Chapter 65 Phakomatoses
The phakomatoses are systemic disorders with neurologic, ophthalmic, and cutaneous manifestations. A common feature is multiorgan hamartomas. The most common are neurofibromatosis, tuberous sclerosis, Sturge-Weber syndrome, and von Hippel-Lindau syndrome. Others are the Klippel-Trénaunay-Weber, Wyburn-Mason, linear nevus sebaceous, Osler-Weber-Rendu, blue rubber bleb nevus syndromes, ataxia telangiectasia, and diffuse congenital hemangiomatosis. There is increasing understanding of the genetic, molecular, and cellular biology underlying the pathophysiology of the phakomatoses leading to clinical trials with biologic agents.
NF1 is a progressive disease and the final manifestations are extremely variable. Existing lesions tend to enlarge gradually and new lesions develop. The National Institutes of Health (NIH) diagnostic criteria are listed in Box 65.1.
NIH diagnostic criteria for NF1
NF1 is the most common single gene disorder affecting the nervous system, occurring in approximately 1 in 3000 people. Inheritance is autosomal dominant with 100% penetrance, but highly variable expressivity. The spontaneous mutation rate is up to 42%.1
The protein associated with NF1, neurofibromin, down regulates the rat sarcoma viral oncogene homolog (RAS)−mitogen activated protein kinase (MAPK) pathway. Unopposed Ras activity leads to cell growth and activation of downstream signaling intermediates, including the mammalian target of rapamycin (mTOR) protein.2 NF1 mutations give rise to malignant tumors consistent with the “two hit” hypothesis: a germ-line mutation is the initial “hit”; neurofibromas arise from Schwann cells that undergo loss of heterozygosity at the NF1 gene through somatic mutations (the second “hit”).
Lisch nodules (melanocytic hamartomas) are dome-shaped, discrete lesions on the anterior surface of the iris or in the angle, usually bilateral. They are usually orange-brown (Fig. 65.1), appearing darker than blue irides but paler than brown irides (Fig. 65.2). Most are round and evenly distributed on the iris. Their size varies from a pinpoint to involvement of a segment of iris, sometimes confluent. In NF1, they are present in one-third of 2.5-year-olds, half of 5-year-olds, three-quarters of 15-year-olds, and almost all adults over 30.3 They occur earlier than neurofibromas and are, therefore, a useful marker for NF1. They need to be distinguished from iris nevi.
Rarely, congenital glaucoma with buphthalmos occurs in NF1, often associated with an ipsilateral upper lid plexiform neurofibroma. Congenital ectropion uveae (Fig. 65.3), iris heterochromia, angle abnormalities, and posterior embryotoxon may predispose to later onset glaucoma. Cataract is not a feature of NF1. Pigmentary hamartomas (choroidal nevi) may involve the posterior uveal tract in up to 35%.
Café-au-lait spots are hyperpigmented macular skin lesions, mostly present at birth and all appear by 1 year, enlarging at puberty. Common on the trunk, they are absent from the scalp, eyebrows, palms, and soles (Fig. 65.4). Histologically, there is melanocytic hyperplasia with increased pigmentation in the basal layer of the epidermis.
Neurofibromas are present in 30–50% of NF1 patients.4 They are network-like tumor growths involving multiple fascicles of nerve(s); four types are recognized (Table 65.1). The presence and growth pattern of neurofibromas is age related; in infancy and early childhood, diffuse plexiform neurofibromas are most active giving rise to cosmetic and visual problems within the orbit. Cutaneous or subcutaneous neurofibromas develop and grow fastest at puberty, the late teens, and during pregnancy. There is a lifelong risk of malignant transformation with poor prognosis for 5-year survival.5
|Neurofibroma types||Location||Clinical signs|
|Discrete cutaneous||Epidermis and dermis||Moves with skin, blueish tinge|
|Subcutaneous||Deep to dermis||Skin moves over, firm and rounded feel, located along peripheral nerves|
|Nodular plexiform||Localized interdigitation with normal tissues||“Bag of worms” feel (Figs 65.5, 65.6)|
|Diffuse plexiform||Infiltrate widely and deeply||Smooth, slightly irregular skin thickening|
(Patient of the University of British Columbia.)
Complete surgical resection of plexiform neurofibromas is difficult due to their large size, location, local invasiveness, or involvement of critical peripheral nerves. Regrowth following subtotal resection is common. Chemotherapy is not effective. Promising clinical trials with biologic agents are underway.6
Hypoplasia of the greater and lesser spenoid wings and widening of the superior orbital fissure may occur. Other osseous abnormalities include abnormal vertebrae, scoliosis, pseudoarthrosis of long bones, and subperiosteal changes (Fig. 65.7). Neurofibromas may interfere with cranial nerve function.
Optic pathway gliomas are a significant cause of visual morbidity (see Chapter 23). Optic disk swelling (Fig. 65.8), strabismus (Fig. 65.9), or pallor suggests optic nerve or chiasmal glioma. Retinal manifestations are rare in NF1. The commonest consequence of NF1 in childhood and a major concern of parents is cognitive impairment. Overt mental retardation is rare, but a wide range of learning disabilities, academic underachievement, and behavioral problems may occur.
Fig. 65.9 Optic nerve glioma. (A) This 13-month-old girl presented with a history of intermittent exotropia since age 6 months, increasing numbers of café-au-lait spots and increasing proptosis on the left side. She appeared to be blind on the left. (B) T2-weighted MRI showed a fusiform tumor of the optic nerve extending up to and involving the chiasm.
Neurofibromatosis type 2 (NF2) affects 1 in 35 000 live births and is characterized by bilateral vestibular schwannomas, multiple central nervous system (CNS) tumors, cataracts, and retinal abnormalities. The diagnostic criteria for NF2 are shown in Box 65.2. Two patterns of presentation exist. Mild disease presents late (> 25 years), with few tumors other than bilateral vestibular schwannoma, and slow progression. Those with severe disease have onset before age 25, multiple CNS tumors (at least two of one type), and rapid progression, severe handicap or death before reproductive age. Treatment is multidisciplinary because of the complexities of the multiple and progressive lesions.7
Revised diagnostic criteria (Manchester) for NF2
NF2 is an autosomal dominant condition; half the cases are sporadic mutations. There is an unusually high rate of somatic mosaics (mutation takes place after conception, resulting in two separate cell lineages). Tumors develop in susceptible organs (i.e. nervous system, eyes, and skin) from cells that lose function of the wild type (normal) NF2 allele. There is correlation between nonsense and frameshift mutations and the severe early phenotype of NF2.
The NF2 tumor suppressor gene Merlin is localized to the cell membrane–cytoskeletal interface where it indirectly acts through its membrane organization of proteins. Merlin regulates downstream mitogenic signaling pathways. Drugs targeting these pathways (i.e. sorafenib, trastuzumab, lapatinib, LY294002, protein kinase inhibitors, p21-activated kinase inhibitors) and tumor angiogenesis (bevacizumab) are under investigation as potential treatments for NF2.7
The hallmark of NF2 is bilateral vestibular schwannomas (“acoustic neuromas”) which may only be evident on gadolinium-enhanced MRI (see Fig. 65.11C ). The origin of the trigeminal nerve is another frequent intracranial site for schwannomas; they may occur on multiple cranial nerves. Anti-VEGF (vascular endothelial growth factor) therapy improves hearing and stabilizes tumor growth.8
Most of the ophthalmic findings in NF2 (see Box 65.2) are congenital but may become more symptomatic over time.9 Visual loss increases morbidity since progressive bilateral hearing loss is so common in this condition.
The ocular changes of NF2 are early diagnostic markers. 55–87% of affected patients have presenile central posterior subcapsular lens opacities, usually with little effect on vision (Fig. 65.10A,B). Corneal hypoesthesia from trigeminal nerve schwannoma, and decreased tear production, reduced blinking and lagophthalmos from facial nerve palsy may adversely affect the outcome of cataract surgery.
Epiretinal membranes occur in up to 80% of patients with severe NF2. They are translucent, semitranslucent, or whitish gray membranes with prominent whitish edges demarcating their borders. They do not usually cause substantial loss of visual acuity (Fig. 65.11).
Fig. 65.11 (A) Epiretinal membrane in a 14-year-old NF2 patient. Note also papilledema secondary to optic sheath meningioma. (B) OCT scan of epiretinal membrane. Note loss of internal limiting membrane. (c) Bilateral vestibular schwannomas as well as bilateral optic sheath meningiomas in a 14-year-old boy − same patient as in (A) and (B).
(MRI scan courtesy Dr. Mark Dexter, Neurosurgeon.)
Combined retinal and pigment epithelial hamartomas occur in 6−22% of NF2 patients, especially with nonsense mutations.9 They are slightly raised masses most frequently in the posterior pole (Fig. 65.12), commonly causing reduced vision. Optic nerve sheath meningiomas, sometimes bilateral, can cause visual loss (see Chapter 23). They may be missed on MRI unless fat suppression techniques are used.
Increased understanding of the clinical manifestations and improved precision of genetic tests and imaging studies have improved early diagnosis of patients. Survival is extended because of advances in treatment available at specialized centers and the recognition of mildly affected people with mosaic disease (Box 65.3).