Families with von Hippel–Lindau disease type 2 can be further classified into those in which some members are affected by renal carcinoma (in addition to their ocular, cerebellar, and renal lesions; type 2B), and those in which renal carcinoma is very rare (type 2A). Types 1 and 2B are the most common subtypes and appear to show a similar susceptibility to ocular angiomatosis.175,214,928

The von Hippel–Lindau disease 2A phenotype suggests the presence of a specific mutation (T505C) in the VHL gene, which is associated with a negligible risk for renal cell carcinoma. Patients with complete deletions of VHL protein have the lowest prevalence of ocular disease (14.5% compared to 37.2% in the overall group with amino acid substitutions, protein-truncating mutations, and complete deletions) and the most favorable visual prognosis. However, genotype category appears to have no correlation with the unilaterality or bilaterality of ocular disease or with the number or extent of peripheral retinal capillary hemangiomas.949

Huson et al413 have suggested that patients carrying the diagnosis and those at risk should undergo an annual retinal examination starting at 5 years of age and biennial neuroimaging of the head, spine, and abdomen and urinary

vanillylmandelic acid (VMA) and meta-adrenaline testing starting at age 10, because life-threatening CNS and visceral tumors can remain clinically occult for long periods.383 No pathologic difference exists between sporadic and von Hippel– Lindau-associated hemangioblastomas, and both are believed to result from identical mutations of the VHL gene.293 However, patients who have von Hippel–Lindau disease typically develop neurologic symptoms at an earlier age and are more likely to harbor multiple cerebellar lesions.199,825

Ataxia Telangiectasia

Ataxia telangiectasia is a rare autosomal recessive neurocutaneous disease characterized by combinations of telangiectasia of the skin and eye, cerebellar ataxia, various immune deficiencies, frequent sinus and pulmonary infections, and a predilection to develop malignancies. Linkage analysis has localized a gene for ataxia telangiectasia to chromosome region 11q22–11q23, but more than one gene locus may be present.336

Ataxia telangiectasia is classified with the “breakage syndromes,” which are diseases with a high frequency of chromosome breaks and rearrangement and an elevated risk of leukemia and other neoplasms. Cutaneous telangiectasias are most often first noted in the conjunctiva, then in the malar area, ears, palate, and across the bridge of the nose. The conjunctival telangiectasia is generally confined to the area of the palpebral fissure. Mottled hypopigmented and hyperpigmented skin regions may also be seen. The major neurological findings arise from characteristic progressive degeneration of the cerebellar cortex, which is readily demonstrable on neuroimaging. Progressive cerebellar ataxia usually develops by the time the affected child begins walking. In contrast, the telangiectatic lesions develop later, usually around 3–7 years of age. The ataxia is followed by progressive neurological deterioration that leaves the patients in a wheelchair. Dysarthria, choreoathetosis, myoclonic jerks, and endocrine abnormalities usually develop.

The characteristic ophthalmologic finding is bilateral bulbar conjunctival telangiectasis, which becomes apparent during childhood (Fig. 11.13). The telangiectatic conjunctival vessels are confined to the area of the palpebral fissure, have numerous sausage-shaped aneurysmal dilatations, and take frequent abrupt turns. Patients later develop abnormalities in ocular motility disturbances described as ocular motor apraxia, because of defective saccadic initiation. Head thrusts may be less conspicuous or absent, however. Nystagmus and other cerebellar eye signs may also be present. Some patients have developed periodic alternating nystagmus.847 In one prospective study of 58 patients with ataxia telangiectasia,292 strabismus was found in 38% (with esodeviation most common), apraxia of horizontal gaze was present in 30%, hypometric saccades were evident in 76%, pursuit abnormalities were present in 63%, and nystagmus was seen in 29%. Interestingly, accommodation was also deficient in the 54 patients in whom it was measured.

The most important neuropathologic abnormality in ataxia telangiectasia is cerebellar degeneration, with reduced number of Purkinje, granular, and basket cells in the cerebellar cortex, and neurons in the vermian and deep cerebellar nuclei. MR is the preferred neuroimaging modality and typically shows vermian atrophy with an enlarged fourth ventricle and cisterna magna.290 A lesser degree of cerebellar hemispheric atrophy may also be present (Fig. 11.13).290,777

Patients develop a variety of immunological abnormalities that include defective cellular and humoral immunity. The thymus is absent or rudimentary. Patients are prone to frequent sinopulmonary infections, skin infections, and T-cell lymphoproliferative disorders (lymphomas and leukemias). Persistent elevated levels of alpha fetoprotein are present in almost all patients.739 Pulmonary failure due to frequent infections and resulting bronchiectasis is the most common cause of death.

Aicardi et al4 described a slowly progressive syndrome that mimics ataxia telangiectasia by showing indistinguishable neurological signs (ocular motor apraxia, spinocerebellar degeneration, choreoathetosis) but with a later onset and with no associated telangiectasia or multisystemic involvement. They excluded other causes of supranuclear ophthalmoplegia, such as Gaucher disease, Niemann–Pick disease, and Huntington disease, by clinical features, family history and, when appropriate, by enzymatic and skin biopsy studies. They suggested that this syndrome represents an unusual form of spinocerebellar degeneration. These patients do not have head thrusts, but saccadic dysfunction and convergence abnormalities are common.467 Patients have slowly progressive ataxia and show cerebellar atrophy on neuroimaging. This condition is due to a mutation in MRE11, a gene also involved in the cellular repair response to double-stranded DNA breaks.136,467

Linear Nevus Sebaceous Syndrome

In 1963, Feuerstein and Mims described two patients with a neurocutaneous disorder consisting of the triad of a midline facial skin lesion (linear sebaceous nevus of Jadassohn), seizures, and mental retardation. Affected children display a nondermatomal linear pigmented nevus that is elevated and plaquelike in appearance and is present at birth (Fig. 11.14).304 Since its original description, numerous descriptions of associated ophthalmological findings have been reported,145,457,509 and its underlying brain malformation has been more clearly defined.167

Linear sebaceous nevus syndrome is now recognized as one of several “coloboma syndromes” with multisystem involvement. In addition to optic disc coloboma, a variety of other optic disc anomalies, including optic nerve hypoplasia457

and peripapillary staphyloma,145 may be present (Fig. 11.14). This syndrome should be included in the differential diagnosis of conjunctival and corneal dermoids, along with Goldenhar syndrome and encephalocranial lipomatosis (discussed later). Other ocular choristomas, such as choroidal osteoma, have also been described.509 A variety of ophthalmological findings have been noted, including lid colobomas, ptosis, and Coats disease.145 These children generally have severe neurological impairment, with seizures and severe mental retardation as the predominant neurological findings. Neuroimaging has shown that most of these children have hemimegalencephaly, which accounts for their poor neurological prognosis.167

Klippel–Trenauney–Weber Syndrome

Klippel–Trenauney–Weber syndrome is a rare congenital angiodysplasia consisting of cutaneous vascular malformations, varicosities, and boney and soft tissue hypertrophy of the involved parts that appear in childhood on the affected side (Fig. 11.15).146,638 Only one side of the body is usually affected, but occasionally, both sides are involved.638 The upper extremity is affected in 60% of cases, the lower extremity in 30%, and the head and trunk exclusively in the remaining 10%.638 While hypertrophy is the most common abnormality of bone and soft tissue, atrophy may also occur. This condition is inherited as an autosomal dominant trait with variable expressivity. Ocular and neurological abnormalities are more common when the cutaneous vascular malformations involve the face.146 According to Parsa,671 its pathophysiology is similar to that of Sturge–Weber syndrome. However, while only atrophy develops in Sturge–Weber syndrome, preferential involvement of the lower extremities (where gravity cannot assist in venous drainage) in Klippel– Trenauney–Weber syndrome, leads to elevation of tissue pressure, impedance of lymphatic flow, with secondary limb hypertrophy.

Unlike in Sturge–Weber, seizures, and mental retardation may occur but are infrequent. A number of intracranial vascular malformations, including leptomeningeal vascular malformations, AVMs, and aplasia of the internal carotid artery have been described.638 Hemimegalencephaly has also been described in several patients with Klippel–Trenauney– Weber syndrome.146,577 One child had ipsilateral facial hypertrophy and high myopia, suggesting an overgrowth syndrome involving both brain and eye.146

Neuro-ophthalmologic abnormalities in Klippel– Trenauney–Weber syndrome include optic disc anomalies, which include tilted disc with telangectatic vessels,638 optic nerve hypoplasia,715 optic nerve sheath meningioma840 and orbital optic nerve enlargement in the absence of visual

Fig. 11.14  Linear nevus sebaceous syndrome. (a) Elevated verrucous, pigmented, plaque-like lesions covering right side of the face in linear distribution. Note characteristic midline lesion on forehead. (b) Left optic disc demonstrating peripapillary excavation and temporal optic disc pallor. No macular structures are identifiable. (c) Hemimegalence­ phaly. T2-weighted axial MR image demonstrating enlargement of the posterior portion of right cerebral hemisphere, dilatation of occipital

horn of right lateral ventricle, and parieto-occipital cortical dysplasia, as evidenced by the increased signal intensity relative to contralateral hemisphere. (d) Right: T1-weighted coronal MR image through level of occipital horns, demonstrating enlargement of right hemisphere and lateral ventricle, with absence of posterior periventricular white matter. With permission from Brodsky et al133

dysfunction,356 Homer syndrome,638 ptosis,638 afferent pupillary defect638; strabismus,638 and nystagmus.146 Additional ophthalmological findings include conjunctival retinal and peripapillary choroidal varicosities (Fig. 11.15),121 choroidal angiomas, orbital varices iris colobomas, iris heterochromia,

strabismus, ptosis, and enophthalmos.146 Glaucoma occurs but with less frequency than in Sturge–Weber syndrome.356 Although this disorder shares cutaneous features with Sturge–Weber syndrome, the relationship, if any, between the two disorders is not known.