Phacomatoses

7.1  Introduction

The Phacomatoses are a group of disorders involving the central nervous system, eye, skin, and viscera (Table 7.1). The term phacomatoses is derived from the Greek word phakomata (fakos), which means “birth mark.” It was introduced by Jan van der Hoeve, a Dutch ophthalmologist, to include neurofibromatosis, von Hippel-Lindau disease (VHL), and tuberous sclerosis. Subsequently, encephalofacial angiomatosis (Sturge-Weber syndrome [SWS]), ataxia telangiectasia (AT), Wyburn-Mason syndrome, and retinal cavernous hemangiomatosis have been added to this group of diseases.

The hallmark of phacomatoses is the manifestation of hamartomas, benign tumors arising from tissues normally present in a specific organ. However, patients with phacomatosis have a higher predisposition to malignancy and reduced lifespan. Advances in molecular genetics have led to the identification of genes responsible for and further understanding of these disorders (Table 7.2).

7.2  Neurofibromatosis

A number of distinct forms of neurofibromatosis have been recognized with the most common variant being neurofibromatosis type 1 (NF1), followed by neurofibromatosis type 2 (NF2). Other rare types include

E.X. Fu and A.D. Singh (*)

Cole Eye Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA

e-mail: singha@ccf.org

multiple meningiomatosis, spinal schwannomatosis, and segmental neurofibromatosis. NF1 and NF2 are two separate diseases involving distinct genetic loci that share some clinical characteristics. NF1 mainly affects the peripheral nervous system and skin with characteristic bony dysplasia. In contrast, NF2 presents with central nervous system involvement, vestibular schwannoma (VN), and a relative paucity of skin manifestations.

7.2.1  Neurofibromatosis Type 1

7.2.1.1  Introduction

The prevalence of NF1 is about 1/3,000 with equal distribution­ in various ethnic groups [1]. Strict clinical diagnostic criteria have been established by the National Institute of Health (Table 7.3) [2].

7.2.1.2  Historical Context

In 1882, Friedrich Daniel von Recklinghausen, a German pathologist, outlined the clinical and pathological findings of NF1 and suggested that the tumors are neural in origin. In his honor, NF1 has also been referred to as von Recklinghausen’s disease. Since its original description, it has been recognized that NF1 has varied clinical manifestations.

7.2.1.3  Overview with Clinical Significance

NF1 is one of the most common genetic disorders with neural, ocular, and cutaneous manifestations. The ocular

findings of Lisch nodules are the most common ocular findings and are extremely useful in establishing the diagnosis [3, 4]. Optic nerve glioma is another common ocular manifestation and can lead to unsightly proptosis and significant visual loss [5]. Unusual choroidal and retinal hamartomas in association with NF1 can cause diagnostic dilemma [6].

7.2.1.4  Genetics

NF1 is an autosomal dominant condition caused by mutations of the NF1 gene on chromosome 17q11.2 [7]. Eighty percent of NF1 mutations lead to premature termination of the gene product, neurofibromin. Neuro­ fibromin is a cytoplasmic GTPase-activating protein

thatnegativelyregulatesrasoncoprotein[8].Inactivation of neurofibromin results in unregulated ras, which in turn stimulates cellular proliferation. Loss of neurofibromin function has been shown to be limited to the Schwann cells of neurofibromas and not the fibroblasts [9]. These findings indicate that the Schwann cell is the cell of origin of the neurofibromas in NF1.

Approximately 50% of all index cases are due to new mutations and the majority of these new mutations are paternal in origin [10]. The estimated new mutation rate is 1 × 10−4 [11]. NF1 mutations usually penetrate completely; however, penetrance may appear falsely low due to variable expression [11, 12]. For example, the parents of children with NF1 may only present with Lisch nodules rather than a full spectrum of the disorder. A large number of NF1 mutations has