Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition

Ocular Manifestations of Systemic Disease

23

Phakomatoses

Alex V. Levin

Thomas W. Wilson

Agnes Wong

The phakomatoses are a group of diseases that have cutaneous, central nervous system, and ocular manifestations. They often present with dermatologic and ocular manifestations, which subsequently lead to diagnosis of the underlying brain involvement. Significant vision loss can occur due to involvement of either the central nervous system or the eyes, or both.

At least three of the major phakomatoses—neurofibromatosis, tuberous sclerosis, and von Hippel-Lindau—share a common genetic basis: Mutation of a tumor suppressor gene leads to local cellular proliferations in the forms of tumor or skin changes. These three disorders are autosomal dominant in inheritance and demonstrate variable expression, though penetrance approaches 100%. As a result, the detection of affected family members may require extensive investigations, including neuroimaging and abdominal ultrasound. When counseling for autosomal dominant disorders, one must remember that even though each child of an affected parent carries a 50% risk of being affected, the severity of the disease may be very different between the parent and the child. Ataxia telangiectasia is the only autosomal recessive phakomatosis.

Some of the phakomatoses, such as Sturge-Weber syndrome, appear to be sporadic with only very rare reports of familial occurrence. This suggests a somatic (postzygotic) mutation resulting in localized affectation of the field of tissues that are the descendants of the mutated cell. Such disorders would only be heritable if the somatic change also affects the patient's sperm or eggs. As the manifestations of these disorders are largely confined to the head and neck, gonadal involvement is uncommon.

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Figure 23.1 Tuberous Sclerosis—Shagreen Patch

Tuberous sclerosis is an autosomal dominant phakomatosis caused by mutations in one of two genes: TSC1 at 9q34 or TSC2 at 16p13. The former produces the protein hamartin and the latter tuberin, both of which appear to have a role in cellular vesicular trafficking. Type 1 tuberous sclerosis has a lower incidence of mental retardation. There are no differences, however, in the ocular or dermatologic manifestations. Shagreen patches, shown here, are rough, raised lesions most commonly found in the lumbosacral region. They sometimes have an orange hue, but they may be more easily detectable by palpation than by inspection.

 

Figure 23.2 Tuberous Sclerosis—Adenomatous Sebaceum

Adenoma sebacea are not true adenomas and are not of sebaceous origin. They are actually angiofibromas. The reddish lesions are distributed in a butterfly distribution on the face extending from the malar region across the bridge of the nose. They may be confused with the common cystic acne, particularly since the lesions can become more prominent during adolescence. This skin manifestation is rarely seen in the first decade of life.

 

Figure 23.3 Tuberous Sclerosis—Subungual/ Periungual Fibroma

Subungual/periungual fibromas are fibromatous growths under or around the nails, usually in the region of the cuticle. Despite their size, they are often asymptomatic but may require surgical intervention. They are rarely observed in the first decade of life and enlarge with age.

 

Figure 23.4 Tuberous Sclerosis—Ash Leaf Spot

Ash leaf spots are hypopigmented lesions of the skin that often have edges and a shape reminiscent of an ash tree leaf. They are sometimes difficult to detect, especially in children with fair skin. However, they can be easily visualized with a Wood ultraviolet light. One must be careful to ensure that a false-positive Wood lamp test is not being caused by debris and other substances, which will also illuminate. The melanosomes in the region of the lesion are abnormally small and contain less melanin than the surrounding skin. The number of melanocytes is normal.

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Figure 23.5 Tuberous Sclerosis—Cortical Lesions

Central nervous system manifestations of tuberous sclerosis include seizures, mental retardation, astrocytic hamartomas of the brain (cortical tubers, shown here), and subependymal calcifications. Seizures are typically myoclonic spasms that present in infancy and occur in many patients with tuberous sclerosis. As shown in these images, the benign astrocytic hamartomas often appear as calcified lesions and are most commonly located in the periventricular area. Neurosurgical intervention is rarely needed and visual field defects from the tubers are also uncommon.

 

Figure 23.6 Tuberous Sclerosis— Retinal Astrocytic Hamartoma

Retinal astrocytic hamartomas are one of the cardinal signs of the disorder. The sessile lesions are located in the nerve fiber layer and, as shown here in an infant, typically begin as noncalcified lesions. Note that the lesion is almost translucent, and in some cases, it may be difficult to recognize as it may only start as a faint gray superficial patch. The lesions have a predilection for the posterior pole but can occur anywhere in the retina. They are benign and usually of no visual consequence.

 

Figure 23.7 Tuberous Sclerosis— Retinal Astrocytic Hamartoma

As the lesion matures, it becomes more opaque and eventually calcifies. In all phases, the differential diagnosis must include retinoblastoma (Chapter 8: Retina and Vitreous, Figs. 8.42, 8.43, 8.44, 8.45, 8.46, 8.47, 8.48, 8.49, 8.50, 8.51, 8.52 and 8.53). It can be differentiated from retinoblastoma based on its smooth surface, the absence of associated vascular abnormalities, exophytic growth, or vitreous seeding; and the presence of other systemic manifestations. Eyes have unfortunately been enucleated due to an incorrect suspicion of retinoblastoma.

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Figure 23.8 Tuberous Sclerosis—Optic Nerve Hamartoma

Astrocytic hamartomas of tuberous sclerosis also have a predilection to involve the optic nerve head. The risk of leakage resulting in an exudative retinal detachment or hemorrhage, but still quite low. This photograph shows the remaining calcified mass following retinal laser to eliminate the exudative tumor. The lesions initially appear to have a multilobulated surface with intralesional calcium that may also be confused with retinoblastoma. The nickname “mulberry lesion” is sometimes applied.

 

Figure 23.9 Tuberous Sclerosis—Retinal Pigmentary Lesion

Areas of depigmentation may occur in the retinal periphery or midperiphery. The discrete lesion represents an area of decreased melanosome size and decreased melanin concentration similar to ash leaf spots (Fig. 23.4) of the skin. The lesion involves the retinal pigmented epithelium. It is benign, may be multiple, usually does not have an ash leaf mulberry appearance, and does not involve the overlying sensory retina. These lesions are visually insignificant. They are not diagnostic of tuberous sclerosis, as small hypopigmented lesions can be due to a variety of causes and may even be seen in normal children.

 

Figure 23.10 Tuberous Sclerosis—Renal Cyst

Other systemic findings of tuberous sclerosis include renal cysts or renal angiomyolipoma, cardiac rhabdomyoma, and other cysts or tumors of bone, liver, pancreas, and lung. Dental findings include pitting of the teeth and gum fibromas. Additional central nervous system manifestations include behavioral disorders, mental retardation, and even psychiatric manifestations. Complete screening of parents to search for low expression in a carrier who may not be aware that he or she is affected should include abdominal ultrasound, dilated retinal examination, dental examination, neuroimaging and dermatologic assessment, including Wood lamp.

 

Figure 23.11 Ataxia Telangiectasia

Ataxia telangiectasia is an autosomal recessive phakomatosis. The ocular findings include conjunctival telangiectasias, concentrated in the canthal region, as shown here. Ocular motor apraxia is the cardinal eye movement feature but there is also an increased incidence of strabismus and nystagmus. The fundus is normal. Telangiectatic vessels also occur on the face, antecubital fossa, and popliteal fossa. The ataxia is secondary to a progressive cerebellar degeneration and dysarthria is common. The causative gene, ATM at 11q22-23, is involved in DNA repair. Patients often have immune dysfunction and suffer from recurrent infections and lymphoproliferative disorders.

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Figure 23.12 Von Hippel-Lindau Disease

Von Hippel-Lindau is an autosomal dominant disorder caused by mutation in the VHL gene at 3p25-26. Retinal angioma, shown here, and cerebellar hemangioblastomas are the two major components. The retinal angioma is classically a small ovoid lesion with a single feeder vessel and a single draining vessel. Leakage from the retinal lesions can result in significant vision loss. Laser photocoagulation, cryotherapy, and surgical removal are treatment options depending on the size and location. The disorder is subcategorized as VHL1 (no pheochromocytoma), VHL2A (low risk for renal and pancreatic cancer), VHL2B (multitissue involvement), and 2C (pheochromocytoma only), all of which are allelic.

 

Figure 23.13 Sturge-Weber Syndrome—Port Wine Mark

This characteristic vascular abnormality of the subcutaneous tissues usually involves the trigeminal distribution and is seen in almost all cases of Sturge-Weber syndrome. The lesion typically presents at birth as a flat red mark (left image) but with age (right image)becomes thickened and purple in color. Early laser treatment helps to prevent this outcome. Evidence suggests that lack of vascular tone from the trigeminal nerve leads to the disease. The incidence of glaucoma is greatly increased if the upper lid is involved, although glaucoma can develop in the absence of upper lid involvement.

 

Figure 23.14 Sturge-Weber Syndrome—Leptomeningeal Angiomatosis

Central nervous system findings of Sturge-Weber syndrome include prominent vessels of the meninges, shown here in this contrast-enhanced computed tomography scan. These lesions are typically present in the temporal and, as shown here, occipital lobes. Intracranial calcifications involving the cerebral blood vessels and gray matter can form a double-line, termed “railroad track,” sign. Vascular abnormalities can be associated with focal deficits, including visual field deficits or seizures. The increased vascularization of the blood–brain barrier also makes these children more susceptible to the sedating effects of topical brimonidine use in the treatment of glaucoma.

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Figure 23.15 Sturge-Weber Syndrome—Cerebral Atrophy

Significant brain atrophy may occur in the region of the leptomeningeal angiomatosis. Patients with this manifestation commonly have associated mental retardation and seizures. Visual field defects may be associated as well as significant contralateral motor abnormalities. Sturge-Weber syndrome is usually a unilateral disorder, with involvement of the brain, skin, and eye on the same side. The disorder is bilateral in 10% of cases. Patients with bilateral disease are usually more severely affected with severe retardation, extensive port wine mark, and bilateral glaucoma.

 

Figure 23.16 Sturge-Weber Syndrome—Choroidal Hemangioma

This patient has a diffuse choroidal hemangioma of the right eye (left image), the most common ocular finding in Sturge-Weber syndrome, which is present in 40% of patients. The hemangioma is always ipsilateral to the port wine mark. The involved fundus has a more reddish color with loss of visible choroidal vasculature markings when compared to the noninvolved eye (right image) and has been described as having a “tomato ketchup appearance.” More localized hemangioma may also occur. Occasionally, overlying retinal vascular tortuosity may occur. Leakage or serous retinal detachment is very uncommon. Therefore, prophylactic treatment is usually not necessary.

 

Figure 23.17 Sturge-Weber Syndrome—Congenital Glaucoma

Glaucoma is present in more than half of patients with Sturge-Weber syndrome and is ipsilateral to the port wine mark. Congenital or infantile glaucoma, indistinguishable from primary infantile glaucoma with typical angle appearance (Chapter 10: Glaucoma, Fig. 10.1), is the earliest form of glaucoma seen in Sturge-Weber. This child has glaucoma in his right eye and presents with corneal haze due to edema, increased corneal diameter, and enlargement of the optic cup. Goniotomy and trabeculotomy are first-line treatments. The contralateral eye is only at risk if a port wine mark is also present on that side, as seen here.

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Figure 23.18 Sturge-Weber Syndrome—Prominent Episcleral Vessels

Patches of dilated episcleral vessels (left image) are frequently observed on the side of the cutaneous lesion. They represent telangiectatic vessels similar to the dilated subcutaneous vessels. The extensive honeycomblike network is often not apparent until the Tenon fascia is retracted at surgery. Between the ages of approximately 4 and 13 years, hypertrophy of these vessels, although not apparent to the observer, results in an increased episcleral venous pressure and impaired outflow from the anterior chamber with secondary glaucoma. On gonioscopy, blood may be seen in the Schlemm canal (right image, arrows).

 

Figure 23.19 Sturge-Weber Syndrome—Optic Nerve Cupping

Glaucomatous changes of the optic cup secondary to Sturge-Weber–related glaucoma are demonstrated in the left image. However, this patient also has a diffuse choroidal hemangioma (Figure 23.16). The presence of diffuse choroidal hemangioma, even in the absence of glaucoma, will also enlarge the optic cup, perhaps by posterior displacement of the lamina cribrosa due to heaping of the hemangioma in the peripapillary region, as demonstrated by this three-dimensional ultrasound (right image). One must therefore be careful about overdiagnosis of glaucoma on the basis of optic nerve cupping in a child with choroidal hemangioma.

 

Figure 23.20 Neurofibromatosis I

Neurofibromatosis type I is an autosomal dominant phakomatosis caused by mutations in the NF1 gene at 17q11.2, the product of which is the protein neurofibromin. The disease is diagnosed when a patient meets at least two of seven criteria: (a) six or more café au lait spots (>0.5 cm in greatest diameter if prepubertal, >1.5 cm if postpubertal); (b) axillary/inguinal freckling (shown here); (c) two or more neurofibromas of any type, or one plexiform neurofibroma; (d) sphenoid bone dysplasia or thinning of long-bone cortex, with or without pseudoarthrosis; (e) optic nerve glioma; (f) two or more Lisch nodules; and (g) a first-degree relative with neurofibromatosis I. This patient met the first two criteria. Subcutaneous neuromas are often more prominent in adulthood, as shown here.

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Figure 23.21 Neurofibromatosis I—Subconjunctival Neuroma

Although much more commonly subcutaneous, neurofibromas can also occur within the subconjunctival space in association with neurofibromatosis. The lesions are typically elevated and represent a collection of peripheral nerve structures including axons, Schwann cells, and fibroblasts. Patients with neurofibromatosis have an increased incidence of other neural tumors and malignancies, including schwannoma. Nonneural tumors, including Wilms tumor, pheochromocytoma, rhabdomyosarcoma, melanoma, and leukemia, also occur with a higher incidence than in a normal population.

 

Figure 23.22 Neurofibromatosis I—Pseudoarthrosis

Pseudoarthrosis in this child's right leg represents pathologic fracture with poor healing and subsequent deformity. This is the most common peripheral skeletal abnormality, which is one of the diagnostic criteria. Other skeletal abnormalities include sphenoid wing dysplasia (Fig. 23.23), scoliosis, and hemivertebra.

 

Figure 23.23 Neurofibromatosis I—Sphenoid Wing Dysplasia

One of the bony manifestations of neurofibromatosis I is dysplasia or absence of the sphenoid wing in the orbit. Note the downward displacement of this patient's left eye and what appears to be ptosis. These findings are due to contact between the intracranial space and the superior orbit. The patient may also demonstrate pulsating proptosis. Computed tomography scan with three-dimensional reconstruction illustrates the defect in the sphenoid bone. The dissolution of the sphenoid is progressive and begins with bony dysplasia. These patients tend to have an orbital form of neurofibromatosis with severe ocular involvement including glaucoma, ipsilateral plexiform neurofibroma, and poor visual prognosis.

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Figure 23.24 Neurofibromatosis—Plexiform Neurofibroma

Plexiform neurofibromas of the upper eyelid are often described as “a bag of worms” on palpation. Involvement of the eyelid causes ptosis with an S-shaped contour to the eyelid margin. The image on the left shows the earliest phases of this lesion in the patients left upper lid before lid margin changes. On the right, a larger lesion is shown. Severe distortion of the face due to cutaneous hypertrophy and progressive growth of the lesion can occur. Surgical repair is difficult and may result in accelerated growth of the tumor. There is a high risk for amblyopia, restrictive strabismus, and glaucoma.

 

Figure 23.25 Neurofibromatosis I—Lisch Nodules

Small, avascular, yellow-brown hamartomas can be present on the iris. These Lisch nodules are diagnostic of neurofibromatosis and rarely occur in any other condition. In patients with known neurofibromatosis type I, approximately 40% of patients will have Lisch nodules by 4 years of age, 60% by 6 years, and 90% by 9 years. The absence of Lisch nodules after puberty indicates a less than 2% chance of the patient being affected.

 

Figure 23.26 Neurofibromatosis I—Lisch Nodules

On a brown iris, Lisch nodules usually appear tan. Lisch nodules can be distinguished from other lesions of the iris (Chapter 6: Iris and Pupils) in that they are raised, usually have discreet borders, are scattered in distribution, are asymmetric between the two eyes, and have a different pigment from the background iris. Iris nevi usually have a chocolate brown pigmentation, no elevation, and indistinct borders. Lisch nodules are benign and have no visual consequence.

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Figure 23.27 Neurofibromatosis I—Amelanotic Lisch Nodules

Rarely, in light-colored eyes, the Lisch nodules can have little or no pigment and have a gray appearance. A group of barely pigmented Lisch nodules can be seen in front of the arrow. Other variants of Lisch nodules (not shown here) include stellate, buried, and clumped patterns. Instead of the typical round domelike appearance, there may be fingerlike extensions into or onto surrounding iris tissues. Regardless of the appearance, vision is unaffected by Lisch nodules.

 

Figure 23.28 Neurofibromatosis I—Optic Nerve Glioma

Optic nerve gliomas are seen in 12% to 15% of patients with neurofibromatosis I. Although frequently asymptomatic and undetectable on clinical examination, they may also present with ipsilateral decreased vision, monocular nystagmus, afferent pupillary defect, visual field changes, color vision defects, proptosis, strabismus, or an abnormal appearance to the optic nerve (Chapter 9: Optic Nerve, Fig. 9.36). These benign tumors grow slowly, but malignant transformation can rarely occur.

 

Figure 23.29 Neurofibromatosis I— Visual Pathway Glioma

Optic nerve glioma may also occur in the absence of the systemic disorder. It is usually asymptomatic even when the optic nerve is grossly enlarged, as seen in the left image. The glioma can extend posterior to involve the chiasm, as shown in the right image where the hyperintense glioma has a “butterfly configuration,” resulting in bilateral visual loss and even hydrocephalus. Rarely, acute growth can occur. Patients with normal neuroimaging by the age of 6 to 7 years old rarely develop a new glioma. Treatment includes chemotherapy and surgical removal. Tumor resection can cause significant visual loss.

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Figure 23.30 Neurofibromatosis I—Brain

Central nervous system manifestations of neurofibromatosis I include benign brain tumors and developmental delay. The left photograph demonstrates hamartomas of the brain, particularly in the frontal region. Malignant transformation can occur. Other associated tumors include glioma, meningiomas, astrocytomas, and neurofibromas. Small tumors may involve isolated nerves such as cranial nerve IV, resulting in superior oblique palsy (left eye, right image). There is some evidence that developmental delay in neurofibromatosis I results from contiguous gene deletion involving the neighboring JJAZ1 gene in some patients. There remains controversy regarding the need for routine neuroimaging in asymptomatic patients with neurofibromatosis I.

 

Figure 23.31 Neurofibromatosis I—Retinal Hamartoma

This patient has an extensive peripapillary retinal hamartoma. As the macula is spared, the visual prognosis is good. Other retinal tumors in neurofibromatosis I include combined hamartomas of the retinal pigment epithelium, retinal pigment epithelial abnormalities (hyper- or hypopigmentation), and, less commonly, hemangioma or melanoma. With the exception of optic nerve glioma (Chapter 9: Optic Nerve, Fig. 9.36), most patients with neurofibromatosis I have a normal fundus.

 

Figure 23.32 Neurofibromatosis I—Choroidal Nevi

Although not common and not a diagnostic criterion, multiple choroidal nevi are seen in neurofibromatosis I and a few other conditions. The lesions are benign, and malignant transformation has not been reported. The nevi have a predilection for the posterior pole. Nevi are more common in adulthood. This patient also has a coincidental peripapillary crescent temporally (Chapter 9: Optic Nerve, Fig. 9.19), which is unrelated to neurofibromatosis.

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Figure 23.33 Neurofibromatosis I—Corneal Nerves

Prominent corneal nerves occur in approximately 25% of patients with neurofibromatosis I. The differential diagnosis is discussed elsewhere (Chapter 5: Cornea, Fig. 5.7), but multiple endocrine neoplasia (MEN) type IIB must be considered in patients with café au lait spots and prominent corneal nerves because of the association with medullary carcinoma of the thyroid. The prominent corneal nerves are not visually significant and are not correlated with other ocular manifestations of neurofibromatosis.

 

Figure 23.34 Segmental Neurofibromatosis

Segmental neurofibromatosis is an uncommon variation with findings limited to one dermatome. The lesions do not cross the midline and associated findings elsewhere in the body are less common. Lisch nodules of the iris have been rarely reported. Brain involvement is also less common.

 

Figure 23.35 Neurofibromatosis Type II

Neurofibromatosis type II is due to mutations in the NF2 gene at 22q12.2, which manufactures the protein merlin/schwannomin. It is also an autosomal dominant phakomatosis. Its major manifestation is acoustic neuroma. Lisch nodules have rarely been reported. Posterior subcapsular cataracts (left image) are common in neurofibromatosis II and may occur as early as the first or second decade. Surgery may be required. Other ocular manifestations include epiretinal membrane formation, as seen in the peripapillary region here(right image).