Diagnosis and Diagnostic Aids

Patients suspected to have NF2 are usually screened by ophthalmic examination and neuro-otologic testing. Magnetic resonance imaging is a cost-effective firstline investigation in the detection of VN and exclusion of NF2 [54]. The entire neural axis should be imaged to detect asymptomatic lesions using contrast-enhanced, multiplanar T1-weighted MRI sequences [55].

Routine clinical and radiologic examinations are required for patients with a first-degree relative with NF2, younger than 30 years old with a unilateral VN, or with multiple intracranial or spinal tumors. Offsprings of patients with NF2 should have annual ophthalmologic examinations soon after birth. Annual neurology examinations with MRI evaluations and biannual audiograms should be performed beginning at the age of 7 years.

First-degree relatives of patients in whom a NF2 mutation has already been identified should be offered genetic screening. The sensitivity of genetic screening in these circumstances is approximately 100% and those who do not carry a NF2 mutation can avoid the frequent MRI examinations. However, genetic screening for firstdegree relatives of a NF2 parent with unknown mutation is controversial. Screening in these cases detects mutations in only about 75% of patients and, thus, has a significant false-negative rate [56–58]. Those with a negative test would still need an annual clinical examination and MRI and biannual audiograms.

Treatment

VN, generally, is a slow growing tumor. Rapid progression may occur in older individuals and those with associated spinal tumors or meningioma [59]. The management of VN involves complex decision-making and choosing among various options including observations, stereotactic radiosurgery, fractionated stereotactic radiotherapy, and surgical resection [59–61].

Complications and Associations

In severe forms of NF2, complications of NF2 can lead to early death.

Social and Family Impact

The social and family impact following a diagnosis of NF2 in a family member is significant. Concerns regarding long-term prognosis and risk to family members

should be addressed by appropriate counseling. Screening methods and genetic testing should be offered to achieve early diagnosis. All the patients and their families should be referred to an audiologist for hearing and speech enhancement [62].

7.3  Von Hippel–Lindau Disease

7.3.1  Introduction

VHL is a multisystem disorder characterized by the development of various tumors and cysts, particularly of the central nervous system (CNS) and retina. It is of particular relevance to the ophthalmologist because retinal capillary hemangioma (RCH) is one of the most common and, frequently, the earliest manifestations of VHL disease. Significant progress has been made in understanding the clinical spectrum, natural history, genetics, and molecular biology of this disease since its original description more than 100 years ago. Such advancements have led to refined diagnostic criteria, improved screening protocols, effective treatment modalities, and accurate genetic testing.

7.3.2  Historical Context

Observations of the ophthalmic manifestations of VHL date back to 1874 when Magnus, a German ophthalmologist, reported aneurysmal dilatation of the retinal vessels. Eugen Von Hippel, also a German ophthalmologist, coined the term “angiomatosis retinae.” In 1926, the Swedish pathologist Arvid Lindau recognized an association between retinal angiomatosis and cerebellar hemangioblastomas. Melmon and Rosen, in 1964, established the clinical spectrum of “Von Hippel– Lindau” disease to involve ophthalmic, CNS, and visceral manifestations [63].

7.3.3  Overview with Clinical Significance

There are approximately 7,000 patients with VHL disease in the United States. The most common and, frequently, the earliest manifestation of VHL is RCH. Extraocular involvement includes CNS

hemangioblastoma, renal cyst, renal cell carcinoma, pancreatic cyst, pancreatic adenoma, islet cell tumors,andpheochromocytoma[64].Endolymphatic sac tumor of the inner ear has been recently described as a manifestation of VHL disease [65]. VHL disease has been characterized as a familial cancer predisposition disease. Individuals at risk are screened for early detection of life-­threatening tumors.

7.3.4  Classification

VHL disease can be classified into two main types clinically. Type 1 are patients without pheochromocytoma and type 2 are those with pheochromocytoma. VHL type 2 is further divided into three subtypes. Type 2a presents without renal cell carcinoma, type 2b presents with renal cell carcinoma, and type 2c, a rare form, has only pheochromocytoma involvement.

blot analysis, conformation-sensitive gel electrophoresis, and direct sequencing, genetic testing for VHL has a 99% detection rate [70, 71]. Patients considering genetic testing of VHL should undergo detailed counseling.

7.3.6  Pathophysiology

Histopathology of retinal and CNS capillary hemangioma shows a network of thin vascular channels lined by endothelial cells and pericytes. These channels are separated by foamy stromal cells and appear capillary-like [72].

7.3.7  Incidence

The incidence of VHL disease is 1 in 40,000 to 1 in 54,000 live births [73, 74]. VHL disease affects approximately 7,000 patients in the United States.

7.3.5  Genetics

VHL disease is an autosomal dominant disorder with age-dependent penetrance. It follows the classic “two hit model” initially hypothesized by Knudson for retinoblastoma [66]. Inactivation of both VHL alleles results in function loss of the VHL gene. The VHL gene is a tumor suppressor gene located on chromosome 3p25– 26 and encodes a protein that causes degradation of hypoxia-inducible factors [67]. Loss of functional VHL protein results in the accumulation of these factors that in turn lead to high levels of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and tumor growth factor-a (TGF-a). Increased VEGF, PDGF, and TGF-a induce microvasculature formation and angiomatosis. Recently, it has been shown that VHL protein dysfunction causes loss of inhibition of apoptosis of neural crest cells in the adrenal gland, which ultimately leads to pheochromocytoma.

Genotype-phenotype correlation has been demonstrated in VHL diseases. The majority (96%) of patients with deletions, insertions, or nonsense mutations have type 1 VHL disease. In contrast, patients with missense mutations tend to have type 2 VHL [68, 69].

Genetic testing for VHL disease is commercially available. Using a combination of techniques of Southern

7.3.8  Natural History and Prognosis

The penetrance of VHL disease is age dependent, achieving full penetrance by the age of 65 years. As a result, VHL disease may be diagnosed at any time during life, and screening of elderly family members who are putative gene carriers has nearly 100% yield of detecting subclinical features [74].

RCH is a well-recognized finding in VHL disease with a frequency of 49–59% [73, 75–77]. The mean age at diagnosis is 25 years with occasional occurrences in the pediatric age group [66, 75, 77–81]. Onset of RCH beyond the age of 60 years is extremely rare [75, 77]. The natural course is usually of progression, but some lesions have remained stable for prolonged periods and others have shown evidence of spontaneous regression on rare occasions. Very rarely, atypical retinal vascular lesions and twin blood vessels may be present [82, 83]. CNS hemangioma may involve the visual pathway to cause optic nerve compression and chiasmal syndrome. Anterior segment complications such as cataract formation and neovascular glaucoma follow extensive retinal exudation, retinal detachment, retinal neovascularization, and vitreous hemorrhage.