentiate from astrocytic hamartoma. The fine differentiating features of these other conditions are discussed elsewhere.1,2

The retinal astrocytic hamartoma has rather typical pathologic features. It is a lightly eosinophilic lesion located mainly in the nerve fiber layer of the retina and is composed of fibrillary astrocytes. The nuclei are round and mitoses are extremely rare. The more calcified tumors show fossilization, larger round cells, and basophilic laminated structures resembling psammoma bodies.1,3,9

OTHER FEATURES

The characteristic brain findings in patients with TSC include subependymal and paraventricular astrocytomas (255).1–9 Both can demonstrate cystic and calcific changes that account for the name tuberous sclerosis (potato-like masses). These lesions may contribute to the seizures and mental deficiency, but severe mental deficiency is not necessarily a part of this syndrome. It is now recognized that many patients are of normal or near normal intelligence.

The main cutaneous manifestations of TSC include adenoma sebaceum, depigmented macules, and café au lait spots.1–9 Adenoma sebaceum is a misnomer, since the lesions are actually angiofibromas. It is characterized clinically by multiple slightly elevated, rubbery, yellow-red papules (256). The lesions are often found on the face in a butterfly-shaped distribution. Similar angiofibromas can occur beneath or adjacent to the fingernails or toenails in patients with TSC. Depigmented macules resembling vitiligo are commonly present on the skin of patients with TSC (257). Because this characteristic lesion

frequently resembles the leaf of an ash tree, it is often referred to as the ‘ash leaf sign’.

MANAGEMENT/TREATMENT AND PROGNOSIS

The majority of retinal astrocytic hamartomas are asymptomatic and nonprogressive and do not require treatment. Ocular examination should be performed yearly and the patient followed for other manifestations of TSC. If there should be associated subretinal fluid that extends into the foveal area, then laser photocoagulation or photodynamic therapy can be employed in order to bring about resolution of the subretinal fluid.1–3

The astrocytic hamartoma of the retina has an extremely low tendency to undergo malignant change and has no recognized tendency to metastasize. The visual prognosis is also excellent, except in the rare instances in which exudation, subretinal fluid, or vitreous hemorrhage occurs. The renal lesion of TSC commonly predisposes the patient to recurrent nephritis and elevated blood urea nitrogen. Histopathologically it is a benign angiomyolipoma, with no tendency to undergo malignant transformation or to metastasize. The characteristic cardiac rhabdomyoma is composed of large spider cells with prominent vacuoles containing glycogen. Some patients with TSC develop slowly progressive subpleural cysts that result from anomalous development of pulmonary tissue.8 These cysts can rupture, leading to spontaneous pneumothorax. Irregular cortical thickenings of bones, particularly the metatarsals and metacarpals, as well as hamartomas of the liver, thyroid, pancreas, testes, and other organs have been recognized.8