General considerations

Neurofibromatosis type 1 occurs at a rate of 1 in 3000 persons, but it is estimated that the frequency could be higher as some individuals manifest only mild features. Approximately one-half of affected patients represent a new mutation. This condition is caused by an autosomal dominant mutation in the NF1 gene that leads to decreased production of the protein neurofibromin, which has a tumor suppressor function. Only one deleted is necessary to manifest this condition. The NF1 gene is on long arm of chromosome 17. There have been more that 250 mutations identified. Complete gene deletion leads to severe phenotype. This highly penetrant phenotype has a wide variety of manifestations and can vary within families. Another locus, the SPRED1 gene, has been found in patients with “mild neurofibromatosis” and this represents Legius syndrome.⁷

The criteria for diagnosis of neurofibromatosis type 1 are listed in Table 132.1.^8,9 This condition more often affects patients of the Caucasian race and equally in boys and girls. Scoliosis can be a prominent feature.

Table 132.1 Diagnostic criteria for neurofibromatosis type 1 (NF1) – at least two of the following seven criteria should be present for diagnosis*

^* Some manifestations do not appear until later life, delaying diagnosis. (Adapted from Stumpf DA, Alksne JF, Annegers JF. Neurofibromatosis. Conference statement. National Institute of Health Consensus Development Conference. Arch Neurol 1988; 45:575–8⁸ and Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997;278:51–7.⁹)

Ophthalmologic features

Neurofibromatosis has the most diversified ocular findings among the phakomatoses.^10–17 This condition can involve the eyelid, conjunctiva, aqueous outflow channels, uveal tract, retina, orbit, and optic nerve (Fig. 132.1).

Fig. 132.1 Neurofibromatosis type 1. (A) Iris Lisch nodules. (B) Multifocal choroidal freckling. (C) Axillary freckling. (D) Multiple cutaneous neurofibromatosis. (E) Vasoproliferative tumor with exudative retinopathy.

Eyelid involvement is characterized by nodular or plexiform neurofibroma. Nodular neurofibroma appears as a solitary or multifocal painless, smooth-surfaced and well-defined mass, often the size of a pea, and without color change. Plexiform neurofibroma presents as a diffuse thickening of the eyelid that can produce the typical S-shaped curvature to the eyelid, a finding highly characteristic of neurofibromatosis. The conjunctiva can be involved by diffuse or localized neurofibromas. Patients with neurofibromatosis have an increased incidence of congenital glaucoma, which can be secondary to several mechanisms.¹⁰ There is a high association of neurofibromatosis type 1 with optic nerve glioma.¹²

A variety of ocular fundus lesions can occur in patients with neurofibromatosis. Multiple iris hamartomas, known as Lisch nodules, are the most common uveal abnormality.¹¹ Iris Lisch nodules are the most common ophthalmic abnormality of neurofibromatosis type 1. These characteristically orange-tan nodules appear in early childhood (usually by age 6 years) as discrete, multiple, bilateral tumors of the anterior border layer of the iris, classically measuring less than 1 mm diameter and best detected by slit lamp biomicroscopy. Histopathologically, iris Lisch nodules are hamartomas composed of aggregates of melanocytes on the anterior border layer of the iris.

The choroidal findings in patients with neurofibromatosis type 1 include unifocal or multifocal choroidal nevus, diffuse plexiform neurofibroma, neurilemoma, and melanoma. Multiple bilateral, choroidal nevi are highly suggestive of neurofibromatosis type 1. They are usually small, ill-defined, and randomly distributed. Choroidal neurofibroma usually appears as a diffuse thickening of the uveal tract from an increased number of neurofibromatous and melanocytic elements. Choroidal neurilemoma (Schwannoma) is a rare finding and manifests as a circumscribed, amelanotic elevated tumor.¹⁴ Most solitary choroidal neurilemomas, however, are not associated with neurofibromatosis. There appears to be a higher incidence of uveal melanoma in patients with neurofibromatosis.^15,16

Several retinal and optic disc lesions can occur with neurofibromatosis. Retinal astrocytic hamartoma is a manifestation of neurofibromatosis, but is more common with tuberous sclerosis complex. Retinal vasoproliferative tumor can occur with neurofibromatosis, leading to exudative retinopathy and risk for blindness.¹⁷ Fundus changes can occur secondary to optic nerve glioma including optic disc edema, optic atrophy, opticociliary shunt vessels and, rarely, central retinal vein obstruction.

Dermatologic features

The most important cutaneous manifestations of neurofibromatosis include café-au-lait spots (pigmented macules), freckles in the axillary or inguinal region, and urticarial pigmentosa. Café-au-lait spots are found in 95% of patients with neurofibromatosis type 1, but they can be seen in patients with other conditions such as McCune–Albright syndrome, tuberous sclerosis complex, and Fanconi anemia. Café-au-lait spots are also found in persons without neurofibromatosis type 1. They represent the earliest manifestation of neurofibromatosis type 1 and can be found in infancy as a very light hyperpigmented spot that becomes more noticeable over time or with sun exposure.

Subcutaneous or cutaneous benign neurofibromas are an important finding but are rare in young children and typically appear in older children or later. Deep neurofibromas might not be visible and are only detected by palpation. Puberty and pregnancy can increase number and growth of neurofibromas. Plexiform neurofibromas can be invasive and ill-defined, occasionally associated with pain. Rapid growth of neurofibroma is suggestive of malignant degeneration.

Central nervous system features

The most important central nervous system feature of neurofibromatosis type 1 is the optic nerve glioma (juvenile pilocytic astrocytoma). Optic nerve glioma can present with obvious features of painless proptosis or subtle features of color or visual acuity abnormalities. Magnetic resonance imaging shows enlargement of the optic nerve, often so large that it develops a fold (kink) within its substance to accommodate the orbit, leading to down and out proptosis. This mass shows enhancement on T1-weighted, gadolinium contrast images, particularly notable in the axial and coronal views. It is important to differentiate this tumor from optic nerve sheath meningioma as the systemic implications and therapy differ. This is best determined using gadolinium-enhanced, orbital fat suppressed, T1-weighted coronal views. With glioma, the central substance of the nerve enhances whereas with meningioma, the peripheral encircling arachnoid sheath enhances. Glioma is more often associated with neurofibromatosis type 1 whereas meningioma is more associated with neurofibromatosis type 2.

Other features

There are numerous orthopedic problems in patients with neurofibromatosis type 1. Sphenoid wing dysplasia, congenital pseudoarthrosis with tibial or forearm bowing, thoracic cage asymmetry with inferior rib prominence, and scoliosis/kyphosis. Scoliosis at a young age (under 10 years) can progress. Other findings include macrocephaly and hypertension.

A number of other benign and malignant systemic tumors have been associated with neurofibromatosis. Sarcomas can arise from the peripheral nerve sheath, either de novo or from pre-existing benign cutaneous nerve sheath tumors. Malignant peripheral nerve sheath tumors can occur in over 20% of patients. There seems to be an increased incidence of breast, genitourinary, and gastrointestinal tumors, as well as cutaneous melanoma. Patients with neurofibromatosis probably have a slightly higher incidence of pheochromocytoma.

Management

The management of neurofibromatosis varies with the location and the extent of the disease. Most fundus lesions require no treatment. Choroidal melanoma and neurilemoma are often clinically indistinguishable, and have usually required plaque radiotherapy, resection, or enucleation. Iris Lisch nodules, congenital hypertrophy of the retinal pigment epithelium, and retinal astrocytic hamartoma are observed. Retinal vasoproliferative tumors often require cryotherapy, laser photocoagulation, photodynamic therapy or plaque radiotherapy to control exudative findings.

General considerations

Neurofibromatosis type 2 is a multisystem disorder with prominent features of central nervous system tumors including bilateral vestibular schwannomas (acoustic neuromas), spinal cord schwannomas, meningiomas, gliomas, and juvenile posterior subcapsular cataract. This condition is also referred to as MISME syndrome, a mnemonic referring to related tumors of MIS (multiple inherited schwannomas), M-meningiomas, and E-ependymomas.¹⁸ Cutaneous features are less often seen with this form of neurofibromatosis. The criteria for diagnosis of neurofibromatosis type 2 are listed in Table 132.2.

Table 132.2 Diagnostic criteria for neurofibromatosis type 2 (NF2). Diagnosis is established with at least one of the three items listed below

(Adapted from Stumpf DA, Alksne JF, Annegers JF. Neurofibromatosis. Conference statement. National Institute of Health Consensus Development Conference. Arch Neurol 1988;45:575–8⁸ and Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997;278:51–7.⁹)

Neurofibromatosis type 2 can be associated with reduced life span secondary to central nervous system tumors, particularly if they are present at a young age and are multiple. The average age at symptom onset is approximately 20 years but can be delayed. Early age at symptoms and the presence of intracranial meningioma at diagnosis are two signs of higher risk for disease severity and mortality. In an analysis of 150 affected patients in 1992, more than 40% were expected to die by 50 years.¹⁹ Recent advances in treatment have extended life prognosis.

The incidence of neurofibromatosis type 2 is 1 in 25 000 live births and has nearly 100% penetrance by 60 years of age.²⁰ It is estimated that this condition has a diagnostic prevalence of 1 in 100 000 people in 2005. Neurofibromatosis type 2 is related to a mutation in the NF2 gene at chromosome 22q12.2. This gene produces merlin (also called neurofibromin-2), a tumor suppressor. When mutated, decreased function of merlin leads to the uncontrolled development of tumors, particularly in the central nervous system. One-half of affected patients have a de novo mutation.

Ophthalmologic features

Neurofibromatosis type 2 displays three important ophthalmologic findings, notably posterior subcapsular cataract in childhood, combined hamartoma of the retina and retinal pigment epithelium, and epiretinal membranes (Table 132.3). The juvenile posterior subcapsular cataract (<50 years) is a criterion for diagnosis of this condition. Other lens opacity in the capsular or cortical region of young patients are believed related to neurofibromatosis type 2. Lisch nodules are not a feature of neurofibromatosis type 2.

Table 132.3 Frequency of clinical features in patients with neurofibromatosis type 2

(Adapted from Asthagiri AR, Butman JA, Kim HJ, et al. Neurofibromatosis type 2. Lancet 2009;373:1974–86.²⁰)

Epiretinal membranes and combined hamartoma of the retina and retinal pigment epithelium can have overlapping clinical phenotype and can be multifocal. Of those with severe clinical features of neurofibromatosis type 2, 80% display epiretinal membranes.²¹ The hamartomas are along the inner retina but lead to prominent retinal dragging, corkscrew retinal vessels, gray-green appearance and tumor formation.^22,23

Dermatologic features

The cutaneous features of neurofibromatosis type 2 are slightly different than those in type 1. Occasionally, overlap of the two conditions can be seen. Café-au-lait spots are occasionally found. Axillary or inguinal freckling is not often found with neurofibromatosis type 2. Subcutaneous schwannomas or neurofibromas can be found and malignant transformation is extremely rare. Neurofibromatosis type 2 displays skin plaques, represented by well-circumscribed, roughened areas less than 2 cm and often with slight hyperpigmentation and hypertrichosis.

Central nervous system features

Neurofibromatosis type 2 is also called central nervous system neurofibromatosis because of the importance of these related tumors. The central nervous system tumors represent the majority of findings in neurofibromatosis type 2 and vary with the size and extent of the associated tumors. Acoustic neuromas (vestibular schwannomas) are the most common and well-recognized feature. If bilateral, they are considered pathognomonic of type 2 neurofibromatosis. Patients present with symptoms of tinnitus, gradual hearing loss, and later growth produces brainstem compression, hydrocephalus, and facial palsy.

Spinal cord schwannomas, particularly dumbbell-shaped, are common. Spinal cord ependymomas, astrocytomas, and meningiomas can occur less frequently. Intracranial meningiomas are frequent and can manifest with or without symptoms. Nonvestibular schwannomas, particularly of cranial nerves 3 and 5, are diagnosed at a fairly early age, but can be indolent and slow growing.

Other features

Sensory motor polyneuropathy can be found, particularly in those with schwannomas.

Management

Patients with neurofibromatosis type 2 should have annual ophthalmic, neurologic, dermatologic, and auditory examinations. This requires a multidisciplinary team. Surgical resection of symptomatic neurologic tumors is performed, but radiotherapy or chemotherapy can be used, particularly for ependymomas. Erlotinib has been used for unresectable progressive vestibular schwannomas and this medication is under trial. Additionally, bevacizumab and Gleevec have been investigated for treatment of schwannomas. Regarding ophthalmic care, cataract surgery can be beneficial. Additionally, monitoring of epiretinal membrane with clinical examination and optical coherence tomography, with surgical removal if progressive, can be considered.²²

General considerations

The Sturge–Weber (SW) syndrome is characterized by congenital hamartomas of the eye, skin, and brain that manifest at different times during life, mostly in childhood. These include choroidal hemangioma, facial nevus flammeus (port wine stain), and brain hemangioma with intracranial calcification.^24–28 Some patients display a forme fruste, or partial expression, rather than the entire syndrome. In contrast to the other systemic hamartomatosis, there is no recognizable hereditary pattern associated with SW syndrome. There is no predisposition for sex or race.

This condition affects 1 per 50 000 persons. Roach has designed a classification for Sturge–Weber syndrome (Table 132.4).²⁹

Table 132.4 Roach diagnostic scale for classification of encephalotrigeminal angiomatosis (Sturge–Weber syndrome)

(Adapted from Roach ES. Neurocutaneous syndromes. Pedatr Clin North Am 1992;39:591–620.²⁹)

In 1987, Happle proposed that Sturge–Weber syndrome was an example of somatic mosaicism of a genetic trait.³⁰ In 2003, Comi and associates supported this theory but demonstrating abnormality in the gene expression of fibronectin in fibroblasts from the region of the port wine stain compared with normal skin.³¹

Ophthalmologic features

The ocular findings associated with Sturge–Weber syndrome include eyelid involvement with the nevus flammeus, prominent epibulbar blood vessels, glaucoma, retinal vascular tortuosity and diffuse choroidal hemangioma (Fig. 132.2). Glaucoma is more common in patients with Sturge–Weber syndrome than it is in the other systemic hamartomatoses. In a study of 50 patients with nevus flammeus, there was an 8% overall incidence of glaucoma. If the facial hemangioma involved both the first and second division of the trigeminal nerve, the incidence was 15%.²⁶ The glaucoma occurs unilaterally on the side of the facial hemangioma. It may gradually lead to extensive cupping of the optic disc and blindness. We have been referred patients with facial nevus flammeus who developed complete blindness from unrecognized glaucoma. The associated glaucoma can be either congenital or juvenile.

Fig. 132.2 Sturge–Weber syndrome. (A) Facial nevus flammeus. (B) Diffuse choroidal hemangioma with shallow serous retinal detachment, reduced visual acuity, and macular fold confirmed on optical coherence tomography (OCT) (C). (D) Following radiotherapy, complete resolution of retinal detachment and macular fold on OCT (E).

Sullivan and associates reviewed eye findings in 51 patients with Sturge–Weber syndrome and found 71% with glaucoma (onset before 2 years of age in most cases), 69% with conjunctival or episcleral prominent vessels, and 55% with diffuse choroidal hemangioma.³²

The main abnormality of the uveal tract in patients in Sturge–Weber syndrome is diffuse choroidal hemangioma.³³ Patients with this tumors display bright red pupillary reflex in the involved eye compared with the contralateral eye. This phenomenon, which is due to the light reflex from the highly vascularized tumor in the posterior pole, has been called the “tomato catsup” fundus. B-scan ultrasonography typically demonstrates a diffuse, highly echogenic thickening of the choroid. The tumor is usually unilateral but bilateral cases associated with bilateral facial nevus flammeus have been recognized. Diffuse tumor is usually diagnosed when the affected patient is young (median age 8 years), either because the associated facial hemangioma prompts a fundus examination or because visual impairment occurs from hyperopic amblyopia or from a secondary retinal detachment. Diffuse choroidal hemangioma can lead to a total retinal detachment and secondary neovascular glaucoma.

Other fundus changes seen with Sturge–Weber syndrome include congenital retinal vascular tortuosity and pigmentary alterations from a longstanding nonrhegmatogenous retinal detachment, sometimes causing a “pseudoretinitis pigmentosa” appearance.

Dermatologic features

The classic skin lesion of Sturge–Weber syndrome is the facial hemangioma, often referred to as nevus flammeus or port wine stain. Although it typically occurs in the cutaneous distribution of the fifth cranial nerve, it can have many variations, ranging from minor involvement of the first division of the nerve to massive involvement of all three divisions.

Central nervous system features

The typical CNS feature associated with Sturge–Weber syndrome is a diffuse leptomeningeal hemangioma that is ipsilateral to the facial hemangioma.¹ This lesion can show secondary calcification that appears radiographically as a radio-opaque double line which has been called the “railroad track” sign. The calcification often increases during the first 20 years of life and usually becomes stable in adulthood. Seizures, stroke, headache, learning disorders, and developmental delay can occur as a result of the leptomeningeal hemangioma (Table 132.5).

Table 132.5 Clinical findings in the Sturge–Weber syndrome

Of all patients with facial port wine stain, only 8% show complete features of Sturge–Weber syndrome.

Other features

Other serious complications of the Sturge–Weber syndrome are rare.

Management

The management of the diffuse choroidal hemangioma varies with the extent of the tumor and secondary retinal detachment. If the tumor is minimally elevated and without subretinal fluid, observation is advised and correction of the induced hyperopic change may be considered. Monitoring for amblyopia is important. Thicker tumors with secondary retinal detachment are treated with photodynamic therapy or external beam radiotherapy.³⁴ Newer information on the use of oral propranolol for treatment of exudative retinal detachment from diffuse choroidal hemangioma may offer another alternative. External beam radiotherapy or plaque radiotherapy with a total dose of 20–40 Gy has been successful in achieving resolution of fluid and return of some visual acuity, depending on the chronicity. The treatment of related glaucoma should be undertaken by an ophthalmologist who is experienced in the management of complicated glaucoma problems.

The cutaneous lesions seen with Sturge–Weber syndrome can be managed by laser photocoagulation in infancy or late cosmetics to cover the defect. Both of these methods can improve the cosmetic appearance.

General considerations

Racemose hemangioma of the midbrain and ipsilateral retina is called the Wyburn-Mason syndrome.³⁵ In contrast to the other oculoneurocutaneous syndromes, it has few skin changes except for occasional small hemangiomas. The ocular and central nervous system changes, however, can be quite striking. Like Sturge–Weber syndrome, this congenital condition does not appear to be familial and does not exhibit a hereditary pattern. The characteristic arteriovenous communications can range from subtle asymptomatic lesions to more extensive lesions that form tumor-like vascular masses, often referred to as racemose or cirsoid hemangiomas.

The exact association of the retinal and central nervous system hemangiomas is not clear but it is estimated that 30% of patients with the retinal findings have brain findings.³⁶ On the other hand, it is estimated that 8% of patients with brain findings have retinal findings.³⁶

Ophthalmologic features

The classic ocular finding is the racemose hemangioma of the retina (Fig. 132.3).^37–39 Similar vascular malformations can occur in the orbit and adjacent structures. These retinal arteriovenous communications have been divided into three groups according to the Archer classification (Table 132.6).³⁹ Group I is characterized by interposition of an abnormal capillary plexus between the major vessels. It is not a true tumor and the affected patient is often asymptomatic. Group II is typified by a direct arteriovenous communication without interposition of capillary or arteriolar elements. The dilated blood vessels in this group can superficially resemble a retinal capillary hemangioma, but no tumor, exudation, or retinal detachment is present. In general, these patients have few visual symptoms, but they can have associated cerebral arteriovenous malformations. Group III is characterized by a more extensive complex arteriovenous communication, which is often associated with visual loss. In this group, the most striking feature is one or more dilated arteries that emerge from the optic disc, pass for a variable distance into the retina, form distinct arteriovenous communications, and then pass back to the optic disc as large veins. There is characteristically no exudation or retinal detachment and the vessels do not leak fluorescein. Although these lesions are believed to remain stationary indefinitely, we have observed changes in the distribution of the blood vessels over several years. Branch retinal vein obstruction can sometimes occur.^40,41 Iris racemose hemangioma has not been associated with retinal racemose hemangioma or the Wyburn-Mason syndrome.⁴²

Fig. 132.3 Wyburn-Mason syndrome. (A) Archer type III retinal vascular malformation seen clinically and on (B) fluorescein angiography.

Table 132.6 Archer classification for Wyburn-Mason syndrome

(Adapted from Archer DM, Deutman A, Ernest JT, Krill AE. Arteriovenous communications of the retina. Am J Ophthalmol 1973;75:224–41.³⁹)

Dermatologic features

There are no significant cutaneous changes associated with racemose hemangiomatosis, except for the rare occurrence of small facial angiomas.

Central nervous system features

The racemose hemangioma of the central nervous system is most often found in the midbrain. Spontaneous intracranial hemorrhage from the malformation can lead to a variety of neurologic symptoms, most notably stroke and focal neurologic defects. Intracranial hemorrhage occurs far more frequently than intraocular hemorrhage. These malformations typically become symptomatic in the second or third decade of life and present with headache, vomiting, or meningismus. Hydrocephalus can ensue.

Other features

The bones of the skull can frequently be involved with the vascular malformation. When the mandible or maxilla is affected, abnormal bleeding can occur during invasive dental work.

Management

In general, no dermatologic or ophthalmic treatment is necessary in patients with racemose hemangiomatosis. The retinal hemangioma per se cannot be treated. If persistent vitreous hemorrhage is found, then blood removal by vitrectomy is performed. Observation for retinal vascular obstruction is important. Branch retinal vein obstruction usually resolves without treatment, but intravitreal injection of antivascular endothelial growth factor or panretinal photocoagulation can be considered to prevent ischemic vascular complications and glaucoma.

General considerations

There are two types of retinal cavernous hemangioma, including those that occur sporadically/independently and those associated with the syndrome of cutaneous and central nervous system vascular malformations. The latter is associated with a highly penetrant autosomal dominant mutation and is a part of the phakomatoses. Genetic abnormalities have been found on chromosomes 3q, 7p, and 7q.

Ophthalmologic features

The only ocular manifestation of this syndrome is the retinal cavernous hemangioma (Fig. 132.4). Ophthalmoscopically, it appears as a dark grape-like cluster of venous intraretinal aneurysms either at the optic disc, macula, or in the peripheral retina.^43–45 There is no obvious feeding artery and the lesion is typically centered along the course of a vein. This lesion produces no exudation or subretinal fluid, likely due to the fact that the thin-walled channels are lined by nonfenestrated endothelium. Repetitive vitreous hemorrhages (often mild and subclinical) can lead to white fibroglial tissue on the surface. This non-progressive thin-walled, aneurysmal retinal tumor can remain hidden in the fundus for decades until dilation is performed or the patient develops vitreous hemorrhage.

Fig. 132.4 Retinal cavernous hemangioma in a patient with brain hemangiomatosis.

The main complication of retinal cavernous hemangioma is vitreous hemorrhage. Larger tumors can be associated with severe fibrogliosis and related retinal dragging with displacement of the macula.

The most important diagnostic test for retinal cavernous hemangioma is fluorescein angiography, which produces highly characteristic, if not pathognomonic, features of hypofluorescence persistent into the late frames with slow nonleaking filling of the aneurysms. Fluorescein is contained within the venous aneurysms of the lesion and pools in the plasma in the superior portion of each vascular space, while the blood elements collect in the inferior portion. This produces the typical fluorescein–blood interface in the late angiograms that characterizes retinal cavernous hemangioma.

Other rare ophthalmic findings include iris cavernous hemangiomatosis with repetitive hemorrhages.⁴⁶

Dermatologic features

The hemangiomas of the skin in this syndrome are variable in their appearance and distribution on the body. The lesions occur most commonly on the back of the neck. Involvement of the eyelids is rare.

Central nervous system features

Cavernous hemangioma can involve any region of the central nervous system but is more common in the supratentorial rather than infratentorial region. Spinal cord involvement can occur. Symptoms include seizures, hemorrhage, and focal neurologic defect most commonly. About 25% of patients display no neurologic symptom despite having a cavernous hemangioma within the brain.⁴⁷ Intracranial hemorrhage occurs in 12% to 48%. Magnetic resonance imaging can provide information to the location and size of the mass.

Other features

Various ophthalmic manifestations related to brain injury can occur such as diplopia due to paresis of extraocular muscles, presumably secondary to bleeding into the oculomotor nuclei. It is likely that many patients have vascular lesions in the central nervous system that remain subclinical throughout life.

Management

The cutaneous hemangiomas seen with this condition are generally small and asymptomatic and require no treatment. Most cavernous hemangiomas of the retina are also asymptomatic and stable and require no treatment. Vitreous hemorrhage can be an occasional complication of larger tumors and the blood could spontaneously resolve over several months. If not, then pars plana vitrectomy with blood removal is performed. For repetitive vitreous hemorrhages, several techniques have been attempted to the vascular retinal tumor including cryotherapy, photocoagulation, photodynamic therapy, and plaque radiotherapy. Plaque radiotherapy induces vascular sclerosis, similar to the gamma knife or CyberKnife radiotherapy used to treat the central nervous system hemangiomas.

General considerations

The organoid nevus syndrome (ONS) is an oculoneurocutaneous condition without clear genetic abnormality. The features include the sebaceous nevus of Jadassohn, cerebral atrophy, arachnoidal cyst, epibulbar complex choristoma, eyelid coloboma, posterior calcified scleral cartilage, and occasionally other features.^48,49 The sebaceous nevus of Jadassohn is a well-recognized dermatologic entity, but the complete syndrome of organoid nevus syndrome is relatively uncommon. This sporadic condition displays more choristomas than hamartomas, unlike other phakomatoses. Despite the lack of genetic understanding, there have been exceptionally rare cases of multiple generations affected with organoid nevus syndrome.

This condition was originally described by Jadassohn with the term “organoid nevus” to emphasize the prominence of the cutaneous component. Later, terms such as “nevus sebaceous of Jadassohn” and “Solomon syndrome” were applied to this condition.

Ophthalmologic features

Although there are several ophthalmic features of the organoid nevus syndrome, two most important ones are the epibulbar complex choristoma and posterior scleral cartilage (Fig. 132.5). The epibulbar complex choristoma is a fleshy lesion of the conjunctiva that often extends onto the cornea. It is composed histopathologically of a dermolipoma that contains variable combinations of ectopic lacrimal gland and hyaline cartilage. The posterior scleral cartilage produces a peculiar yellow-white discoloration of the fundus in the area of involvement that has been reported erroneously in the literature as optic nerve coloboma or choroidal osteoma. With ultrasonography and CT, there is a bone density plaque at the level of the choroid and sclera that corresponds to cartilage in the posterior sclera and not bone as seen with an osteoma.

Fig. 132.5 Organoid nevus syndrome. (A) Facial nevus sebaceous of Jadassohn. (B) Subtle epibulbar choristoma. (C) Subtle cartilaginous choristoma superior to disc but confirmed on computed tomography as calcified (D).

Dermatologic features

The main dermatologic feature of the organoid nevus syndrome is the sebaceous nevus of Jadassohn. It appears as a geographic yellow-brown lesion that often involves the preauricular or brow region and extends onto the scalp where it is associated with alopecia and often down along the neck and nose. This lesion becomes hypertrophied with time. There are three stages of this cutaneous lesion dependent on patient age.⁴⁸ The first stage occurs in infancy with underdevelopment of hair, sebaceous glands and adnexal structures. The second stage occurs at puberty with massive overdevelopment of adnexal structures. The third stage occurs in adulthood with benign and malignant tumors including basal cell carcinoma, syringocystadenoma papilliferum, sebaceous adenoma, keratoacanthoma, and others. It is estimated that 20% of patients with sebaceous nevus of Jadassohn will develop basal cell carcinoma arising from the nevus.

Central nervous system features

Patients with the organoid nevus syndrome can develop seizures, due mainly to enlarging subarachnoid cysts in the central nervous system, and mental retardation. Imaging studies have shown arachnoidal cysts, leptomeningeal hemangiomas, hamartomas, cerebral cortical atrophy, and the MEAN tumor (meningoencephaloangioneuronomatosis).

Other features

Rarely, organoid nevus syndrome can have cardiac and renal abnormalities including patent ductus arteriosus, ventricular septal defect, coarctation of the aorta, nephroblastomatosis, and horseshoe kidney. Other rare relationships include vitamin D-resistant rickets and liver cysts.

Management

The epibulbar choristoma generally remains stationary and can be safely observed. However, there is a strong predisposition for amblyopia which should be monitored and corrected. Larger or progressive lesions might require surgical excision, but often the lesion is full thickness within the wall of the eye and complete resection is not possible. There is no treatment of the benign cartilaginous fundus lesion. There has been no documentation of enlargement of this lesion. A consideration for related affect on vision should be monitored. This should be differentiated from choroidal osteoma and retinoblastoma, particularly since it occurs in infancy. The cutaneous sebaceous nevus is usually resected to minimize risk for basal cell carcinoma or other adnexal tumors. Monitoring of the central nervous system with imaging is advised for arachnoidal cyst and tumor.

General considerations

Phacomatosis pigmentovascularis is a rare condition representing the coexistence of cutaneous vascular malformation (usually nevus flammeus) with melanocytic nevus (usually melanocytosis). Since the first report on this condition by Ota in 1947, there have been few reports, mostly in the dermatologic literature.⁵⁰ In 2005, Tran and Zografos reported three cases, all with uveal melanoma.⁵¹ In 2005, Happle proposed reclassification (Table 132.7).⁵² According to Happle, phacomatosis pigmentovascularis is divided into three types: phacomatosis cesioflammea, phacomatosis spilorosea, and phacomatosis cesiomarmorata (Table 132.7). Phacomatosis cesioflammea is characterized by coexistence of a dermal melanocytosis (blue spot) and nevus flammeus (port wine stain). “Caesius” is Latin for “bluish gray” and “flammea” for “flame” or “fire.” The other two types have less relationship to the eye.

Table 132.7 Classification of phacomatosis pigmentovascularis (PPV)

(Adapted from Happle R. Phacomatosis pigmentovascularis revisited and reclassified. Arch Dermatol 2005;141:385–8.⁵²)

The association of dermal melanocytosis with cutaneous nevus flammeus is believed to be due to the “twin spotting” phenomenon, which is the association of two genetically different clones of cells within a region of normal cells. This involves sporadic somatic recombination and a mosaic distribution of lesions. Moutray and associates describe monozygotic twins discordant for phacomatosis cesioflammea, supporting post-zygotic twin spotting theory.⁵³ In that report, twin #1 was normal and twin #2 had cutaneous nevus flammeus of the arm, maxilla, and periocular region in addition to Mongolian spot and bilateral ocular melanocytosis.

In 2011, Shields and associates reported seven patients with this condition: three with related uveal melanoma; one with primary acquired melanosis of the conjunctiva (melanoma in situ); and one with optic disc melanocytoma.⁵⁴ The serious relationship of this phakomatosis to melanoma was emphasized.

Ophthalmologic features

The ophthalmologic features of phacomatosis pigmentovascularis includes a spectrum of findings with unilateral or bilateral periocular facial nevus flammeus (port wine stain), ocular or oculodermal melanocytosis, secondary glaucoma, and risk for uveal or conjunctival melanoma (Fig. 132.6). There are only few reports in the ophthalmic literature.

Fig. 132.6 Phacomatosis pigmentovascularis. (A) Newborn baby with facial nevus flammeus, subsequently treated with laser photocoagulation and regressed at a later date (B). (C) Fundus photography demonstrates dark ocular melanocytosis in right eye and normal fundus left eye (D).

Dermatologic features

Fernandez-Guarino reviewed the published dermatologic literature on 216 cases of phacomatosis pigmentovascularis and classified 77% as cesioflammea, 13% as spilorosea, 1% as cesiomarmorata, and 8% unclassifiable.⁵⁵ The cutaneous manifestations included mostly pigmented lesions of nevus of Ota (melanocytosis), Mongolian spot, or café-au-lait spot, nonpigmentation of vitiligo, as well as vascular lesions of nevus flammeus (port wine stain) or nevus anemicus. These cutaneous findings tended to be patchy without midline separation and scattered over the surface of the body.

Central nervous system features

Neurologic features of phacomatosis pigmentovascularis include seizures, cortical atrophy, Arnold Chiari type 1, bilateral deafness, idiopathic facial paralysis, hydrocephalus, diabetes insipidus, plexiform neurofibroma, psychomotor developmental delay, and electroencephalogram alterations.⁵⁵

Other features

Miscellaneous features include scoliosis, extremity length asymmetry, syndactyly, macrocephaly, renal agenesis, renal angiomatosis, hepatosplenomegaly, cavernous hemangioma, umbilical hernia, hypoplasia of leg veins, IgA deficit, hyper IgE syndrome, eczema, and premature eruption of teeth.⁵⁵

Management

The cutaneous features should be managed by a dermatologist. Often the port wine stain responds to infantile laser therapy. The ophthalmologist should follow the patient lifelong for the development of glaucoma and melanoma. Monitoring of neurologic status should also be performed.

General considerations

Ocular or oculodermal melanocytosis is a congenital pigmentary condition that can affect the periocular skin, sclera, uvea, orbit, palate, ear drum, and meninges.1–3,56–61 This condition predisposes the patient to melanoma, particularly uveal melanoma and occasionally orbital or meningeal melanoma.^61–66 Ocular or oculodermal melanocytosis can occur as a diffuse condition, affecting all quadrants of the eye in a homogeneous fashion, or as a sectoral condition, affecting only a portion of the eye.⁶⁷ This is a sporadic condition with no genetic mutation identified.

Ophthalmologic features

The ophthalmologic features of ocular or oculodermal melanocytosis include dermal periocular pigmentation (flat blue nevus) with occasional pigment in the temporal fossa along the hair line, scleral pigmentation, and uveal pigmentation involving the iris, ciliary body, and choroid (Fig. 132.7). Orbital pigmentation with blue nevus cells is occasionally found. The iris can manifest mammilation, or clumping of tissue into a “polka dot” appearance, related to the dense pigment.⁶⁸ Early onset equatorial drusen is often found. The main concern of this excessive pigmentation is the risk for the development of uveal melanoma (1/400 risk for Caucasians), orbital melanoma, and meningeal melanoma. Occasionally, optic disc melanocytoma and ipsilateral headache are a part of this syndrome.

Fig. 132.7 Oculodermal melanocytosis. (A) Diffuse melanocytosis manifesting with nevus of Ota surrounding right eye and sclera with melanocytosis (B). (C) Sector melanocytosis of iris. (D) Sector melanocytosis of choroid.

Genetic evaluation following enucleation of an eye with melanoma arising from melanocytosis revealed normal disomy chromosome 3 in the melanocytosis and monosomy chromosome 3 in the melanoma.⁶⁸

Dermatologic features

The dermatologic features include predominantly the flat blue dermal nevus of Ota, classically in the periocular region and often with extension into the temporal region. This rarely leads to cutaneous melanoma.

Central nervous system features

The blue nevus can extend to involve the meninges and carries a small risk for the development of meningeal melanoma.⁶⁹

Other features

Similar blue nevus pigmentation can involve the ipsilateral palate and tympanic membrane.

Management

The main concern with this condition is the development of uveal melanoma. Twice yearly dilated examination is advised. Any patient with the development of unexplained subretinal fluid or lipofuscin orange pigment should be suspected of harboring uveal melanoma. Melanoma develops at a slightly earlier age (approximately 35 years) in those with oculo(dermal) melanocytosis compared to those without (approximately 55 years).