Retinocerebellar hemangioblastomatosis (von Hippel–Lindau syndrome)

DEFINITION/OVERVIEW AND ETIOLOGY

In 1895, von Hippel reported the clinical findings of so-called retinal angiomatosis and in 1926, Lindau made a study of cerebellar lesions and pointed out their relationship to the retinal tumors previously described by von Hippel.18,19 Consequently, the combination of retinal and cerebellar involvement has been called the von Hippel–Lindau (VHL) syndrome. VHL syndrome has since been recognized to have several other components in addition to the eye and CNS findings, including renal cell carcinoma, pheochromocytoma, endolymphatic

sac tumors, and other less common cystic lesions (Table 21).20–24

The incidence of VHL syndrome is about 1 in 40,000 live births. There is no clear-cut predilection for race or gender, although all our patients have been Caucasians.3 The VHL syndrome is recognized to be a hereditary disorder, with an AD mode of inheritance and incomplete penetrance. Many cases seen by the ophthalmologist, however, occur as spontaneous mutations with no apparent family history of the disease. Probably about 20% of cases have a positive family history. The condition is related to a partial deletion of the short arm of chromosome 3.3,24

CLINICAL PRESENTATION

The ocular manifestations of VHL syndrome are not so diversified as they are in the other systemic hamartomatoses. Hemangioblastoma (‘retinal capillary hemangioma’) of the retina and/or optic disc are the only intraocular hamartomas that are known to occur. When associated with the VHL syndrome, the retinal

and optic disc tumors are often multiple and bilateral.1,3,24 The diagnosis of the ocular

lesions is usually made in the second or third decade of life.

The ophthalmoscopic appearance of a retinal hemangioblastoma varies with the location of the lesion in the fundus. In the earliest stages, a tumor in the peripheral retina is often subtle ophthalmoscopically. A somewhat larger tumor

Table 21 Clinical features of retinocerebellar hemangioblastomatosis (von Hippel–Lindau syndrome)

Skin

No consistent findings

appears as a distinct red nodule with a typical dilated tortuous afferent artery and an efferent vein that come from the optic disc to the tumor, and yellow lipoproteinaceous exudation (262). Retinal hemangioblastoma can eventually assume either an exudative form or a vitreoretinal form or a combination of the two.1

The exudative form is characterized by localized or intraretinal and subretinal yellow exudation. The exudation with larger tumors may be contiguous with the tumor or it may be remote from the tumor in the foveal area as stellate-shaped exudation. The vitreoretinal form of hemangioblastoma is characterized by fibrosis of the overlying vitreous, and traction bands elevating the retina may be visible. Flat preretinal fibrosis, especially in the macular area, are typical of this form of hemangioblastoma.1 The tumors located on the optic disc itself do not usually develop the well-defined feeding and draining blood vessels (263).

262

262 von Hippel–Lindau syndrome.Typical retinal hemangioblastoma,showing red tumor with dilated afferent and efferent retinal blood vessels and lipoproteinaceous exudation.

OTHER FEATURES

The cerebellar or spinal cord hemangioblastoma

is the classic CNS lesion in VHL syndrome.1,21,24 It can be small and asymptomatic

but it usually enlarges slowly and can eventually produce profound cerebellar signs and symptoms. The cerebellar symptoms usually occur in the fourth decade of life, and patients with known ocular disease should have periodic neurologic evaluation and brain imaging to detect their early onset. Identical lesions can occasionally occur in the medulla oblongata and in the spinal cord. Like retinal hemangioblastoma, cerebellar hemangioblastoma characteristically has large blood vessels that supply and drain the lesion. The vascular tumor frequently occurs within a cerebellar cyst. Histopathologically, the tumor is a hemangio-

blastoma with features identical to the vascular tumor that occurs in the retina.1,21

In contrast to the other systemic hamartomatoses, VHL syndrome usually has no major cutaneous involvement.

263

263 von Hippel–Lindau syndrome. Hemangioblastoma adjacent to optic disc, with mild surrounding exudation.

DIAGNOSIS

Fluorescein angiography is the most helpful ancillary study in confirming the diagnosis of a hemangioblastoma.1 In the early arterial phase, the dilated retinal feeder arteriole appears prominent. Within 2–3 seconds the retinal tumor is fluorescent as the fine capillaries that comprise the tumor fill with fluorescein. In the venous phase, the dilated draining vein fills with dye and the tumor maintains its bright fluorescence. In the late phase the tumor generally remains fluorescent and leaks dye into the vitreous. The intrinsic rapid fluorescence of the optic disc hemangioma assists in differentiating these tumors from other optic disc lesions.

Histopathologically, retinal hemangioblastoma consists of a proliferation of retinal capillaries that replace the architecture of the sensory retina.3,25 There is a proliferation of endothelial cells, pericytes, and vacuolated interstitial cells called stromal cells. The nature of the stromal cells is still uncertain, but they may be the cell of origin of the tumor.25

MANAGEMENT/TREATMENT AND PROGNOSIS

The management of retinal hemangioblastoma is difficult and controversial. No active treatment may be necessary for small asymptomatic retinal tumors because some of them remain stable for many years and some even regress spontaneously. The patient should be examined periodically and treatment instituted if the tumor grows or if there is accumulation of exudation or subretinal fluid. In such instances, several methods of treatment have been advocated including argon laser, cryotherapy, photodynamic therapy, and intravitreal injection of angiostatic agents. No single treatment has emerged as the treatment of choice. If a hemangioblastoma has caused an extensive retinal detachment with subretinal exudation, a vitrectomy and/or a scleral buckling procedure may be necessary to reattach the retina. The authors have used plaque radiotherapy for selected tumors with extensive retinal detachment.

Analysis of the deoxyribonucleic acid (DNA) of the patient and all family members can be performed in an attempt to identify markers indicating VHL disease. The gene for VHL syndrome has been mapped to the short arm of chromosome 3. All patients with VHL syndrome should be followed carefully with yearly testing for systemic tumors. Furthermore, relatives of patients with VHL disease may benefit from a screening protocol depending on the results of DNA testing (Table 22). The retinal hemangioblastoma is often the initial sign of VHL disease and the various other systemic tumors found in this disease are best treated at an early stage. Therefore, it is important to evaluate these patients systemically.

Various systemic hamartomas can occur in patients with VHL syndrome (Table 21).21 These include hypernephroma, pheochromocytoma, and cysts of the kidney, pancreas, and epididymis. A detailed medical and family history should be taken from all patients with retinal hemangioblastoma and, if indicated, appropriate studies be undertaken to detect any of the systemic components of VHL syndrome.

Table 22 Systemic evaluation for von Hippel–Lindau syndrome

Affected patient

Testing performed every year:

•Physical examination

•Eye exam (indirect ophthalmoscopy)

•Urinanalysis

•Urine 24 hour collection for vanillylmandelic acid (VMA)

•Renal ultrasound

Testing performed every 3 years:

•MRI (or CT) of brain

(after age 50 years, brain scan is performed every 5 years)

•CT of kidneys

At-risk relative

Testing performed every year:

•Physical examination

•Eye examination (indirect ophthalmoscopy)

•Urine analysis

•Urine 24 hour collection for VMA

•Renal ultrasound

Testing performed every 3 years:

•MRI (or CT) of brain (brain scan recommended every 3 years between ages 15 and 40 years and then every 5 years until age 60 years)

•CT of kidneys

(abdominal scan recommended every 3 years between ages 20 and 65 years)

Racemose hemangiomatosis (Wyburn-Mason syndrome)

DEFINITION/OVERVIEW AND ETIOLOGY

Racemose hemangioma of the midbrain and ipsilateral retina is called the Wyburn-Mason (WM) syndrome (Table 23). Wyburn-Mason described this relationship in 1943.31 It consists of an abnormal congenital arteriovenous communication that can involve any combination of lesions in the retina, midbrain, and sometimes other areas including the orbit, mandible, maxilla, and pterygoid fossa.1,3 This congenital condition does not appear to be familial and does not exhibit a hereditary pattern.

CLINICAL PRESENTATION

The classic ocular finding is the racemose (cirsoid) hemangioma of the retina.31,32 It is actually a retinal arteriovenous (AV) communication, and can range from a very subtle asymptomatic lesion (264) to a more extensive one that consists of tumor-like vascular masses. The lesion has been divided into three groups that are detailed in the literature.32

OTHER FEATURES

AV communications similar to those in the retina can also occur in the midbrain. They can cause spontaneous intracranial hemorrhage that can produce stroke-like symptoms, oculomotor palsies, and seizures.1,3 The bones of the skull, including the mandible and maxilla, can frequently be involved with the vascular malformation and abnormal bleeding can follow dental treatment.

There are no significant cutaneous changes associated with racemose hemangiomatosis, except for the rare occurrence of small facial angiomas.

DIAGNOSIS

The diagnosis of the retinal racemose hemangioma is made ophthalmoscopically, but fluorescein angiography can be of assistance. The affected artery fills rapidly with fluorescein and transit to the venous side is quick due to the lack of an intervening capillary network.

Table 23 Clinical features of racemose hemangiomatosis (Wyburn-Mason syndrome)

No consistent findings

264

264 Retinal racemose hemangioma in Wyburn-Mason syndrome.

The retinal racemose hemangioma has not been studied extensively histopathologically. The affected vessels develop acellular fibrohyaline adventitial coverings and the retina is thin and degenerated.1,3

MANAGEMENT/TREATMENT AND PROGNOSIS

In general, no dermatologic or ophthalmic treatment is necessary for patients with racemose hemangiomatosis. If the retinal lesions produce persistent vitreous hemorrhage that does not resolve, then the blood can be removed by vitrectomy. WM syndrome generally exhibits no systemic manifestations other than those mentioned above.