Phakomatoses and Allied Conditions

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Chapter 40 Phakomatoses and Allied Conditions

The disorders referred to as phakomatoses are notable for their dysplastic nature and tendency to form tumors in various organs, particularly the nervous system. Bielschowsky observed these characteristic features in neurofibromatosis and tuberous sclerosis complex [Bielschowsky, 1914, 1919], and van der Hoeve called particular attention to these disorders and named the disease category the “phakomatoses” (Greek phakos, “mole” or “birthmark”) [Van der Hoeve, 1923]. Von Hippel–Lindau disease and Sturge–Weber syndrome were thought to belong to this category of diseases [Van der Hoeve, 1923, 1932] and Louis-Bar identified a syndrome, ataxia-telangiectasia, that she believed also had the typical clinical characteristics of the phakomatoses [Louis-Bar, 1941]. Some of these conditions have been referred to as “neurocutaneous disorders” because of the frequent involvement of the skin in addition to the nervous system. Cutaneous features are not present in all phakomatoses, however (e.g., von Hippel–Lindau syndrome), and many include features outside the skin and nervous system, so the term can be misleading. Box 40-1 lists disorders associated with specific cutaneous findings; Table 40-1 summarizes the phakomatoses.

Table 40-1 Phakomatoses and their Clinical Features

Syndrome Common Non-neurologic Features Common Neurologic Features
Neurofibromatosis type 1 Café-au-lait spots, malignant peripheral nerve sheath tumor, skeletal dysplasia Neurofibromas, optic glioma, learning disabilities
Neurofibromatosis type 2 Posterior subcapsular cataract Vestibular schwannomas, other cranial and peripheral nerve schwannomas, meningiomas, ependymomas
Schwannomatosis   Schwannomas
Tuberous sclerosis complex Hypopigmented macules, collagenous plaques, angiofibroma, renal angiomyolipoma, pulmonary lymphangiomyomatosis, periungual fibromas Cortical dysplasias, subependymal nodules, subependymal giant cell astrocytomas, seizures
Sturge–Weber syndrome Port-wine stain Leptomeningeal angiomatosis, seizures
von Hippel–Lindau disease Ocular hemangioblastoma, renal cell carcinoma, pheochromocytoma, endolymphatic sac tumor Hemangioblastomas
Maffucci’s syndrome Multiple endochondromas  
Epidermal nevus syndrome Epidermal nevus, skeletal dysplasia Seizures, developmental impairment
Parry–Romberg syndrome Facial hemiatrophy  
Neurocutaneous melanosis Multiple melanocytic nevi, melanoma Leptomeningeal melanosis, seizures, hydrocephalus, Dandy–Walker malformation
Klippel–Trenaunay–Weber syndrome Hemihypertrophy, angioma Macrocephaly, hydrocephalus
Incontinentia pigmenti Females only; hyperpigmented skin lesions, abnormalities of teeth, hair, and bone Seizures, developmental impairment
Hypomelanosis of Ito Hypopigmented skin lesions Seizures
Wyburn–Mason syndrome Retinal arteriovenous malformations Cerebral arteriovenous malformations

This chapter surveys the clinical features of the three major phakomatoses: neurofibromatosis, tuberous sclerosis complex, and von Hippel–Lindau syndrome. Also included in this chapter are a number of additional disorders that are commonly considered along with the phakomatoses, including vascular malformation syndromes, pigmentary disorders, and several other rare disorders. Ataxia-telangiectasia is considered in detail in Chapter 67 on the hereditary ataxias.

The Neurofibromatoses

It was only with the report of Young et al. [1970] that the distinction between a peripheral and a central form of neurofibromatosis came to be recognized. The classification was formalized by the National Institutes of Health (NIH) Consensus Development Conference in 1987 [Stumpf, 1988], with the peripheral form of neurofibromatosis referred to as NF1, and the central form, the hallmark of which is bilateral vestibular schwannomas, called NF2. The distinction between the disorders was subsequently verified when the two genes were found to be distinct, first by mapping and later by cloning. More recently, a third disorder, referred to as schwannomatosis, has been split out [MacCollin et al., 2005]. This disorder is characterized by the development of multiple schwannomas of cranial nerves except the vestibular nerve, and of spinal and peripheral nerves.

Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is transmitted as an autosomal-dominant trait and is notable for its great variability of expression. It can involve not only the peripheral and central nervous systems, but also many other systems, including the skin, bone, endocrine, gastrointestinal, and vascular systems. Although von Recklinghausen is credited with the initial clinical and pathologic account of this disease in 1882 [von Recklinghausen, 1882], he cited Tilesius for the first description of a patient with multiple fibrous skin tumors. Wishart [Wishart, 1822] and Smith [Smith, 1849] also provided clinical accounts of the disorder before the report of von Recklinghausen, although early reports failed to recognize the distinction between the disorders known as NF1 and NF2. Diagnostic criteria for NF1 are presented in Box 40-2.

Clinical Characteristics

In NF1, the usual presenting signs are cutaneous manifestations. These skin changes include café-au-lait macules, cutaneous neurofibromas, hypopigmented macules, patchy and diffuse areas of hyperpigmentation, juvenile xanthogranulomas, and angiomas. Café-au-lait macules usually are present at birth and range in size from a few millimeters to centimeters [Crowe et al., 1956] (Figure 40-1). They do not significantly increase in number after the first 2 years of life. Six or more café-au-lait macules measuring at least 5 mm across before puberty or 15 mm after puberty constitute one diagnostic criterion for NF1. Rare persons with variant forms of neurofibromatosis, such as spinal neurofibromatosis [Messiaen et al., 2003; Korf et al., 2005], may lack café-au-lait macules, and one rare NF1 gene mutation is associated with café-au-lait macules and no neurofibromas in affected individuals [Upadhyaya et al., 2007]. Individuals with mutation in the SPRED1 gene may also present with multiple café-au-lait macules, skinfold freckles, and macrocephaly, but do not appear to develop neurofibromas or other tumor-related NF1 complications [Brems et al., 2007; Messiaen et al., 2009]. Nevertheless, in a majority of children who present with six or more café-au-lait macules and do not have an alternative diagnosis, signs of NF1 eventually develop [Korf, 1992]. Usually the second sign to appear is skinfold freckling [Crowe, 1964] (Figure 40-2). Freckles begin in the inguinal region in children at 3–4 years of age, and eventually appear in the axillae, at the base of the neck, and in the inframammary region in females. Areas of freckling also can be found over the trunk and extremities. Diffuse, patchy areas of hyperpigmentation also may appear, sometimes overlying plexiform neuromas [Riccardi, 1980]. Areas of hypopigmentation or hypovascularity also may occur. Juvenile xanthogranulomas appear as firm yellowish papules in infants and young children, and eventually regress. Although an association with leukemia has been suggested [Zvulunov, 1996], this has not been verified.

Cutaneous neurofibromas are a prominent finding in NF1 and are located in the dermis or adjacent to it (Figure 40-3). They are discrete, soft or firm papules, ranging in size from a few millimeters to several centimeters, can be flat, sessile, or pedunculated, and can be readily impressed into the skin below. Neurofibromas can develop at any time and in any location, and may affect any component of the peripheral nervous system, from the dorsal root ganglion to the terminal nerve twigs. Plexiform neuromas represent tumors that involve a longitudinal section of nerve and can involve multiple branches of a major nerve [Korf, 1999]. Near the surface of the body they can cause thickening and hypertrophy of the skin and soft tissues (Figure 40-4). They may occur deeper in the body and be detected only by imaging [Tonsgard et al., 1998]. Tumors of the orbit or limbs can cause major physical deformity. Plexiform neurofibromas can be congenital lesions, often growing rapidly in the early months of life; they then may remain quiescent for long periods of time or grow unpredictably. The tumors are easily visualized by magnetic resonance imaging (MRI), and display a characteristic “target sign.” Volumetric MRI may be helpful in following their growth [Dombi et al., 2007; Cai et al., 2009]. Neurofibromas originating at the dorsal roots may grow in a dumbbell shape and invade the spinal canal (Figure 40-5], sometimes causing spinal cord compression. The gastrointestinal tract can also be affected by growth of neurofibromas or ganglioneuromas. These tumors can cause intestinal obstruction or bleeding.

Ophthalmologic features of NF1 include Lisch nodules, glaucoma, and optic glioma. Iris Lisch nodules are melanocytic hamartomas that are highly specific to NF1 [Lisch, 1937; Lewis and Riccardi, 1981]. Their appearance is age-dependent, usually beginning at the age of approximately 6 years. Lisch nodules occur in approximately 95 percent of adults with the disorder [Lubs et al., 1991] and are therefore helpful in diagnosis. Glaucoma usually occurs when a plexiform neurofibroma involves the upper eyelid (Figure 40-6) [Morales et al., 2009]. Orbital plexiform neurofibroma, arising from the trigeminal nerve, often is associated with sphenoid dysplasia, and can present with pulsating exophthalmos or enophthalmos [Jacquemin et al., 2002].

Optic pathway gliomas are found in approximately 15 percent of patients [Lewis et al., 1984]. Most are asymptomatic, but these tumors can manifest with symptoms of decreased visual acuity, visual field defects, or precocious puberty [Listernick et al., 2007]. The glioma can involve the optic nerves, chiasm, optic radiations, and hypothalamus (Figure 40-7); it rarely manifests as the diencephalic syndrome of infancy or precocious puberty. Optic gliomas are pilocytic astrocytomas, but often are slow-growing.

Aside from optic gliomas, astrocytomas of the cerebrum, brainstem, and cerebellum are the most common intracranial tumors encountered in NF1 [Albers and Gutmann, 2009]. Malignant peripheral nerve sheath tumor occurs in upwards of 8–13 percent of affected persons [Evans et al., 2002]. These manifest with pain or sudden growth, usually within a pre-existing plexiform neurofibroma [D’Agostino, Soule and Miller, 1963]. Various other neoplastic disorders occur more frequently in patients with NF1 than in the general population, including leukemia, especially juvenile myelomonocytic leukemia [Stiller, Chessells and Fitchett, 1994] and pheochromocytoma [Walther et al., 1999a].

Macrocephaly and short stature are common in NF1 and scoliosis has been reported to occur in 10–40 percent of patients [Crawford and Herrera-Soto, 2007]. Scoliosis usually does not develop before the age of 6 years and most commonly involves the thoracic spine. Bowing of the tibia, fibula, and other long bones can be present in early life, with occurrence of spontaneous fractures at the junction of the middle and distal thirds of the bone shaft, resulting in pseudarthrosis [Elefteriou et al., 2009; Stevenson et al., 1999]. Non-ossifying fibromas may occur and can present with pain or fracture [Howlett et al., 1998]. There is also evidence for decreased bone mineral density in children and adults with NF1, which may contribute to an increased risk of fracture [Stevenson et al., 2008; Kuorilehto et al., 2005].

Approximately 50 percent of patients have learning disabilities, with no specific pattern unique to those with NF1 [Hyman, Arthur Shores and North, 2006]. Both verbal and nonverbal disabilities occur, as well as attention-deficit disorder [Mautner et al., 2002] and hypotonia [Souza et al., 2009]. Fewer than 10 percent have mental retardation, and most of these patients have large deletions of the NF1 gene [Kayes et al., 1994]. Seizures occur in approximately 6–10 percent of patients [Korf, Carrazana and Holmes, 1993]. The pathogenesis of the cognitive phenotype is not known. Abnormal cortical architecture and heterotopias have been reported in the brains of some patients with severe cognitive deficits [Rosman and Pearce, 1967]. It has been suggested that the areas of enhanced T2 signal intensity characteristically seen in the brains of children with NF1 (Figure 40-8) may be associated with learning disabilities [Hyman et al., 2007]. These lesions occur in the basal ganglia, brainstem, cerebellum, and internal capsule; tend to disappear with age [Hyman et al., 2003; Ferner et al., 1993]; and are characterized by increased myelin water content and gliosis [DiPaolo et al., 1995].

Vascular anomalies in NF1 include regions of intimal proliferation and fibromuscular changes in small arteries [Friedman et al., 2002]. Renal artery stenosis can lead to hypertension in children [Fossali et al., 2000], and involvement of other vessels can cause vascular insufficiency or hemorrhage as a result of arterial wall dissection [Hinsch et al., 2008]. Stenosis of the internal carotid artery can lead to moyamoya disease and stroke [Cairns and North, 2008], although lesions often are asymptomatic. The stenotic changes can arise spontaneously in children with NF1, but frequently develop after radiation therapy for brain tumors in young children [Kestle, Hoffman and Mock, 1993].

Pathology

Neurofibromas consist of a mixture of cell types, including Schwann cells, fibroblasts, perineurial cells, and mast cells [Pineda, 1965]. They are polyclonal [Fialkow et al., 1971], but genetic studies have confirmed that the “tumor cell” is the Schwann cell [Sherman et al., 2000; Zhu et al., 2002], or in the case of dermal neurofibromas, stem cells referred to as skin-derived precursors [Le et al., 2009]. The other cell types present in the lesion apparently proliferate as a secondary phenomenon, perhaps in response to stimulation by cytokines [Yang et al., 2003]. Mast cells are present in large numbers and have been suspected of being a source of cytokines [Yang et al., 2008]. In plexiform neurofibromas, the pathologic process extends across multiple nerve fascicles instead of occurring at a focal site in a nerve, and may extend across branches of a larger nerve. Malignant peripheral nerve sheath tumor manifests as a malignant tumor of Schwann cell origin, although sometimes rhabdoid elements are present in such tumors [Buck, Mahboubi and Raney, 1977]. Most, if not all, of these neoplasms arise from pre-existing tumors, usually plexiform neurofibromas. The pathology of other NF1-associated lesions is less well understood than that of the neurofibroma.

Genetics

NF1, inherited as an autosomal-dominant trait, has an estimated prevalence of 1 in 3000; about half of cases are new mutations [Crowe, Schull and Neel, 1956; Huson, Harper and Compston, 1988]. The NF1 gene is located at 17q11.2 and encodes a 3818-amino-acid protein referred to as neurofibromin [Cawthon et al., 1990a, b; Viskochil et al., 1990; Wallace et al., 1990]. Neurofibromin is expressed in multiple cell types but is highly expressed in Schwann cells, oligodendrocytes, and neurons [Daston et al., 1992]. The protein includes a functional GTPase-activating protein (GAP) domain that regulates conversion of Ras-guanosine triphosphate to Ras-guanosine diphosphate [Ballester et al., 1990; Xu et al., 1990a, b]. Ras is a membrane-bound intracellular signaling molecule that is activated by complexing with guanosine triphosphate (GTP) on ligand binding to membrane receptor tyrosine kinases. GAP proteins regulate this process by stimulating a GTPase activity that is intrinsic to Ras [Bernards, 2003]. Neurofibromin functions as a tumor suppressor gene with respect to neurofibroma formation [Sherman et al., 2000; Cichowski and Jacks, 2001; Zhu et al., 2002]. The germline mutation of one NF1 allele constitutes the first “hit”; the second hit is a somatic mutation [Upadhyaya et al., 2004] in a Schwann cell that causes that cell to proliferate and attract other cells, such as mast cells, fibroblasts, and perineurial cells, which also proliferate. These cells, being heterozygous for the NF1 mutation, may be hypersensitive to cytokine stimulation [Vogel et al., 1995]. Transformation to malignancy requires additional genetic changes, such as mutation of p53 [Legius et al., 1994]. Biallelic NF1 gene mutation also occurs in melanocytes within café-au-lait macules [Maertens et al., 2007] and in dysplastic bone tissue [Stevenson et al., 2006]. It is unclear whether other dysplastic lesions also occur as a result of a tumor suppressor mechanism, or whether haploinsufficiency of neurofibromin expression itself causes these lesions. Mice rendered heterozygous for an NF1 mutation do display cognitive deficits [Costa et al., 2002], suggesting that haploinsufficiency might account for some of the NF1 phenotype.

NF1 exhibits a wide range of variability of expression and complete penetrance. Mutations are widely scattered across the gene and include a wide variety of mutational mechanisms [Messiaen et al., 2000]. Most of the mutations lead to decreased level of expression of neurofibromin or complete lack of expression. Few genotype–phenotype correlations have been established. Large deletions that include the NF1 gene and multiple contiguous genes over a 1.5-Mb region tend to lead to a particularly severe form of NF1, with mental retardation, early onset of large numbers of neurofibromas, facial dysmorphism, and increased risk of cancer [De Raedt et al., 2003; Kayes et al., 1994; Wu et al., 1995]. Another variant form of neurofibromatosis, familial spinal neurofibromatosis, may represent an additional genotype–phenotype correlation. Persons with this disorder have multiple spinal neurofibromas and subcutaneous tumors but lack skinfold freckling and dermal tumors, and tend to have missense mutations or splicing mutations [Korf, Henson and Stemmer-Rachamimov, 2005]. Individuals with a three-base deletion in exon 17 have only café-au-lait spots and do not develop neurofibromas [Upadhyaya et al., 2007]. Approximately 50 percent of cases of NF1 occur sporadically, as a result of a new mutation of the NF1 gene. Because of the high penetrance of the disorder, unaffected parents of a sporadically affected child have a low risk of recurrence, barring the rare instance of germline mosaicism [Lazaro et al., 1995]. Somatic mosaicism for NF1 may manifest with segmental distribution of features [Tinschert et al., 2000; Vandenbroucke et al., 2004]. Genetic testing for diagnosis of NF1 is available on a clinical basis. It is used to confirm a diagnosis in patients who fulfill only a single diagnostic criterion, to characterize patients with unusual clinical presentations, and to enable prenatal testing. The discovery of mutation in the SPRED1 gene accounting for patients with multiple café-au-lait spots but lacking other features of NF1 [Brems et al., 2007] (now referred to as “Legius syndrome”), provides additional rationale for genetic testing in young children with multiple café-au-lait spots. The majority of mutations are found in the NF1 gene, making it cost-effective to begin with NF1 testing, followed by SPRED1 testing if no NF1 mutation is found [Messiaen et al., 2009].

Management

Treatment of patients with neurofibromatosis is symptomatic. Affected persons should be followed on a regular basis by a physician who is familiar with the disorder to recognize treatable complications early and to provide anticipatory guidance and counseling. Genetic counseling should be provided. Controversy surrounds the use of imaging, especially MRI, in screening patients with NF1. Most of the lesions that will be identified are not amenable to treatment, so such testing may create needless anxiety, and in children the procedure carries the risks associated with sedation. The value of the “baseline” examination is questionable because most of the lesions of NF1 are slow-growing and will be followed both clinically and by imaging once they come to attention [Listernick et al., 1994]. Current consensus guidelines do not recommend routine imaging [Gutmann et al., 1997], although care should be individualized for specific clinical needs.

Neurofibromas of the peripheral nerves need not be removed unless they are subject to repeated irritation and trauma or develop malignant change. Some plexiform neuromas can be removed for cosmetic reasons, although complete resection is difficult and regrowth is common [Needle et al., 1997]. Malignant tumors are managed with appropriate neurosurgical measures, radiation therapy, and chemotherapy. Optic gliomas tend to behave in an indolent manner and therefore are followed clinically without treatment in asymptomatic children [Listernick et al., 2007]. Symptomatic tumors most often are treated with chemotherapy [Packer et al., 1997]; radiation therapy may be associated with second malignant tumors [Sharif et al., 2006] or moyamoya disease [Desai et al., 2006; Kestle, Hoffman and Mock, 1993]. Malignant peripheral nerve sheath tumors tend to be highly malignant, so early diagnosis is essential [Evans et al., 2002]. Patients with unexplained pain or growth of a neurofibroma should be evaluated, with consideration of biopsy. Positron emission tomography (PET) scanning may be helpful in distinguishing a malignant peripheral nerve sheath tumor from plexiform neurofibroma [Ferner et al., 2000; Karabatsou et al., 2009; Warbey et al., 2009].

Clinical trials of drugs to treat specific complications are on-going. These include the use of statins to treat learning disabilities [Krab et al., 2008] and several experimental treatments for neurofibromas [Babovic-Vuksanovic et al., 2007; Gupta et al., 2003; Packer and Rosser, 2002; Packer et al., 2002].

Neurofibromatosis Type 2

Clinical Characteristics and Pathology

Diagnostic criteria for NF2 are presented in Box 40-3 [Gutmann et al., 1997; Stumpf, 1988; Baser et al., 2002]. The defining feature of NF2 is the occurrence of bilateral vestibular schwannomas. Age at onset is highly variable, ranging from early childhood to the seventh decade and beyond [Evans 1999; Mautner et al., 1993]. In view of this variability in age at onset of vestibular tumors, NF2 also should be considered in patients with early onset of associated tumors or those with combinations of associated tumors.

Vestibular schwannomas commonly manifest with tinnitus and/or hearing loss, and may cause problems with balance [Evans, 1999]. Audiology and auditory brainstem-evoked response testing can be helpful, but definitive diagnosis is based on MRI findings (Figure 40-9). Early tumors may be confined to the internal auditory canal and require careful search with thin MRI slices to be detected. Schwannomas can occur along any other cranial nerve, the fifth being most common after the eighth. Schwannomas also may occur along spinal nerves, with the potential for causing radiculopathy or cord compression, or along peripheral nerves. In some patients, a polyneuropathy develops as a result of Schwann cell proliferation around peripheral nerves [Gijtenbeek et al., 2001; Hagel et al., 2002]. Dermal schwannomas appear as plaquelike lesions, often with associated hair growth. Café-au-lait macules are not a reliable indicator of NF2, unlike in NF1 [Mautner et al., 1997]. Other major central nervous system tumors associated with NF2 are meningiomas and ependymomas. Multiple meningiomas may not be surgically resectable and can be responsible for significant morbidity. Virtually the entire NF2 phenotype is characterized by proliferative lesions; the one exception is the occurrence of posterior subcapsular cataracts or cortical wedge opacities [Pearson-Webb et al., 1986].

Genetics

NF2 is transmitted as an autosomal-dominant trait with complete penetrance and variable expression. Prevalence is estimated at approximately 1 in 60,000, and birth incidence at 1 in 30,000 [Evans, 2009; Evans et al., 2010]. Approximately half of cases occur sporadically as a result of new mutation. The NF2 gene was mapped to chromosome 22 [Rouleau et al., 1987], and the responsible gene was identified by two groups in 1993 [Rouleau et al., 1993; Trofatter et al., 1993]. The protein is variously referred to as schwannomin or merlin (the latter an acronym for moesin, ezrin, and radixin-like protein]. Merlin is a cytoskeletal protein that appears to play a role in the control of cell growth in tissues [Xiao, Chernoff and Testa, 2003]. Schwannomas are clonal tumors, and the NF2 gene acts as a tumor suppressor in formation of these tumors, as well as other NF2-associated tumors [Seizinger et al., 1987]. Genetic testing for NF2 is available for diagnostic purposes. Some genotype–phenotype correlations have been identified; specifically, missense or splicing mutations tend to predict milder disease than do mutations that lead to protein truncation [Parry et al., 1996; Ruttledge et al., 1996]. Somatic mosaicism for NF2 mutation may produce localized disease or ameliorate disease severity [Baser et al., 2000a].

Management

Patients benefit from multidisciplinary care at a center with experience in dealing with the varied manifestations of the disorder [Evans et al., 1993]. Management of tumors associated with NF2 is primarily surgical [Evans et al., 2005]. Timing of surgery and the decision to treat one or both vestibular tumors depends on tumor size, degree of hearing loss, and involvement of other cranial nerves or compression of the brainstem. Stereotactic radiosurgery is also used for the treatment of vestibular schwannomas [Battista, 2009], though there may be an increased risk of malignancy in residual tumor [Baser et al., 2000b]. Recent trials with the vascular endothelial growth factor (VEGF) inhibitor bevacizumab have shown promising results in reduction in size of vestibular schwannomas [Plotkin et al., 2009; Mautner et al., 2010].

Schwannomatosis

Schwannomatosis is a more recently recognized entity [MacCollin et al., 1996; Evans et al., 1997], characterized only by the occurrence of schwannomas on cranial and spinal nerves other than the vestibular nerve. It often manifests with pain or nerve compression. Diagnostic criteria are provided in Box 40-4. Schwannomatosis is most commonly sporadic, but familial cases have been observed, in which case inheritance is autosomal-dominant with incomplete penetrance. The gene responsible for the disorder is designated INI1 (also designated SMARCB1; Hulsebos et al., 2007; Boyd et al., 2008], and encodes a protein component of a chromatin remodeling complex. It is located on chromosome 22 near the NF2 locus but is distinct from that locus. Symptomatic tumors are treated surgically. Many patients require management for chronic pain.

Tuberous Sclerosis Complex

Tuberous sclerosis complex is a disorder of autosomal-dominant inheritance that affects multiple organ systems, resulting in manifold clinical expressions. Tuberous sclerosis complex is currently recognized as one of the most common single-gene disorders seen in children and adults, with an estimated incidence of 1 in 5800 live births [Osborne et al., 1991] The first description of tuberous sclerosis complex was by von Recklinghausen, who described a newborn who had died of respiratory distress and was found at postmortem examination to have multiple cardiac tumors and a “great number of cerebral scleroses [von Recklinghausen, 1862].” Bourneville usually is credited with the first detailed description of the cerebral manifestations of the disease, describing “sclérose tubéreuse,” indicating the superficial resemblance of the lesions of a potato [Bourneville and Brissard, 1880]. He attached no significance to the facial skin rash of his first patient, calling it acne rosacea, but he and Brissard believed that the renal tumors and cerebral scleroses were associated findings [Bourneville and Brissard, 1900]. Facial angiofibromas, previously referred to as adenoma sebaceum, were independently described in several reports, but Vogt emphasized the association of adenoma sebaceum and the cerebral scleroses described by Bourneville [Vogt, 1908]. He also described a “classic” triad of clinical features comprising mental retardation, intractable epilepsy, and adenoma sebaceum, which is now known to be present in less than one-third of patients with tuberous sclerosis complex.

Clinical Characteristics

Diagnostic criteria are provided in Box 40-5. The clinical presentation of tuberous sclerosis complex depends on the age of the patient, the organs involved, and the severity of involvement. Of importance, both the brain and the skin have more than one major criterion for diagnosis; therefore, a diagnosis of definite tuberous sclerosis complex can be based on skin findings alone, or on neuroimaging findings alone.

Epilepsy is the most common presenting symptom in tuberous sclerosis complex and also is the most common medical disorder. In up to 80–90 percent of persons with tuberous sclerosis complex, seizures will develop during their lifetime, with the onset most frequently in childhood [Gomez, 1999; Thiele, 2004; Chu-Shore et al., 2009]. A majority of children with tuberous sclerosis complex have the onset of seizures during the first year of life, and approximately one-third develop infantile spasms. Almost all seizure types can be seen in persons with tuberous sclerosis complex, including tonic, clonic, tonic-clonic, atonic, myoclonic, atypical absence, partial, and complex partial. Only “pure” absence seizures are not observed.

Infantile spasms will develop in approximately one-third of children with tuberous sclerosis complex, although some reports suggest an incidence as high as 75 percent [Riikonen and Simell, 1990; Fukushima et al., 1998; Hamano et al., 2003; Husain et al., 2000]. Tuberous sclerosis complex is thought to be the most common single cause of infantile spasms, and in some series, 25 percent of symptomatic infantile spasms are secondary to tuberous sclerosis complex. Partial complex seizures precede infantile spasms in approximately one-third of patients with tuberous sclerosis complex in whom infantile spasms develop [Curatolo et al., 2001, 2002]. A strong association between the presence of infantile spasms in tuberous sclerosis complex and subsequent developmental impairment has been noted, although children with tuberous sclerosis complex and infantile spasms can have a normal cognitive outcome [Goh et al., 2005; Yamamoto et al., 1987; Muzykewicz et al., 2009].

The electroencephalogram (EEG) in infantile spasms associated with tuberous sclerosis complex often demonstrates hypsarrhythmia or modified hypsarrhythmia. It is important to realize, however, that the EEG, although usually abnormal, frequently does not have the features of hypsarrhythmia; in some series, up to 70 percent of children with tuberous sclerosis complex and infantile spasms did not have the characteristics of hypsarrhythmia [Curatolo et al., 2001]. Several reports have characterized the EEG patterns of persons with tuberous sclerosis complex and have found a high incidence of abnormalities, including diffuse slowing and epileptiform features [Ganji and Hellman, 1985; Westmoreland, 1999; Muzykewicz et al., 2009].

Tuberous sclerosis complex is associated with a wide range of cognitive and behavioral manifestations. Approximately one-half of persons with tuberous sclerosis complex have normal intelligence, whereas the other half have some degree of cognitive impairment, ranging from mild learning disabilities to severe mental retardation. A bimodal distribution of cognitive abilities is evident, with affected persons falling into a severely cognitively impaired group or a group with normal intelligence [Gillberg et al., 1994; Winterkorn et al., 2007]. Risk factors for cognitive impairment include a history of infantile spasms, intractable epilepsy, and a mutation in the TSC2 gene. Persons with tuberous sclerosis complex, particularly those with cognitive impairment, also are at high risk for developmental disorders. Autistic spectrum disorders affect up to 50 percent of persons with tuberous sclerosis complex [Wiznitzer, 2004; Curatolo et al., 2004; Smalley, 1998], and attention-deficit hyperactivity and related disorders also are common, affecting approximately 50 percent of the patients [de Vries and Watson, 2008]. During adolescence and adulthood, anxiety disorders, depression, or mood disorders develop in a majority of patients with tuberous sclerosis complex [Muzykewicz et al., 2007; Raznahan et al., 2006; Pulsifer et al., 2007].

Cutaneous manifestations are found in up to 96 percent of patients with tuberous sclerosis complex [Gomez et al., 1987; Webb et al., 1996]. Angiofibroma, the skin manifestation initially described in the disorder as adenoma sebaceum, typically appears between the ages of 1 and 4 years and can progress through childhood and adolescence [Gomez et al., 1987; Webb et al., 1996; Pampiglione and Moynahan, 1976]. These lesions typically are pink or red papules that appear in patches or in a butterfly distribution on or about the nose, cheeks, and chin (Figure 40-10).

image

Fig. 40-10 Typical angiofibroma in an adult with tuberous sclerosis complex.

(Courtesy of Dr. TN Darling, Uniformed Services University of Health Sciences, Bethesda, MD.)

Hypopigmented, oval, or leaf-shaped macules, ranging from a few millimeters to several centimeters in length and scattered over the trunk and limbs, are commonly seen [Fitzpatrick, 1991]. The lesions often are apparent at birth and can appear more prominent during the first several years of life as the child’s body size and surface area increase. In fair-skinned persons, visualization of these hypopigmented spots is facilitated by using a Wood’s light, an ultraviolet light that accentuates the hypopigmented spots [Fitzpatrick et al., 1968; Roth and Epstein, 1971]. At least three types of hypopigmented macules occur: polygonal (similar to a thumbprint) is the most frequent shape (0.5–2 cm); an ash leaf-shaped hypopigmented macule is characteristic but is not the most common shape (1–12 cm); and the third common type is a confetti-shaped arrangement of multiple, tiny white macules (1–3 mm) [Fitzpatrick, 1991] (Figure 40-11). Histologic assessment of the hypopigmented spots usually demonstrates a normal number of melanocytes, and on electron microscopy a reduction in the number, diameter, and melanization of melanosomes in the melanocytes from the white macule is seen [Jozwiak and Schwartz, 2003]. If hypopigmented macules occur on the scalp, the affected person will have poliosis, or a patch of gray or white hair [McWilliam and Stephenson, 1978].

image

Fig. 40-11 Hypopigmented macule in a child with tuberous sclerosis complex.

(Courtesy of Dr. TN Darling, Uniformed Services University of Health Sciences, Bethesda, MD.)

Another skin manifestation currently considered a major criterion for clinical diagnosis of tuberous sclerosis complex is the shagreen patch, a connective tissue hamartoma that is distributed asymmetrically on the dorsal body surfaces, particularly on the lumbosacral skin (Figure 40-12). In a majority of the cases, the shagreen patch is characterized by multiple and small areas of connective tissue hamartoma, ranging in size from a few millimeters to 1 cm. Present from birth, the shagreen patch is more easily identified as the child grows and body surface area increases. Subungual or periungual fibromas (Koenen’s tumors) are present in at least 20 percent of patients and usually first appear during adolescence, although they can be seen earlier. These typically involve the toes more often than the fingers [Barroeta and Grinspan Bozza, 1962] (Figure 40-13). Oral fibromas or papillomas occur in about 10 percent of patients and usually are found on the anterior aspect of the gingiva [Papanyothou and Verzirtzi, 1975]. Dental enamel pits have been found in all adult patients with tuberous sclerosis complex, compared with 7 percent of controls [Hoff et al., 1975; Mlynarczyk, 1991; Weits-Binnerts et al., 1982].

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Fig. 40-12 Shagreen patch (arrows) over the lumbosacral region of an adolescent with tuberous sclerosis complex.

(Courtesy of Dr. TN Darling, Uniformed Services University of Health Sciences, Bethesda, MD.)

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Fig. 40-13 Periungual fibroma on finger of a patient with tuberous sclerosis complex.

(Courtesy of Dr. TN Darling, Uniformed Services University of Health Sciences, Bethesda, MD.)

The kidneys are frequently affected in persons with tuberous sclerosis complex, and after neurologic manifestations, renal involvement is the most common cause of morbidity and mortality [Franz, 2004]. The two main types of renal lesions are angiomyolipoma and renal cysts. Angiomyolipoma are present in up to 80 percent of patients with tuberous sclerosis complex and can develop in either childhood or adulthood [Rakowski et al., 2006]. Persons with tuberous sclerosis complex can have multiple small angiomyolipomas on the surface of the kidneys, throughout the kidney, or one or more larger lesions. The larger lesions are considered to be at greater risk of becoming symptomatic, particularly when they reach 4–6 cm in size. They can produce nonspecific complaints such as flank pain, but they also carry a risk of potentially life-threatening hemorrhage from rupture of dysplastic, aneurysmal blood vessels in the angiomyolipoma. Renal cysts are seen in fewer than 20 percent of persons with tuberous sclerosis complex and are rarely, if ever, symptomatic. Polycystic kidney disease occurs in 3–5 percent of patients with tuberous sclerosis complex and, when present, usually reflects a contiguous gene syndrome, because the polycystic kidney disease gene is adjacent to the TSC2-tuberin gene on chromosome 16 [Brook-Carter et al., 1994].

The cardiac manifestation, rhabdomyoma, is seen in 50–60 percent of persons with tuberous sclerosis complex [Jozwiak et al., 1994]. Typically, rhabdomyomas, which can frequently be detected prenatally, are maximal at birth and early childhood, and undergo spontaneous regression during the first few years of life. If symptomatic, they result in outflow tract obstruction or valve dysfunction. If the lesions involve the cardiac conduction system, they can predispose the patient to dysrhythmias not only in infancy and childhood, but also throughout life.

Pulmonary involvement in tuberous sclerosis complex includes lymphangioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia, and pulmonary cysts. While multifocal micronodular pneumocyte hyperplasia is seen fairly commonly in both men and women with tuberous sclerosis complex, lymphangioleiomyomatosis is thought to occur almost exclusively in women. Although lymphangioleiomyomatosis was once thought to be quite rare, affecting less than 1 percent of women, recent studies have found such abnormalities in up to 40 percent of women with tuberous sclerosis complex, many of whom are asymptomatic [Moss et al., 2001].

Retinal hamartomas are relatively common, affecting at least 50 percent of patients, although typically they are not clinically significant [Rowley et al., 2001]. A nodular (mulberry) tumor can be seen on or about the optic nerve head, and round or oval gray–yellow glial patches can be central or peripheral. The large retinal tumors can be cystic [Walsh and Hoyt, 1969; Messinger and Clarke, 1937]. Papilledema is not present, except in those patients with an intracranial mass lesion that obstructs the normal circulation of the cerebrospinal fluid, resulting in increased intracranial pressure [Kapp et al., 1967].

Hamartomas also can be found in other organ systems, including stomach, intestine, colon, pancreas, and liver. Hepatic angiomyolipoma and cysts have been reported in up to 24 percent of persons with tuberous sclerosis complex and are thought to be asymptomatic and nonprogressive [Fricke et al., 2004]. Sclerotic and hypertrophic lesions of bone often can be seen, although these typically are not symptomatic.

Clinical Laboratory Testing

As a result of the multi-organ involvement in tuberous sclerosis complex, a variety of clinical testing is recommended both at time of diagnosis and subsequently, to monitor for involvement and allow appropriate intervention (Table 40-2).

Table 40-2 Diagnostic and Follow-Up Management in Tuberous Sclerosis Complex

Evaluation Initial Testing Follow-up Testing
Neuroimaging At diagnosis Every 1–3 years until age 20
Neuropsychologic testing At diagnosis At school entry and as indicated
Electroencephalogram If seizures occur As indicated
Opthalmologic examination At diagnosis As indicated
Echocardiogram, electrocardiogram At diagnosis As indicated
Renal ultrasound examination At diagnosis Every 1–3 years, more frequently as indicated
Chest computed tomography At onset of adulthood (women only) As indicated

(From Roach ES et al. Tuberous sclerosis consensus conference: Recommendations for diagnostic evaluation. National Tuberous Sclerosis Association. J Child Neurol 1999;14(6):401–407.)

Neuroimaging studies, particularly MRI and also computed tomography (CT), are important in confirming the diagnosis of tuberous sclerosis complex, demonstrating cortical tubers, subependymal nodules (Figure 40-14), and subependymal giant cell tumors (Figure 40-15

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