NF2 is inherited in an autosomal dominant manner with an incidence of 1:37,000 and has no gender predilection (Mautner et al. 1993; Parry et al. 1994). Generally NF2 patients become symptomatic at puberty or thereafter, but age of onset is highly variable. The mean age of onset of symptoms is approximately 17 years, usually with tinnitus and/or acute hearing loss due to vestibular tumors.

The NF2 gene is located on chromosome 22q12, and the protein consists of 595 amino acids. It was identified in 1993 in two different laboratories and named merlin and schwannomin (Rouleau et al. 1993; Bianchi et al. 1994). The name merlin refers to a high degree of homology with a family of F-actin-binding proteins including moesin, ezrin, and radixin (De Vitis et al. 1996a, b).

Merlin localizes at the cell membrane and acts as a membrane-cytoskeletal linker. It can revert Ras-induced malignant phenotypes, indicating that the NF2 gene product has a tumor suppressor activity. More recently, merlin has been shown to control a broad cellular proliferation signaling program through inhibition of the CRL4^DCAF1 E3 ubiquitin ligase and modulation of the Hippo signaling pathway by a variety of mechanisms (Cooper and Giancotti 2014; Karajannis and Ferner 2015). Multiple canonical downstream growth signaling pathways including Rac-PAK, PI3K-Akt, FAK-Src, and EGFR-Ras-Erk appear to be negatively regulated by active merlin. Mechanistic links between these canonical pathways and upstream events in the setting of merlin inactivation remain to be fully elucidated.

Despite considerable efforts, it also remains unclear if any of the known merlin-regulated signaling pathways are keys to the development of NF2-associated tumors (Scoles 2008). Mutations leading to the loss of merlin expression are the most common gene defect in meningiomas. A total of 50–60 % of all spontaneous meningiomas and NF2-associated meningiomas have mutations in the NF2 gene. Schwannomas are caused by loss of merlin expression, whereas only 29–38 % of ependymomas show alteration in merlin expression (Lamszus et al. 2001; Rajaram et al. 2005). Mutations of the NF2 gene occur not only in neoplasms associated with NF2 but also in 30 % of melanomas and 41 % of mesotheliomas (De Vitis et al. 1996a, b). It remains unclear why NF2 mutations predispose to the formation of bilateral vestibular schwannomas.

Recently, a third disorder within neurofibromatosis was distinguished as schwannomatosis. This disorder is characterized by the presence of schwannomas of cranial nerves other than the vestibular nerve. This disorder has been associated with two genes on chromosome 22 near the NF2 locus, SMARCB1, and LZTR1 (Paganini et al. 2015).

Clinical criteria are used to diagnose NF2 (Table 12.2). Bilateral vestibular schwannomas, which are characteristic lesions in patients with NF2, usually present with tinnitus and/or hearing loss (Uppal and Coatesworth 2003). These tumors are found in 96 % of NF2 patients: bilateral in 90 %, and unilateral in 6 %. Vestibular schwannomas were formerly called acoustic neuromas, an inaccurate term because they arise from Schwann cells and typically involve the vestibular rather than the acoustic (cochlear) branch of the eighth cranial nerve. NF2 patients exhibit an overall predilection for tumors of the meninges and Schwann cells and may also present with facial nerve, trigeminal nerve, and multiple spinal nerve schwannomas, as well as meningiomas and retinal hamartomas. Symptoms at time of presentation include hearing loss, tinnitus, and disequilibrium from vestibular schwannomas. NF2 patients under 10 years of age present most commonly with visual deficits or rapidly growing skin tumors.

NF2 patients develop other central neurofibromas including paraspinal tumors that may compress the spinal cord and present with myelopathy. These lesions are surprisingly common (67–90 %) in patients with NF2 and are a source of major morbidity and mortality (Mautner et al. 1995; Dow et al. 2005). Additional lesions associated with NF2 include posterior subcapsular cataracts (63 %), retinal hamartomas, optic nerve sheath meningiomas, meningiomas, ependymomas (usually spinal cord), gliomas, and trigeminal schwannomas (Mautner et al. 1996).

The mean age of onset of symptoms is 17 years, while the mean age of NF2 diagnosis is 22 years. Relentless progression of vestibular schwannomas and other tumors may lead to loss of vision, paresis, and eventual death from brainstem compression (Parry et al. 1994). Overall, NF2 patients have been demonstrated to have a decreased life expectancy as compared to the general population (Wilding et al. 2012). However, the prognosis for NF2 patients is variable, as a spectrum of phenotypes exists. The type of mutation in the NF2 gene influences the disease severity. Constitutional nonsense and frameshift mutations that cause protein truncation confer a poorer phenotype (Baser et al. 2004; Selvanathan et al. 2010). Early detection offers distinct advantages to the patients as hearing preservation remains a challenge. The diagnosis of NF2 increases the likelihood of developing CNS tumors (schwannomas, meningiomas, gliomas, and neuromas) that may involve the brain, cranial nerves, or spinal cord.

Schwannomas on CT head scanning are round or ovoid extra-axial masses. They are iso- to mildly hypodense on noncontrast CT scan, unless cystic or hemorrhagic. Meningiomas are dural-based, extra-axial masses, often with an associated dural tail. They are typically isodense to brain on nonenhanced CT scan (Aoki et al. 1989; Mautner et al. 1996; Fischbein et al. 2000).

On MR imaging, schwannomas are iso- to mildly hypointense compared to brain parenchyma on T1-weighted images. They are iso- to hyperintense to brain parenchyma on T2-weighted images. Intense homogeneous enhancement after contrast administration is typically seen (Fig. 12.4a), although areas of cystic change or hemorrhage may lead to heterogeneous enhancement. Large lesions may cause brainstem compression and/or hydrocephalus. The multilobulated-appearing vestibular schwannomas often seen in NF2 have recently been shown to consist of mixed cell populations bearing a variety of somatic NF2 mutations, suggestive of a collision between several distinct tumor clones, which may account for their relative resistance to treatment (Dewan et al. 2015).

Similar to schwannomas, meningiomas are isointense to gray matter on T1- and T2-weighted images. They usually enhance intensely and homogeneously following gadolinium administration, and calcifications are common (Fig. 12.4b) (Mautner et al. 1996; Fischbein et al. 2000).

The best approach to the management of schwannomas remains controversial, although expert consensus recommendations have been published (Blakeley et al. 2011). Hearing loss in the setting of vestibular schwannomas generally progresses slowly, and if the lesions are small and asymptomatic, patients can be followed by serial imaging studies. A natural history study performed on a large, newly diagnosed NF2 patient cohort with vestibular schwannomas showed rates of hearing decline of 5 % at 1 year, 13 % at 2 years, and 16 % at 3 years. Rates of radiographic tumor progression in this population were higher: 31 % at 1 year, 64 % at 2 years, and 79 % at 3 years (Plotkin et al. 2014). Any progression of symptoms such as hearing loss may be considered failure of conservative management. By contrast, large lesions >3 cm are approached with frontline surgery, and those with brainstem compression may require urgent surgical intervention (Blakeley et al. 2011).

Vestibular schwannoma surgery is challenging and often is performed by multidisciplinary teams of neurosurgeons and neuro-otologists. Several surgical approaches have been described including translabyrinthine, middle cranial fossa, and suboccipital, each with its own advantages and potential risks. Ipsilateral facial nerve damage has been reported in 17 % of patients undergoing removal of vestibular schwannomas greater than 2.5 cm (Grey et al. 1996). This complication can have significant impact on patient quality of life.

Recently, radiosurgery has become more popular in the management of vestibular schwannomas. The main goal of radiosurgery is tumor control, which appears to be decreased in the setting of NF2 as compared to patients with sporadic vestibular schwannomas. In one large retrospective single institutional series of NF2-associated vestibular schwannomas treated with radiosurgery, 8-year local control was 50 % and 3-year hearing preservation was 40 % (Rowe et al. 2008), though subsequent, smaller, series have reported more favorable tumor control outcomes (e.g., Mallory et al. 2014). While secondary malignancies and malignant transformation of vestibular schwannomas following radiosurgery are rare, the majority of described cases have been in the setting of preexisting NF2, suggesting that these patients are at an increased risk of radiation-induced cancer induction (Balasubramaniam et al. 2007).

The therapeutic landscape in NF2-associated lesions has recently been transformed by successes in early trials of targeted biologic therapies based on our evolving understanding of schwannoma biology and the signaling consequences of merlin loss. Schwannomas are known to express high levels of the pro-angiogenic signaling factor VEGF (Caye-Thomasen et al. 2003). In a pilot trial of the anti-VEGF antibody bevacizumab in ten NF2 patients with progressive vestibular schwannoma who were not candidates for standard therapy, six patients exhibited radiographic tumor responses, and four of seven hearing-evaluable patients had objective improvement in hearing (Plotkin and Stemmer-Rachamimov 2009). Similarly promising tumor and hearing response rates were seen in a larger bevacizumab-treated NF2 cohort with longer-term follow-up; however, continuous therapy was required for sustained responses (Plotkin et al. 2012). Unfortunately, in NF2-associated meningiomas, bevacizumab responses were transient and much less frequent, implicating signaling pathways other than VEGF in the growth of these entities (Nunes et al. 2013). Based on the finding that the EGFR signaling pathway was negatively regulated by NF2 (Curto et al. 2007), a recent phase II trial of the EGFR/ErbB2 inhibitor lapatinib in children and adults with NF2-associated vestibular schwannomas revealed volumetric responses in 24 % of patients and hearing responses in 31 % of patients with a median time to overall progression of 14 months (Karajannis et al. 2012). mTOR signaling was also shown to be dysregulated in preclinical models of NF2; however, a recent phase II study of the mTOR inhibitor everolimus in NF2-associated vestibular schwannoma was negative (Karajannis et al. 2014). At this time, more clinical experience is warranted to better define the most effective treatment(s) and key criteria for initiating therapy. Multiple rationally informed clinical trials of a variety of targeted agents in NF2 including lapatinib, axitinib, everolimus, and bevacizumab are ongoing (Karajannis and Ferner 2015).

Tuberous sclerosis complex (TSC), previously known as Bourneville’s disease, is an autosomal dominant disorder with a growing incidence currently estimated to be 1:6000 to 1:9000 due to improved diagnostic tests (Roach and Sparagana 2004). There is no race or gender predilection, and onset of symptoms varies from infancy to late childhood (Roach et al. 1998; Sparagana and Roach 2000).

TSC is genetically heterogeneous with two implicated genes: TSC1 on chromosome 9q34 encodes hamartin, a 130 kDa tumor suppressor protein, and TSC2 on chromosome 16p13 encodes tuberin, a 200 kDa tumor suppressor protein. Both proteins form a ubiquitous intracellular complex called the TSC complex, which is involved in many cell regulatory processes.

Through the GTPase-activating function of tuberin, the TSC tumor suppressor complex drives the small GTPase, termed Ras homolog enhanced in brain (Rheb), into the inactive guanosine diphosphate-bound state. Rheb in the guanosine triphosphate-bound active state is a positive effector of mammalian target of rapamycin (mTOR). Mutations in either hamartin or tuberin drive Rheb into the guanosine triphosphate-bound state, which results in constitutive mTOR signaling. mTOR appears to mediate many of its effects on cell growth through the phosphorylation of the ribosomal protein S6 kinases (S6Ks) and the repressors of protein synthesis initiation factor eIF4E, the 4EBPs. The S6Ks act to increase cell growth and protein synthesis, whereas the 4EBPs serve to inhibit these processes. mTOR interacts with the S6Ks and 4EBPs through an associated protein, raptor.

Mutation of tuberin or hamartin leads to constitutive activation of mTOR, which results in the hamartomatous lesions in the brain, kidney, heart, lung, CNS, and other organs of the body. More aggressive tumors, such as angiomyolipomas, can also arise. Such mutations are commonly found in patients with TSC, but up to one third of clinically diagnosed patients have no discernable mutation (Jones et al. 2000). This might be in part due to somatic mosaicism. Reasons for the clinical variability associated with identical mutations remain elusive. Recent reports suggest that patients with mutations in TSC1 gene are less severely affected than patients with mutations in the TSC2 gene, a finding that provides some help when counseling parents (Jansen et al. 2008; van Eeghen et al. 2012).

TSC is characterized by seizures, behavioral problems, mental retardation, and development of benign tumors (hamartomas) in multiple organs. The classic TSC triad consists of seizures, mental retardation, and adenoma sebaceum (Hanno and Beck 1987; Curatolo 1996; Roach et al. 1998). Adenoma sebaceum are pathologically best characterized as facial angiofibromas. The CNS lesions seen with TSC include cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas (SEGA). Cortical tubers present a hallmark for the disease. They form during development and represent a disorder of neural proliferation. Recently updated diagnostic guidelines rely upon molecular testing and a variety of clinical criteria to establish the diagnosis of TSC (Table 12.3). A definite diagnosis of TSC requires identification of a pathogenic mutation in TSC1 or TSC2 or a combination of either two major features or one major feature and two minor features. For a probable diagnosis of TSC, one major feature or two or more minor features must be present.

Epilepsy is the most common neurological symptom associated with TSC, present in 60–90 % of cases, and often beginning in the first year of life (Jozwiak et al. 2000; Thiele 2004). In one analysis of 105 patients diagnosed with TSC, 47 % had abnormal cognitive function that was associated with refractory seizures and mutations in the TSC2 gene (Winterkorn et al. 2007). Patients with tuberous sclerosis complex face a high risk of neuropsychiatric impairments: for example, the prevalence of autism spectrum disorders in TSC has recently been estimated to be as high as 25–50 % (de Vries et al. 2015).

Hypomelanotic lesions, ash-leaf macule depigmented nevi resembling vitiligo, may be noted at birth and can be seen in more than half of TSC patients before 2 years of age. These are best visualized with ultraviolet light (Wood lamp). Ash-leaf spots are seen in up to 90 % of patients with TSC. Facial angiofibromas (adenoma sebaceum) skin lesions consist of vascular and connective tissue elements. The red papular rash typically extends over the nose and down the nasolabial folds toward the chin, cheeks, and malar regions. Skin lesions gradually enlarge, manifesting ultimately in 90 or more percent of TSC patients (Northrup and Krueger 2013).

The leading cause of morbidity and mortality in TSC patients is caused by neurologic manifestation of the disease followed by renal complications (Franz 2004). Refractory epilepsy is common and leads to poor cognitive outcome (Winterkorn et al. 2007). SEGAs can cause hydrocephalus and require surgical intervention (Cuccia et al. 2003). Additional abnormalities occur in the eyes, skin, kidneys, bones, heart, and lungs. Prognosis varies with the individual manifestations of the disease. Major causes of death in a large TSC Scottish cohort were renal disease, followed by brain tumors, pulmonary lymphangiomyomatosis, status epilepticus, and bronchopneumonia (Shepherd and Stephenson 1992). In severe cases, death occurs in the second decade of life (Curatolo 1996; Webb et al. 1996; Sparagana and Roach 2000).

Molecular genetic testing has become available in clinical practice and may be helpful in young patients who are less than 2 years of age, since many of the clinical signs are not present until later in life. Recently updated consensus diagnostic criteria for TSC now include the identification of a pathogenic TSC1 or TSC2 mutation as sufficient for the formal diagnosis of tuberous sclerosis, independent of clinical findings (Table 12.3, Northrup and Krueger 2013). Various molecular assays reveal the presence of a mutation in 75–90 % of cases (Northrup and Krueger 2013). According to recently updated TSC management guidelines, genetic testing is indicated for genetic counseling purposes or when the diagnosis of TS is suspected but cannot be clinically confirmed (Krueger and Northrup 2013).

In addition to the recent adoption of genetic testing to formally establish a diagnosis of TSC, clinical criteria are commonly used as detailed in Table 12.3.

Approximately 95 % of patients with clinical features of TSC have abnormalities on CT scans (Menkes and Maria 2000). Typically, there are hypodense subependymal nodules lining the ventricles (Fig. 12.5a), usually calcified after the first year of life, and 50 % of affected individuals demonstrate calcified cortical hamartomas. SEGAs located at or near the foramen of Monro enhance brightly following contrast administration. Calcified subependymal and cortical nodules are seen in 95 % of individuals with TSC, leaving CT as a simpler diagnostic tool than MRI by obviating the need for general anesthesia in children (Braffman et al. 1990; Menor et al. 1992; Mukonoweshuro et al. 1999; Fischbein et al. 2000).

Brain MRI is preferable for defining the exact number and location of cerebral cortical and subcortical tubers, white matter lesions, and areas of heterotopias (Braffman et al. 1990; Menor et al. 1992; Mukonoweshuro et al. 2001; Fischbein et al. 2000). Tubers or sclerotic white patches involving the gyri or white matter occur mostly in the cerebrum, while cerebellar, brainstem, and spinal cord lesions occur less commonly. Cortical tubers and hamartomas change in appearance as the brain myelinates. They are initially hyperintense on T1-weighted images and hypointense on T2-weighted images, but as brain myelination progresses, this imaging pattern reverses. White matter lesions appear as hyperintense linear bands in cerebrum and cerebellum. In infants, bands are hypointense to unmyelinated white matter on T2-weighted images and are hyperintense to white matter in older children and adults (Fig. 12.5b). SEGAs at or near foramen of Monro display intense postcontrast enhancement, although the pattern can be heterogeneous (Fig. 12.5c). MR spectroscopy can be useful to distinguish them from cortical tubers.

Refinement of MRI techniques and interpretation to identify the location of epileptogenic lesions in TS patients remains an area of active research (Jahodova et al. 2014; Gallagher et al. 2009, 2010; Peters et al. 2013). PET/MRI fusion imaging has been studied to identify epileptogenic tubers with great promise for improving surgical cure rates for intractable epilepsy (Chandra et al. 2006).

TSC affects multiple organs, and treatment recommendations vary according to each specific organ manifestation. Recently developed consensus surveillance and management guidelines for TSC patients provide detailed recommendations for diagnosis, surveillance, and treatment of organ site-specific manifestations of TSC (Krueger and Northrup 2013). For diagnosis of CNS abnormalities, all TSC patients are recommended to have an initial MRI of the brain with and without gadolinium contrast to identify tubers, subependymal nodules, and subependymal giant cell astrocytomas. CT or cranial ultrasound are second-line diagnostic modalities. All pediatric patients are recommended to undergo a baseline EEG even in the absence of seizures. A baseline neuropsychiatric assessment and referral for specialized management is also strongly recommended in view of the risk of significant neuropsychiatric manifestations in TSC.

Neurologically asymptomatic patients with TSC should undergo neuroimaging surveillance every 1–3 years until the age of 25 and, if SEGAs are present, continuing into adulthood. Updated treatment recommendations for TSC-associated SEGA have recently been published (Roth et al. 2013). Surgical resection is recommended for acutely symptomatic SEGAs, while growing or asymptomatic SEGAs can be managed by surgical resection or medical therapy with mTOR inhibitors. The efficacy of mTOR inhibition with everolimus in shrinking or stabilizing TS-associated SEGAs has been demonstrated in a randomized phase III trial (Franz et al. 2013) and has revolutionized the management paradigm for such patients. Early results (e.g., Krueger et al. 2010) suggest that mTOR inhibition may reduce seizure frequency in some TS patients; however, the efficacy of this approach awaits larger-scale prospective verification. Everolimus has also been shown to be efficacious in reducing the volume of renal angiomyolipomas in TS patients (Bissler et al. 2013).

Treatment and surveillance recommendations for extracranial manifestations of TS have also been updated at the 2012 International Tuberous Sclerosis Consensus Conference (Krueger and Northrup 2013). An organ site-specific summary of recommendations for newly diagnosed and established tuberous sclerosis patients is provided in Table 12.4.

Ataxia telangiectasia (AT) is an autosomal recessive disorder with an incidence of 1:40,000 to 1:80,000 and equal predilection in both sexes. Patients with AT may present during infancy with ataxia without any cutaneous manifestations, which may become apparent after 2 years of age (Gosink et al. 1999; Lavin 1999).

The gene for AT has been mapped to the long arm of chromosome 11 (11q23.3). The ataxia telangiectasia mutated (ATM) gene is very large with 66 exons spanning 150 kb of the genome, which renders mutation analysis challenging (Bakkenist and Kastan 2003). The ATM gene product is a member of the phosphatidylinositol 3-kinase (PI3-kinase) family and is activated by autophosphorylation in response to DNA double-strand breaks, as well as by direct ATM protein oxidation (Guo et al. 2010) and by membrane receptors such as PDGFRβ (Kim et al. 2010). It contains a PI3-kinase domain, a putative leucine zipper, and a proline-rich region. The ATM protein detects DNA double-strand breaks and activates a number of substrates including p53, chk-2, nibrin, BRCA1, and TSC2, the latter serving to downregulate mTOR signaling (Ambrose and Gattia 2013; Kastan and Lim 2000; Shiloh 2003). ATM plays an important role in cellular responses to DNA damage, cell cycle control, and maintenance of telomere length and has recently been shown to be important for mitochondrial homeostasis (Ambrose et al. 2007; Eaton and Lin 2007). Additional roles of ATM outside of DNA repair, such as in regulation of synaptic vesicle trafficking and in epigenetics, are emerging and may be critical to fully understanding the neurodegenerative phenotype of its deficiency in humans (Herrup 2014).

Over 400 different mutations have been identified in AT patients. Database screening has revealed that most mutations are unique to a given family. Mutations are distributed anywhere in the gene, and no hotspots or high-frequency mutations have been reported (Concannon and Gatti 1997; Mitui et al. 2003). Approximately 90 % of mutations are of the frameshift or premature truncation type, making the majority null mutations. Missense mutations occur in 10 % of the known mutations among AT families (Chun and Gatti 2004; Nakamura et al. 2014). Increased variant protein expression and residual kinase activity have been shown to correlate with a milder phenotype and increased life expectancy in AT patients (Staples and McDermott 2008; Micol et al. 2011; Verhagen et al. 2011).

AT is the most common ataxia in infancy (Kamiya et al. 2001), although the initial manifestations of cerebellar ataxia may not be noted until early walking. AT is a common cause of progressive ataxia in children younger than 10 years of age, second only to tumors of the posterior fossa. Ataxia is generally the presenting symptom of AT. Oculomotor apraxia is a distinguishing feature of the disease, which is often present prior to the cutaneous findings.

Telangiectasias are a second major clinical manifestation of the disease (Table 12.5). Progressive oculocutaneous telangiectasias represent a key feature of AT. Bulbar conjunctivae telangiectasias first appear between 2 and 8 years of age and subsequently involve the ears, eyelids, malar prominences, neck, antecubital and popliteal fossae, as well as dorsum of hands and palate. Initially they appear as bright-red, thick, symmetrical streaks that resemble atypical conjunctivitis and only later become frank telangiectasias. These skin lesions become more prominent with sunlight exposure and age. Premature aging of hair and skin is frequent.