Later on, to accommodate Sturge-Weber syndrome, Hogan and Zimmerman reinterpreted the phakomatoses as conditions of multisystem hamartoses, irrespective of malignancy potential.⁴ Duke-Elder protested by excluding Sturge-Weber from his discussion of phakomatoses.^5,6 Over time it seems that the cutaneous lesions, as a marker of multisystem disease, have gained prominence. This may explain inclusion of the phakomatoses as part of the “neurocutaneous disorders,”^7–10 even though cutaneous findings are not part of the diagnostic criteria of von Hippel-Lindau syndrome. Given multiple definitions to choose from, the phakomatoses have become a loose category, expanding as a convenient way to group syndromes.^5,7,11

We believe that the term phakomatosis should be restricted to the original three syndromes as molecular genetics support Van der Hoeve's observation: neurofibromatosis, tuberous sclerosis complex, and Von Hippel-Lindau syndromes are disorders of tumor suppressor genes,^12–15 a common link explaining the familial pattern (autosomal dominant), variable expressivity, multisystem tumors, and risk of malignant transformation. Thus we will restrict the phakomatoses to the original three syndromes:

1. The neurofibromatoses (NF1 and NF2)
   
2. Tuberous sclerosis complex
   
3. Von Hippel-Lindau syndrome
   

Each section is divided into: epidemiology; systemic features (cutaneous, neurologic, skeletal/visceral); ophthalmic features; diagnostic criteria; genetics and screening. Sturge-Weber and related syndromes will be discussed separately.

TABLE 1. Neurofibromatosis Classification/Subtypes

NEUROFIBROMATOSIS TYPE 1

Epidemiology

Neurofibromatosis type 1 (NF1) accounts for 90% of the neurofibromatoses and shows autosomal dominant inheritance. Its prevalence is 1/3500 to 1/5000.^20,21 (Prevalence is an estimate of the frequency of a condition in the general population; incidence is an estimate of the number of new cases over a given period of time, typically 1 year.) Although the penetrance of NF1 is close to 100% by age 5 years, its expressivity even within the same family may be highly variable. (Penetrance is the proportion of individuals with the defective gene who show clinical evidence of the disorder; expressivity is the degree of variability in clinical findings among individuals with similar mutations.) The NF1 gene has a high mutation rate, with up to half of newly diagnosed cases representing de novo mutations.²²

Systemic Features

NF1 can involve any organ system.

CUTANEOUS FINDINGS.

1. Café au lait spots: Evenly pigmented flat brown macules that generally appear in the first year of life, are present in 95% of adults with NF1, and tend to fade in the elderly.²³ One or two café au lait spots are not uncommon in normal patients.²⁴ Overall, 75% of children with six or more café au lait spots develop other clinical findings of NF1 by 5 years of age (Fig. 1).²⁴ A regular border differentiates café au lait spots in NF1 from the café au lait spots of McCune Albright syndrome (fibrous dysplasia and precocious puberty). Café au lait spots may be an isolated dominant condition in rare instances.²⁵
   
2. Freckling in non–sun-exposed areas: the axilla, inguinal region, and the submammary folds (typically after age 20 years). Freckling may not have developed by the time café au lait spots appear (first year of life). Eighty percent to 90% of NFI patients show axillary or inguinal freckling by 5 years (Fig. 2).^25,26
   
3. The skin overlying dermal neurofibromas and plexiform neurofibromas is often abnormal and will be discussed with nerve-associated tumors below.
   

NEUROLOGIC FINDINGS.

1. Cutaneous neurofibromas are benign tumors associated with peripheral nerves. There is evidence for a single-cell origin despite multiple cell types within the tumors, although the cell of origin is unclear.^27,28 Neurofibromas are typically soft and mobile on palpation. The overlying skin may be dimpled and have a violacious color due to dilated capillaries. Neurofibromas often enlarge and increase in number during puberty or pregnancy. In all, 95% of adults over age 30 with NF1 have neurofibromas, compared with less than half of adolescents and rarely in infants. Neurofibromas occur predominantly on the trunk—only 20% of patients have lesions on the head or neck. Less common subcutaneous peripheral neurofibromas are palpable as firm tumors along the trunks of peripheral nerves.^22,25,29
   
2. Plexiform neurofibromas are subcutaneous tumors with ill-defined borders. The overlying the skin is often hypertrophic, hyperpigmented, and may have excessive hair growth. They affect 25% to 30% of individuals with NF1, most commonly on the trunk, less commonly on the limbs, head, and neck. They may carry about a 5% lifetime risk for malignant transformation (neurofibrosarcoma).^25,29,30 Plexiform neurofibromas are a surgical challenge. They do not respect tissue planes, making complete removal difficult. They regrow when not fully excised and are not radiosensitive.²⁵
   
3. Brain tumors. Gliomas will be discussed below. Other brain tumors occur infrequently (<1%) in NF1. With the exception of brainstem astrocytomas and optic gliomas, the outcome of brain tumors in children affected with NF1 is similar to children without NF1.²⁵ Brainstem and optic gliomas show slower progression in NF1.³¹ Vestibular schwannomas and spinal meningiomas, known complications of NF2, are probably no more common in NF1 patients than in the general population.^22,25
   
4. Cognitive impairment. Thirty percent to 60% of children with NF1 have learning difficulties, which are typically mild and nonprogressive. These include visual-spatial problem-solving difficulty, language disorders, and attention deficit disorder. The reason for this is not clear but may be related to unidentified bright objects (UBOs) seen on T2-weighted brain magnetic resonance imaging (MRI) scans. These hyperintensities are common in young patients with NF1 but decrease with advancing age. The histopathologic correlate of UBOs is unclear. It has been postulated that the prevalence of learning difficulties in children with NF1 may be related to heterozygosity of the NF1 gene (i.e., the gene may have additional functions that affect cognition when the full complement of its gene product is not expressed in the central nervous system).^25,32–34
   

SKELETAL/VISCERAL FINDINGS.

1. Bone dysplasia²⁵
   
   • Scoliosis affects a significant number of NF1 patients (10% to 15%) and may be severe enough to require surgical correction
     
   • Thinning of long bones, especially medial bowing of the tibia, may predispose to fractures and pseudoarthrosis
     
   • Congenital absence of the greater wing of the Sphenoid bone
     
   
   
2. Hypertension.²² There is increased incidence of aortic coarctation and pheochromocytomas. Retroperitoneal neurofibromas may compress the renal artery. These complications may manifest as hypertension in affected children
   

Ophthalmic Features

Virtually any part of the visual system may be affected by NF1: the bony orbit, extraocular muscles, orbital nerves, eyelids, conjunctiva, cornea, uvea, retina, optic nerves, chiasm, and optic radiations.

OCULAR FEATURES.

Conjunctiva.

Neurofibromas of the conjunctiva are infrequent, affecting about 2% of patients with NF1, often on the perilimbal conjunctiva.³⁵

Cornea.

Enlarged corneal nerves have been reported in association with NF1 but are more commonly seen with multiple endocrine neoplasia syndrome (MEN-IIb).^36,37

Uveal Tract.

Lisch nodules are hamartomas (a tumor involving only those tissue elements normally found at the involved site) of the iris pigment epithelium. They are dome-shaped discrete lesions, are typically light brown in color, and may also be found in the angle.³⁸ Lisch nodules appear earlier (33% at 2.5 years, 50% at 5 years of age)³⁹ than neurofibromas. They are benign and can help to confirm diagnosis in children who may have café au lait spots as the only other clinical finding. Lisch nodules are present in nearly all adults with NF1^39,40 but are rare in NF2 (Fig. 3).^41,42 Diffuse nodular iris nevi (also known as iris mamillations) should not be confused with Lisch nodules. Its clinical significance is not well established.^43,44

Like Lisch nodules of the iris, pigment epithelial hamartomas may affect the choroid. In one series, flat pigmented lesions of the choroid were found in 35% of patients with NF1. Fluorescein angiography suggests these are choroidal nevi.⁴⁵The entire uveal tract may be thickened by a diffuse neurofibroma, thought to be hamartomatous hyperplasia of Schwann cells. This may result in the development of glaucoma.^46,47

Retina.

Retinal involvement in NF1 is unusual. Astrocytic hamartomas (similar to those in tuberous sclerosis), retinal capillary hemangiomas, and combined hamartoma of retina and retinal pigment epithelium (RPE) occur.^48,49

EYELID AND ORBIT.

Orbital neurofibromas may arise from any nerve in the orbit, especially the trigeminal nerve.⁵⁰ Classically the triad of visual loss, optic atrophy and optociliary shunt vessels have been associated with optic nerve sheath meningiomas,⁵¹ but these findings may be nonspecific for optic nerve compression,^52,53 particularly in children. If a child with a presumed diagnosis of NF1 is found to have an optic nerve meningioma, NF2 should be considered.

The eyelids are frequently involved in NF1. The lateral portion of the upper lid is prone to develop a plexiform neurofibroma, producing a sinusoidal or S-shaped deformity of the lid margin.^54–56 Amblyopia develops from ptosis and astigmatism (Fig. 4).

Growth of a plexiform neuroma may be directed posteriorly, infiltrating orbital tissues and involving the bony walls. Congenital plexiform neuromas of the orbit are often associated with absence of the sphenoid wing (Fig. 5). Intracranial pulsation can be transmitted to the orbit causing pulsatile proptosis or enophthalmos.^57–59 Plexiform neuromas of the lid and orbit are difficult to treat; complete excision is difficult and potentially disfiguring. The tumors are vascular and may bleed copiously at surgery. They are not radiosensitive and there is also risk of inducing malignant transformation. Trials with antiangiogenic chemotherapeutic agents (thalidomide, interferon alpha) and mitotic-signaling pathway blockers (inhibition of Ras by Farnesyl protein tranferase inhibitor) are in progress.^60,61

OPTIC NERVE GLIOMAS

Optic pathway gliomas arise from the astrocytes of the optic nerve. Most are pilocytic astrocytomas and typically remain intradural, extending in the subdural space. Malignant transformation is rare. There appear to be two growth patterns⁶²:

1. Perineural growth pattern, correlating with a diagnosis of NF1. The tumor expands in the subarachnoid space and the optic nerve is compressed as a central ribbon. On T2-weighted MRI, this may be seen as a low-intensity core with surrounding high-intensity rim. Increased tortuosity of the optic nerve is also associated with this growth pattern (Fig. 5).⁶³
   
2. Intraneural growth pattern, correlating with the absence of NF1.
   

The incidence of optic pathway gliomas in NF1 is difficult to estimate, as the majority are asymptomatic and do not affect vision. In NF1, radiographic evidence of an optic nerve glioma occurs in 15% of patients.^64,65 Most tumors are neither suspected historically nor detected by ophthalmic examination.⁶⁵ Even when optic nerve gliomas become clinically detectable, visual function often remains stable in the absence of any intervention.^66,67 Thus routine computed tomography (CT) imaging, even in patients with a known optic nerve glioma, is controversial. The potential risks of repeated radiation exposure in a child with a tumor-suppressor gene defect is a consideration. MRI studies are more revealing than CT but may require sedation or anesthetic and are costly. An MRI is often recommended at the time of diagnosis, but in most cases routine “follow-up” MRIs are unnecessary. Annual ophthalmic clinical examination for relative afferent pupillary defect (RAPD), visual acuity, visual fields, color vision, and funduscopy is usually all that is required, as no therapeutic action is likely to be taken unless there is significant and progressive visual involvement.

Optic nerve gliomas may involve the optic chiasm and be associated with endocrine disorders or nystagmus.^68–70 Surgical excision of chiasmal gliomas (Fig. 6) carries a high risk of visual loss. Invasion of the hypothalamus or the third ventricle carries a poor prognosis, with greater than 50% 15-year mortality rate.⁷¹ One review of radiation treatment for chiasmal gliomas collated data from small case series and found no significant long-term improvement in visual function, progression, or mortality with radiation treatment.⁷¹ Other reports suggest that radiation doses over 4500cGy improve symptoms and slow progression of chiasmal gliomas over several years.⁷² Adequate tumor coverage by radiotherapy results in irradiation of normal brain and nearly all children need hormone replacement.⁷³ Chemotherapy is an alternative.^74,75

Diagnostic Criteria

The NIH has defined 7 criteria,²² at least two of which must be present:

1. A first-degree relative with NF1
   
2. At least two Lisch nodules (Fig. 3)
   
3. At least five café au lait spots ≥ 5 mm before puberty or at least 6 café au lait spots ≥ 15 mm after puberty (Fig. 1)
   
4. Axillary or inguinal freckling (Fig. 2)
   
5. Optic glioma (Fig. 5)
   
6. A “distinctive” bone lesion: sphenoid bone dysplasia or thinning of long bone cortex (with or without pseudoarthrosis)
   
7. At least two neurofibromas of any type or one plexiform neurofibroma
   

In young children, nearly half of sporadic cases fail to meet NIH criteria by 1 year of age, but meet them by age 8 to 12 years. The clinical features appear in the following order: café au lait spots, axillary freckling, Lisch nodules, neurofibromas.²⁶ The inclusion of UBOs on MRI also aids the diagnosis of very young children²⁵ but may require a general anesthetic.

Genetics and Screening

All family members of patients with NF1 should be screened. Lisch nodules are present in 90% or more of patients with the disease, so ophthalmic examination is essential. Annual ophthalmic examination with visual acuity, visual field, color vision, and fundoscopy is recommended for affected individuals.

The NF1 gene (17q11.2) was cloned in 1990.^76,77 Its protein, neurofibromin, is expressed throughout the body but particularly in the central and peripheral nervous system.¹² It is a tumor-suppressor gene with autosomal dominant inheritance, high penetrance, and variable expressivity. NF1 has been called a neurocristopathy, but the disease is not limited to neural crest derived tissues.^12,78

Neurofibromin has structural similarity to GTPase, activating proteins that inhibit the function of G proteins such as Ras. Inhibition of Ras by neurofibromin has been shown in vitro and in vivo. NF1-deficient tumors show increased levels of Ras-GTP. Increased Ras function has been shown in a number of human tumors.^12,79–81

NEUROFIBROMATOSIS TYPE 2

Neurofibromatosis type 2 (NF2) was described in 1822 by the Scottish surgeon Wishart.⁸² Initially, NF1 and NF2 were lumped together despite their differences.⁸³ The identification of different genes re-established them as separate entities.⁸⁴

Epidemiology

The NIH consensus conference²² estimated an incidence of 1:50,000 but there are varying estimates internationally.⁸⁴ NF2 is autosomal dominant with full penetrance by age 60.⁸⁵ In all, 10% of affected patients are symptomatic by age 10, 50% by 20 years, and 80% by 30 years.⁸⁶ Some sporadic cases reflect parental mosaicism.^87,88

Systemic Features

Several studies have established the clinical picture of NF2.^85,89–91 Patients may become severely disabled because of the combination of deafness and imbalance from vestibular schwannomas, weakness from multiple spinal tumors, and poor sight from cataracts, optic nerve meningiomas, and retinal hamartomas.

CUTANEOUS FINDINGS.

Skin findings in NF2 may be subtle but not uncommon. Skin tumors were found in 60% and were the first presenting sign in more than 25% of patients.⁹² The skin tumors are predominantly schwannomas. A minority are neurofibromas and mixed types. Clinically differentiating the histological types may be difficult.⁹² They may present as dermal tumors or subcutaneous nodules of peripheral nerves.

NF2 plaques are well circumscribed, slightly raised, often pigmented, and hairy. They are a sensitive marker for NF2²² and are more common on the limbs and trunk than the neck and face.⁹²

Café au lait spots are not uncommon in NF2, but it is unusual to find more than five and most tend to be restricted to the trunk. Plexiform neurofibromas and axillary/inguinal freckling are uncommon.^92,93

NEUROLOGIC FINDINGS.

1. Schwannomas most commonly affect the fifth cranial nerve (CN), but any cranial nerve may be affected. In contrast to vestibular schwannomas (CN VIII), these typically do not grow large.^84,90 Vestibular schwannomas (acoustic neuromas) are the classic finding in NF2 (Fig. 7). The risk for malignant transformation is low, but may be higher with radiation exposure.^84,94
   
2. Meningiomas are most likely to affect the spinal cord and supratentorial part of the cranium.⁸⁴
   
3. Other tumors: low-grade ependymomas and gliomas may affect the cervical spine and Brainstem (Fig. 7).⁸⁴
   
4. Neuropathy: A generalized polyneuropathy affects 3% to 5% of affected adults and is associated with an “onion-bulb” appearance on nerve biopsy. In children, mononeuropathy, particularly the facial nerve (CN VII), may be an early sign of NF2. Some children may present with a poliomyelitis-like illness with lower-limb muscle wasting.^86,95,96
   

VISCERAL FINDINGS.

NF2 does not appear to have significant visceral complications

Ophthalmic Features

The most common ocular findings in NF2 include premature cataracts and retinal hamartomas. Ocular motor nerve deficits may also be associated with NF2.

Cataracts in NF2 were recognized in 1986.⁹⁷ They are common, reported to be found in 69%,⁹⁸ 81%,⁹¹ 85%,⁹⁹ and 87%¹⁰⁰of cases. They are typically mild⁹⁸ and a lens opacity may be the initial manifestation of disease, as found in 10% (5 of 49 patients) in one study.⁹⁸

Retinal hamartomas affect about 10% to 20% of patients (8% in one study⁹¹and 22% in another⁹⁸) and may be associated with a more severe phenotype of NF2.^91,98 Combined pigment epithelial and retinal hamartomas (CPERH) and epiretinal membranes have been reported.^101–103 Lisch nodules are rare in NF2. The absence of Lisch nodules, in association with the presence of posterior subcapsular or cortical cataracts (Fig. 8) may aid the differentiation of NF1 and NF2.^97,104,105 Optic nerve sheath meningiomas may cause significant visual impairment in the first years of life (Table 2).^84,106

TABLE 2. Ocular Findings in Neurofibromatosis Type 2⁹⁸

Lens opacities (most common finding)
    Posterior subcapsular cataract
    Cortical wedge opacities
Lisch nodules (rarely)
Optic nerve sheath meningiomas
Retinal hamartomas
Combined pigment epithelial and retinal hamartomas
Epiretinal membranes
Optic disc gliomas
Motor nerve palsies

Diagnostic Criteria

The NIH scheme is most commonly used:^95,107

1. Bilateral eighth nerve schwannoma, or
   
2. Positive family history of NF2, plus either unilateral eighth nerve schwannoma or two of the following:
   
   • Neurofibroma
     
   • Meningioma
     
   • Glioma
     
   • Schwannoma affecting other nerve(s)
     
   • Juvenile lens opacity
     
   
   

A significant proportion of cases (20% to 30%) may present with intracranial meningioma, spinal tumors, or cutaneous tumors. Vestibular schwannomas may account for as little as 15% to 30% of presenting signs in children. Thus, expanded criteria have been proposed to include individuals with multiple schwannomas/meningiomas who have not developed vestibular schwannomas as yet and do not have a clear family history.⁸⁴

Genetics and Screening

Cataracts can affect vision in early life. For children at risk, annual ophthalmic examination is prudent. Central nervous system (CNS) tumors rarely become symptomatic before age 10 years. Vestibular schwannomas tend to grow faster in younger patients; therefore, asymptomatic at-risk individuals may benefit from MRI scanning every 2 years under age 20 and every 3 years over age 20. Epiretinal membranes and combined hamartomas should lead to investigation for NF2. An annual neurologic exam has also been recommended.⁸⁴

The NF2 tumor-suppressor gene product is known as schwanomin¹⁰⁸ or merlin¹⁰⁹. The gene is located at 22q11.1–22q13.1 (Online Mendelian Inheritance in Man [OMIM] #607379).¹¹⁰ The NF2 gene shows homology to the highly conserved ezrin-radixin-moesin (ERM) family of membrane-cytoskeleton linking proteins. The NF2 protein is believed to interact with the actin cytoskeleton. Disruption of NF2 function has been linked to loss of cell-to-cell contact inhibition of growth and division.¹⁴

There have been exciting developments in regard to the molecular genetics of tuberous sclerosis complex (TSC). Two tumor suppressor genes have been identified: TSC1 and TSC2. Further insight into the role of these genes promises potential treatments to halt the progression of disease,¹¹⁵ thus emphasizing the need for early diagnosis.

EPIDEMIOLOGY

Tuberous sclerosis is autosomal dominant with 65% to 75% of new cases representing spontaneous mutations.¹¹⁶ Many “sporadic” cases may actually reflect somatic or germ-line mosaicism of a parent.^117,118 Its prevalence is approximately 1:10,000 to 1:15,000.^119,120 TSC has high penetrance but variable expressivity, even within the same family.¹²¹

SYSTEMIC FEATURES

Cutaneous Findings

1. Facial angiofibromas typically manifest as a papular rash over the nose and cheek (Fig. 9). Angiofibromas may also be found on the chin but they spare the upper lip. Pain and bleeding in association with minor trauma is common.^24,122 They eventually affect 75% to 85% of patients, but are infrequent before the age of 2 years and may not be present until late childhood or adolescence. Facial angiofibromas may be treated cosmetically with laser.^122–125 A forehead fibrous plaque is raised, red, and waxy. It is found in 20% to 35% of affected individuals. This feature is important diagnostically as it may be present at birth and is a sensitive marker for TSC.^122,125,126
   
2. Subungal (Fig. 10) and periungal fibromas are histologically similar to facial angiofibromas. These are infrequent in childhood and become more prevalent with age (>50% of adults). Ungual fibromas, may be the only sign of TSC.¹²² Ungual fibromas are more common on the toenails than the fingernails. Gingival (gum) fibromas may also be found.^24,122,125
   
3. Skin tags occur on the neck, axilla, and upper back in 10% to 20% of affected individuals. Though common in normal elderly patients, extensive skin tags are uncommon in normal children and adolescents.^122,125
   
4. Hypomelanotic macules (or ash leaf spots) are depigmented patches (Fig. 11) that occur in 90% to 95% of affected children, but may become less apparent with age.^122,125 They commonly take the form of “ash leaf spots,” appearing lanceolate, pointed at one end and round at the other like the leaves of the mountain ash tree. They are the feature of TSC most likely to occur in the first year of life. A Wood's ultraviolet light (which is selectively absorbed by skin melanin) helps in their detection: ash leaf spots stand out as white patches.^119,122 Hypomelanotic macules also occur in normal infants.^127,128 Histologically, they have a normal numbers of melanocytes, but the melanosomes are smaller and contain less melanin than the surrounding normal skin.^{3,122,125,128}
   
5. Shagreen patches are reported in about 50% of older children.^122,125 This is a connective tissue nevus^129,130 with a yellowish, plaque-like appearance like rough leather or shark's skin. The shagreen patch is typically found in the lumbosacral area (Fig. 12) but may also be found on the eyelids.^3,25
   

Neurologic Findings

INTRACRANIAL LESIONS.

Mental retardation and seizures in TSC are often associated with benign CNS astrocytic hamartomas.¹³¹ On imaging, the cerebral lesions show three patterns:¹³²

1. Superficial cortical sclerosis (parenchymal hamartoma) which distort the gyri. Microscopy shows large atypical fibrillary type astrocytes with few associated neurons and areas of calcification.¹³³ The numerous abnormal glial processes and fibers make the tissue abnormally firm or “sclerotic” on palpation (Fig. 13).¹³²
   
2. Subependymal nodules (SEN) are typically found along the lateral borders of the ventricles and parehncymal brain lesion (“cortical tubers”) (Figs. 14 and 15). Calcification in the first year of life is rare.¹³²
   
3. White matter abnormalities are a characteristic “ventriculofugal” pattern corresponding to the embryological migratory paths of neurons and glia. These lesions may represent aberrant neuronal migration, a possible reflection of haploinsufficiency for the TSC gene.^116,132,134
   On MRI imaging, the subependymal nodules and parenchymal brain lesions of infants (age ≤3 months) and adults show different signal characteristics. Infant CNS tubers are hyperintense on T1-weighted images and hypointense on T2-weighted images, which is the opposite of the pattern seen in adults.¹³⁴ Malignant transformation of SEN occurs in about 10% to 15% of patients and the resultant subependymal giant cell astrocytoma accounts for 25% of premature deaths in TSC.^135,136
   

SEIZURES.

Typically observed first in infancy, seizures are a common presenting sign of TSC and a frequent source of morbidity. The seizures often begin as “salaam spasms”—repetitive myoclonic spasms that produce head nodding with associated extension/flexion of the trunk and limbs. They often progress to grand mal seizures^25,116 and may be difficult to control. Vigabatrin has been advocated for control of infantile spasms but it carries a risk for irreversible visual field loss. Other treatments include corticosteroids, adrenocorticotrophic hormone, and a ketogenic diet.^25,137–139 Selective surgical excision of an “epileptogenic tuber” may be an option for intractable epilepsy.¹⁴⁰

MENTAL RETARDATION.

Mental deficiency, part of Vogt's diagnostic triad (adenoma sebaceum, epilepsy, mental deficiency),³ affects about 50% of patients overall.^25,141 TSC2 mutations may carry a higher risk than TSC1.¹⁴²

AUTISM.

This may affect 50% to 60% of TSC patients, possibly correlating with numbers of cerebellar and temporal tubers.^25,143,144

Visceral Findings

Patients with TSC may have renal, cardiac, pulmonary and other visceral involvement.

RENAL.

The TSC2 gene was localized by linkage with the polycystic kidney disease gene in patients with TSC and polycystic kidneys. This represents a contiguous gene syndrome in which adjacent genes (PKD1 and TSC2) are deleted together.^145–147

Multiple angiomyolipomas of the kidney are benign hamartomas of blood vessels, smooth muscle, and fat. By 10 years of age, the frequency of angiolmyolipomas is 75%, similar to adults.¹⁴⁸ The fat signal of angiomyolipomas helps to distinguish them from renal cell carcinoma.²⁵

Renal insufficiency/failure may be the complication of both cystic disease and angiomyolipomas and is one of the leading causes of morbidity and mortality in TSC.^138,149

CARDIAC.

Rhabdomyoma are usually multiple, typically asymptomatic, and often regress with age.^150,151

PULMONARY.

Lymphangioleiomyomatosis is a progressive lung disease characterized by bronchiolar smooth muscle infiltration and cystic changes of the lung parenchyma. About 1% of adult females with TSC are affected.^116,152,153

OPHTHALMIC FEATURES

The principal ophthalmic manifestations of TSC are in the posterior segment.

Astrocytic Retinal Hamartomas

Although in Van der Hoeve's original description the term phakoma or phakomata was a generic term for the tumors occurring in various organ systems,¹ it has become associated with the retinal astrocytic tumors of TSC,³ which occur in about 50% of affected patients and are bilateral in 25% to 30% (Table 3, Fig. 16).^154,156

TABLE 3. Astrocytic Retinal Hamartomas in Tuberous Sclerosis

Historically, the presence of mixed (type 3) hamartomas led to the suggestion of evolution from the type 1 to the type 2.¹⁵⁷ A long-term photographic study found that although the types remained unchanged, a minority of types 1 and 3 increased in calcification and a new lesion was noted that had not been evident on an earlier photograph.¹⁵⁷ All three types of retinal hamartomas may be found in young children. There is no correlation between age and the predominant type of lesion.¹⁵⁶

Histologically, phakomata are composed of glial astrocytes—elongated, fibrous astrocytes with small oval nuclei, arising from the retina or the optic disc. The type 2 lesions contain basophilic, calcified drusen-like deposits within a dense vascular network. On fluorescein angiography, the type 2 lesions show autofluorescence, leakage with transit of dye, and marked late hyperflorescence.^3,113

Astrocytic retinal hamartomas usually do not affect vision and require no treatment. Vitreous seeding and vitreous hemorrhage have been reported in association with phakomata, but these are rare.^158,159 Laser photocoagulation may be considered in rare cases were exudation induces serous retinal detachments.¹⁶⁰ The differential diagnosis of “white retinal lesions” includes retinoblastoma, toxoplasmosis and toxocara.^3,113

Pigmentary Abnormalities

Depigmented “punched-out” chorioretinal lesions in the midperiphery have been reported in up to 40% of patients. Similar lesions may be found in normal patients.¹⁵⁶

Nonretinal Features

The adnexae may be involved by angiofibromas: eyelid skin and “salmon-colored” subconjunctival nodules. Sector iris depigmentation and iris coloboma have been reported in a minority of patients.^113,156,161

DIAGNOSTIC CRITERIA

When TSC is classical (“Salaam seizures,” facial angiofibroma, developmental delay), the diagnosis is straightforward. However, children can be mildly affected, and many of the classical signs may become apparent later.

Based on the revised clinical diagnostic criteria set forth by the Tuberous Sclerosis Consensus Conference¹⁶², a diagnosis of TSC may be made if the patient has two major features, or one major feature plus two minor features. Genetic testing for TSC still has a high false-negative rate (Table 4).^25,162,163

TABLE 4. Features of Tuberous Sclerosis Complex

GENETICS AND SCREENING

The Tuberous Sclerosis Consensus Conference¹⁶² recommendations for screening once a diagnosis of TSC is established are:

1. Cranial neuroimaging every 1 to 3 years
   
2. Renal ultrasound every 1 to 3 years
   
3. Chest CT for females at least once upon reaching adulthood to screen for lymphangio-leiomyomatosis.
   

Two genes have been identified, TSC1 (9q34, OMIM #605284) and TSC2 (16p13.3, OMIM #191092), which appear to be tumor-suppressor genes. The gene product of TSC1 is hamartin and the gene product of TSC2 is tuberin. Of sporadic cases of TSC, 70% have been linked to TSC2 mutations. Among the familial cases, half are linked to the 9q34 locus and half to the 16p13.3 locus. Hamartin and tuberin appear to interact together in vivo, which may be why mutations of two different genes produce a similar phenotype. Together they form a cytoplasmic protein complex that has an inhibitory effect on cell growth and division. The tuberin-hamartin complex inhibits the activity of TOR (target of rapamycin). This has raised the possibility of reestablishing the regulatory effect of the tuberin-hamartin complex on TOR with drugs such as rapamycin.^115,164

The main manifestations of von Hippel-Linau syndrome are: histologically similar hemangiomas of the retina and CNS, renal cysts, renal cell carcinomas, pancreatic cysts, pheochromocytomas, and endolymphatic sac tumors.¹³

EPIDEMIOLOGY

The prevalence of VHL syndrome is about 1 in 35,000 to 40,000.¹⁶⁸ It is autosomal dominant with greater than 95% penetrance by age 60 years.¹⁶⁹ Its expression, even within the same family, may be quite variable, especially for renal disease and pheochromocytoma.^170,171

SYSTEMIC FEATURES

Cutaneous Findings

Cutaneous findings are not part of the diagnostic criteria for VHL syndrome.

Neurologic Findings

CNS hemangiomas are the most common tumor of VHL, affecting 60% to 80%, with a predilection for the cerebellum and spinal chord. An enlarging cystic component is a frequent finding in symptomatic tumors. Patients typically present in their early 30s; headaches or neck pain in affected individuals should not be ignored.^172,173 On microscopy, CNS hemangiomas resemble retinal capillary hemangiomas. Their malignant potential is low.¹⁷⁴ The treatment is surgical (Fig. 17, A and B).¹³

Endolymphatic sac cystadenomas are a sensitive marker of VHL. Patients may present with hearing loss, tinnitus, disequilibrium or facial nerve palsy.^175,176

Visceral Findings

KIDNEY.

Renal cysts are often asymptomatic and do not require treatment. However, complex cysts may carry a risk for malignant transformation.

Renal carcinoma affects about a third of patients. Patients typically present in their late 30s. These tumors may be completely asymptomatic, underscoring the necessity for ultrasound screening.^13,177

ADRENALS.

Pheochromocytomas are benign neural crest tumors of the adrenal medulla (chromaffin cell derived) and probably affect 10% to 20% of patients. Mean age at diagnosis is at about 30 years of age. Pheochromocytomas may be multiple and bilateral. They are catecholamine-secreting tumors that classically produce severe hypertension and anxiety attacks, but they may also be asymptomaic.¹⁷⁸ The National Cancer Institute classification of VHL syndrome is in part based on the absence (type I) or presence (type II) of pheochromocytoma (Table 5).¹⁷¹

TABLE 5. Classification of von Hippel-Lindau Syndrome

PANCREAS.

Pancreatic lesions may be nonsecretory (most commonly cysts or cystadenomas) or secretory (islet cell tumor).¹⁷⁹ In one study of 52 patients, 56% (29 patients) were found to have pancreatic lesions. The majority (19 of 29) had cystic changes only (Fig. 17C). Pancreatic lesions were the only abdominal manifestation of disease in 6 of 52 patients.¹⁸⁰ In a separate study, pancreatic cysts did not show significant progression on follow-up examinations over an average period of 5 years.¹⁸¹ Like pancreatic cysts, islet cell tumors appear to be frequently asymptomatic.¹⁸²

EPIDIDYMIS AND BROAD LIGAMENT.

Papillary cystadenomas of the epididymis are typically benign and asymptomatic. In one study, about half of patients were affected.¹⁸³ Papillary cystadenomas of the broad ligament are thought to be the female equivalent of papillary cystadenomas of the epididymis.¹⁸⁴

OPHTHALMIC FEATURES

VHL syndrome does not appear to have significant anterior segment manifestations.

Posterior Segment

Retinal capillary hemangiomas are among the most frequent and earliest manifestations of VHL syndrome. Most patients present between 10 and 40 (mean age of 25) years of age and 5% present before age 10. Overall, retinal capillary hemangiomas affect about 60% of individuals with VHL syndrome. Development of new retinal capillary hemangiomas after age 60 years is unusual.^169,170

Retinal capillary hemangiomas (Fig. 18) may be the only manifestation of the syndrome,¹⁸⁵ and typically involve the midperipheral temporal retina.¹⁸⁶ A pair of dilated and tortuous retinal vessels (artery and vein) classically supply the vascular tumor. Without fluorescein angiography, it may be difficult to distinguish artery from vein on fundus examination.¹⁷⁰

Retinal capillary hemangiomas may also occur in the absence of VHL syndrome, but the age at presentation is typically later (50 vs. 25 years).¹⁸⁷ Small retinal capillary hemangiomas may remain stable for many years, but most tend to enlarge and may become symptomatic secondary to exudation and retinal detachment.

On microscopy, retinal capillary hemangiomas are similar in appearance to the CNS hemangiomas of VHL syndrome. Thin vascular channels are lined by endothelial cells and pericytes. The vascular channels are separated by foamy stromal cells. The foamy appearance is due to phagocytosed lipids that escape the fenestrated endothelium of the vessel walls. The lipid is plasma–derived cholesterol stearate.^188–190 Hemangioma is more appropriate than hemangioblastoma.^170,188,190

The cellular origin of capillary hemangiomas in VHL is controversial,¹⁷⁰ but loss of heterozygosity of the VHL gene has been demonstrated in the stromal cells of capillary hemangiomas.¹⁹¹

There are various classification schemes based on morphology (endophytic, exophytic, and sessile) and the presence or absence of exudation. Endophytic tumors grow on the retinal surface, protruding into the vitreous cavity. Exophytic tumors tend to be nodular and orange-colored, growing the in outer layers of the retina. The sessile growth pattern implies a flat tumor, gray or orange in color, and grows within the middle layers of the retina.¹⁸⁵ The “natural history” of the retinal capillary hemangioma has been divided into four¹⁹² or five¹⁹³ stages¹⁷⁰:

• Stage 1: Preclassical, small capillary retinal angioma with or without feeder vessels
  
• Stage 2: Classical, hemangioma enlarges and draining vein becomes more prominent
  
• Stage 3: Exudation, often in association with enlargement of feeding artery and draining vein
  
• Stage 4: Retinal detachment
  
• Stage 5: End stage, rubeosis, glaucoma, phthisis
  

On occasion, an exophytic-type capillary hemangioma adjacent to the optic nerve can masquerade as chronic disc edema.¹⁹⁴ The frequency of optic-disc angiomas was 15% in a group of 175 patients.¹⁸⁶ Optic-disc hemangiomas may be the only manifestation of disease in VHL syndrome.¹⁸⁶ In the absence of effective treatment, exudation from capillary hemangiomas may induce retinal detachment and macular star formation.^170,186

Early detection (i.e., when the hemangioma is small) and treatment are associated with better visual outcomes.¹⁸⁶ The exception may be small juxtapapillary hemangiomas, in which treatment may produce significant loss of acuity. Small juxtapapillary hemangiomas may remain stable.¹⁸⁵

Both direct and feeder vessel photocoagulation with a yellow-dye laser have been shown to be effective for treating small (<1.5mm) capillary hemangiomas. Feeder vessel technique may require a greater number of treatment sessions.¹⁹⁵ Direct treatment may be associated with a smaller scotoma than feeder vessel treatment, but direct photocoagulation carries a potential for hemorrhage and retinal detachment.¹⁸⁶ Hemoglobin absorbs yellow laser more than green or blue wavelengths. Complete obliteration of the hemangioma may not be necessary to achieve resolution of symptoms.¹⁷⁰

When the retinal capillary hemangioma is located in the far anterior periphery, or when it is larger than 3.0 mm in diameter, cryotherapy may be more effective than photocoagulation.¹⁷⁰ To treat hemangiomas 4 to 5 mm in diameter, plaque radiotherapy has been recommended.¹⁹⁶

The VHL gene product appears to inhibit the production of VEGF (vascular endothelial growth factor). Treatment with SU 5416, a VEGF-receptor inhibitor, has been reported to restore and maintain visual acuity and visual field in a patient with an optic-disc hemangioma.¹⁹⁷

Retinal “twin vessels”—a paired retinal arteriole and venule of normal caliber, separated by less than the diameter of the venule—have been described as part of VHL¹⁹⁸ but the finding has not been reproduced.¹⁸⁶ Twin vessels are not associated with retinal capillary hemangiomas, and may be found in normal patients.¹⁹⁹

Differential Diagnosis

In the presence of subretinal exudates, the peripheral hemangioma may be overlooked, giving a false impression of Coats disease (diffuse unilateral retinal telangiectasias with exudation in young boys). Dilated feeder vessels may be confused for the arteriovenous malformation of Wyburn Mason disease (racemose hemangioma). Exudation is not a feature of Wyburn Mason disease and there is no angioma. Retinal cavernous hemangiomas lack prominent feeder vessels and do not leak fluid into the subretinal space. Retinal macroaneurysms may leak fluid but do not have dilated feeder vessels. Uveal melanomas usually have only a dilated vein.¹⁷⁰

DIAGNOSTIC CRITERIA:

If there is a positive family history of VHL syndrome, transmission is likely based on finding any one of the following¹³:

• CNS hemangioma (including retinal capillary hemangioma)
  
• Characteristc visceral lesion (e.g., renal carcinoma, pheochromocytoma)
  

If family history is negative, a diagnosis is likely based on:

• At least two CNS hemangiomas (including retinal capillary hemangioma), or
  
• A single CNS hemangioma (including retinal capillary hemangioma) and a characteristic visceral lesion (excluding epididymal and renal cysts, which are not uncommon in the general population)
  

The National Cancer Institute has classified VHL syndrome into two main categories on clinical grounds: type I without pheochromocytoma and type II with pheochromocytoma. Type II is further subdivided based on the presence or absence of renal cell carcinoma and CNS hemangioblastoma, and type IIC implies pheochromocytoma only (Table 5).¹⁷⁰

GENETICS AND SCREENING

Subclinical lesions are common in VHL syndrome and there is more than one “accepted” protocol.^13,169,200 In general, the protocols are similar, differing in the age to start screening for the different manifestations of the syndrome. Annual fundoscopy and urinary catecholamine testing should begin early in childhood (age 1 to 5 years). Spine and brain MRI should be carried out every 1 to 2 years and abdominal ultrasonography annually beginning age 10 years.

Autosomal dominant inheritance of multisystem tumors with malignant potential is the “trademark” of tumor-suppressor gene defects and the phakomatoses. New mutations are thought to represent about 10% of affected individuals. The VHL gene product (OMIM #193300) located at 3p25–26 appears to downregulate the transcription factors that turn on the production of VEGF as part of the cellular response to hypoxia. This may account for the predilection to form hemangiomas.²⁰¹ Molecular analysis suggests that missense mutations of the gene predispose to pheochromocytomas, which is type II (96% of mutations in VHL syndromeand pheochromocytoma were found to be missense mutations in one study).²⁰² No particular type of mutation has been associated with frequency or severity of retinal capillary hemangiomas.¹⁸⁶

DNA testing for VHL gene mutations can achieve 99% detection rates.²⁰³ This may be valuable for counseling of young parents of an affected child who do not have a clear family history and may still be too young to manifest features of the syndrome themselves.

STURGE-WEBER SYNDROME

Sturge (1879) reported the case of a child with facial “port-wine stain,” epilepsy, buphthalmos, and a dark choroid.²⁰⁴ Schirmer had noted the association of the facial vascular malformation and glaucoma in 1860.³ Weber (1922) reported brain X-ray findings of parallel streaks (“railtrack” sign), which he interpreted to represent calcific changes (Fig. 19).²⁰⁵

Port-wine stains (PWS) affect 0.3% of live births. The majority of isolated PWS occur in the head and neck.^206–208 The possibility of Sturge- Weber syndrome (SWS) is raised when a newborn is noted to have a facial PWS. SWS does not have any clear inheritance pattern. The minimum diagnostic criteria for SWS is a subject of debate.^209–211 The complete syndrome includes:

1. Facial capillary vascular malformation (“port-wine stain”)
   
2. Intracranial leptomeningeal (the two innermost layers of the meninges, which consists of the dura mater, arachnoid, and pia mater) capillary vascular malformation
   
3. Seizures
   
4. Contralateral neuromuscular weakness
   
5. Ipsilateral increased choroidal vascularity, often with increased retinal vessel tortuosity
   
6. Glaucoma
   

Facial capillary vascular malformation (Fig. 20) is the most obvious feature of SWS. It consists of many dilated capillaries lined by a single layer of endothelial cells.³ The PWS is present at birth and partially blanches with pressure. Historically it has also been referred to as a “naevus flammeus.” The PWS is typically unilateral, and may follow the distribution of the trigeminal (CN V) nerve divisions. The conjunctiva and episclera ipsilateral to the PWS are often involved.

The PWS may not entirely respect the midline, possibly a reflection of transmedian innervation.²¹² The lesion grows proportionally with the child, often becoming darker in color. ²¹³ The overlying skin may develop nodularity or hypertrophy in two-thirds of patients (by the fifth decade).²¹⁴ Treatment with a pulsed-dye laser may significantly improve the appearance, but recurrence (i.e., redarkening) is possible.^215,216 A deficit in the number of perivascular nerves in port-wine stains suggests that abnormal neural modulation of vascular flow may be involved in their pathogenesis.²¹⁷

Intracranial leptomeningeal capillary vascular malformation (Figs. 21 and 22) is associated with seizures and contralateral neuromuscular weakness. Central nervous system involvement correlates highly with ipsilateral involvement of the V1 dermatome by a PWS.^208,218

It has been hypothesized that the calcific changes reflect cellular anoxic injury secondary to venous stasis/poor drainage.^219,220 Abnormal autonomic innervation has also been reported in association with the malformed cortical vessels—innervation only by noradrenergic fibers.²²¹ Studies suggest that the normal increase in brain-blood flow to accommodate increased metabolic demand during seizure activity is blunted in affected brain regions of SWS.²²² Thus, seizures in the setting of impaired perfusion may be exacerbating brain injury. Periods of contralateral weakness (days to weeks) can follow a prolonged seizure episode.^206,223

When seizures begin early in life, the risk of developmental delay is much higher. In a review of 171 patients with a facial PWS and associated intracranial vascular malformation, 80% were found to have a seizure disorder. Of those, 75% with seizures had an onset during the first year of life, rising to 95% before age 5 years. Nearly all patients had a PWS that included (or was limited to) the V1 distribution. Developmental delay was strongly associated with seizures (71% of children with seizures as compared to 6% without seizures).²²⁴

Glaucoma affects 50% to 70% of SWS patients^224,225 and it is a therapeutic challenge. From the time of diagnosis, the intraocular pressure, the optic discs, and the corneal diameters need to be measured intermittently, even if an occasional examination under anesthetic is required.

The development of glaucoma appears to follow a bimodal age distribution: early-onset/congenital-type and later-onset. The glaucomatous eye is nearly always on the same side as the PWS.²²⁴ The highest risk for glaucoma appears to be when the PWS involves both the upper and lower lid: 72% vs. 21% for VI-only (upper eyelid) involvement in one study.²²⁴

The bimodal age distribution of glaucoma suggests that more than one mechanism is involved. Angle abnormalities (“trabeculodysgenesis” with or without flat anterior iris insertion) have been reported in association with the early-onset/congential type.²²⁵ Other proposed mechanisms include uveal capillary dilation²²⁶ and elevated episcleral venous pressure. Reports of blood in Schlemm's canal on gonioscopy support the idea of increased episcleral venous pressure pathomechanics.^227,228

Glaucoma in SWS often responds poorly to medical therapy alone. The “trabeculodysgenesis” of early onset Sturge-Webber glaucoma is reported to be similar in gonioscopic appearance to primary congenital glaucoma.²²⁹ On this basis, goniotomy was suggested as a treatment of choice in early-onset SWS glaucoma.

One group looked at the success of goniotomy, trabeculotomy, trabeculectomy, laser trabeculoplasty and medication in the management of SWS-associated glaucoma.²³⁰ In the early onset subgroup receiving goniotomy, median stable interval of intraocular pressure reduction after one procedure was 8 months; with multiple goniotomies and the addition of medical treatment, the median stable interval was extended to 9 years. Other investigators have found that goniotomy alone may be insufficient, requiring filtering surgery at some point. However, trabeculectomy carries a significant risk of choroidal expansion in association with hypotony. Theoretically, the risk may be higher when there is increased choroidal vascularity in association with the facial PWS—a “tomato ketchup” fundus.²³¹

Often, there is associated increased tortuosity of the retinal vessels as well. Placement of a prophylactic posterior sclerotomy prior to filtering surgery to prevent choroidal expansion is controversial.²³² Cryo- or thermocoagulation of the ciliary body in combination with medical therapy may be an alternative to surgery.²³³

KLIPPEL TRENAUNAY—WEBER SYNDROME

Klippel-Trenaunay syndrome consists of combined capillary, lymphatic, and venous malformations, in association with varicosities and limb enlargement (Fig. 23). In the majority of cases, the lower limb is affected.^234,235

The occurrence of “merged” Klippel-Trenaunay and Sturge-Weber syndromes has recently been questioned. The contention is that the presumed combined cases actually represent Sturge-Weber syndrome with capillary malformations below the head and neck, without the associated lymphatic malformations of Klippel-Trenaunay syndrome.²³⁵ Extracranial port-wine stains are relatively common in SWS (45% in a study of 171 patients).²²⁴

PHACES SYNDROME

PHACES^236,237 is an acronym for the association of:

• Posterior fossa brain malformation, most commonly Dandy-Walker type (which exists when there is marked dilation of the fourth ventricle—“posterior fossa cyst”—in association with cerebellar vermis hypoplasia; 70% to 90% may develop hydrocephalus)
  
• Hemangioma, most commonly facial and “plaque-like”
  
• Arterial malformation
  
• Cardiac anomalies and coarctation of the aorta
  
• Eye abnormalities
  
• Sternal clefting
  

The majority of patients are female, and affected children may have only one extracutaneous manifestation. The facial vascular lesion is typically large, segmental, and plaque-like.^238,239 Unlike the vascular malformation of Sturge-Weber Syndrome, the PHACES facial vascular lesion is likely a true hemangioma.²⁴⁰ Visceral and/or CNS hamangiomas may affect up to 50% of patients.²⁴¹ The most common associated ocular abnormalities appear to be microphthalmos and increased vascularity on examination of the fundus. Glaucoma does not appear to be a common association of the syndrome (Fig. 24).²⁴²

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