Syndromes with Neuro-Ophthalmologic Overlap

Cerebroretinal Vasculopathies

Rare disorders produce a combination of cerebrovascular retinopathy and systemic angiopathy in children.248 Vahedi et al897 recently described a syndrome of hereditary infantile hemiparesis, retinal arteriolar tortuosity and leukoencephalopathy associated with dilated perivascular spaces. Three patients also had migraine with aura.

Conrath et al198 described an 11-year-old child with digestive tract and renal small-vessel hyalinosis, idiopathic nonarteriorsclerotic intracerebral calcifications, retinal ischemic syndrome, and phenotypic abnormalities. All four reported patients manifested kidney failure due to glomerular endothelial cell alterations and mesangiolysis.198

The autosomal dominant retinal vasculopathies with cerebral leukodystrophy, which generally present in adulthood.737 include cerebroretinal vasculopathy,364,878 hereditary vascular retinopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) Unlike in Leber hereditary optic neuropathy, the (juxtafoveal, in this case) retinal telangiectasias that characterize this condition are not present in childhood and therefore cannot be used to predict that a given child in an affected kindred will be affected in adulthood.

Syndromes with Neuro-Ophthalmologic Overlap

Proteus Syndrome

Proteus syndrome is a rare disorder associated with multiple irregular areas of patchy tissue overgrowth involving multiple tissues and cell lineages.83 Clinical manifestations include hyperostosis (usually near the epiphyses) and impaired mobility. Hyperplastic connective tissue nevi often involve the palms and soles, producing deep grooves and a cobblestone or “cerebriform” “appearance.”83 Multiple lipomas in the abdomen and pelvis may be accompanied by a paradoxical lipoatrophy.83 Proteus syndrome is not heritary and is believed to be caused by a postzygotic somatic mutation in a gene that is lethal in the nonmosaic state.83 Its differential diagnosis includes Klippel–Trenauney–Weber syndrome, hemihyperplasia, Parkes Weber syndrome, Maffuci syndrome, NF1, linear sebaceous nevus syndrome, Bannayan Riley Ruvalcaba syndrome, and familial or symmetric lipomatosis.84

In an older child with cutaneous manifestations of NF1, the absence of Lisch nodules raises the rare possibility of Proteus syndrome, which can also produce skeletal, vis-

ceral, and cutaneous abnormalities.105 The macrocephaly, hemihypertrophy, and cutaneous tumors of Proteus syndrome can simulate neurofibromatosis, but children with Proteus syndrome lack the other neuro-ophthalmologic manifestations of neurofibromatosis.83,105 Periorbital exostosis, epibulbar tumors, and “eye enlargement” are considered to be the most characteristic ophthalmologic signs in Proteus syndrome,105 but cataract, vitreous abnormalities, myopia, and a large retinochoroidal mass have also been described.812 Long-term systemic complications that include progressive skeletal deformities, invasive lipomas, benign and malignant tumors, deep venous thrombosis, and pulmonary embolism.83

PHACE Syndrome

The PHACE syndrome is a neurocutaneous syndrome that includes the following primary features: (posterior fossa malformations, facial hemangioma, arterial cerebrovascular anomalies, cardiovascular anomalies, and eye anomalies).316,592 It occurs almost exclusively in girls.316 Several recent reports have documented the association of PHACE syndrome with excavated optic disc anomalies, most notably the morning glory disc anomaly (Fig. 2.14).400,473,478 The orofacial hemangiomas seen in PHACE syndrome are characteristically large, segmental, and plaquelike.316,592 In addition to a variety of structural cardiac abnormalities and aortic coarctation, ventral developmental defects such as sternal pits, sternal clefting, and supra-abdominal raphe are common.316,592

A spectrum of posterior fossa lesions, ranging from focal cerebellar hypoplasia with or without arachnoid cyst to the Dandy–Walker complex, have been described.392 Focal dysplasia of the cerebral cortex, including pachygyria, polymicrogyria, thickening of the cerebral cortex, heterotopic gray matter, and cerebral volume loss (all occurring in the hemisphere ipsilateral to the hemangioma) is less commonly seen.392 Children with PHACE syndrome often have progressive ipsilateral stenosis, most often involving the carotid circulation, leading to cerebral infarction.148 These patients have been reported to benefit from preemptive cranial revascularization procedures.392

Goldenhar Syndrome

(Oculoauriculovertebral Dysplasia)

The Goldenhar syndrome comprises a complex of hemifacial microsomia, preauricular appendages, auricular abnormalities, vertebral anomalies, and epibulbar dermoids.567

Patients with Goldenhar syndrome show a phenotypic spectrum ranging from mild facial asymmetry to severe hypoplasia of one side of the face with ipsilateral macrostoma.390,570 As a minimal sign, microtia must be present.791 Auricular abnormalities are usually unilateral and, in addition to microtia, may include malpositioning of the ear and hypoplasia of the external auditory canal, with or without hearing loss.622 Additional features are cardiac and renal anomalies, cleft lip/palate, and CNS, cervical, and radial limb anomalies.791 Colobomas and focal upper lid defects may also be present. The eye on the involved side may be microphthalmic or anophthalmic in severe cases. Gorlin et al359 now use the term oculo-auriculo-vertebral spectrum (OAVS) because of the extreme heterogeny of the condition. This nonhereditary spectrum affects males more than females, and right-sided involvement is more common and more severe.749

Neuro-ophthalmologic abnormalities include unilateral or bilateral fourth nerve palsy, congenital corneal anesthesia,612 unilateral and bilateral Duane syndrome,10,567 sixth nerve palsy,390 optic nerve hypoplasia and coloboma on the affected side,570 and ptosis.68 Amblyopia may also result from associated strabismus or anisometropia.390 The association of Goldenhar syndrome with predominantly ipsilateral cranial nerve palsies is explained by the occurrence of aplasia of the cranial nerve nuclei in this condition. Intelligence is usually normal, but mental retardation is more likely to be present in severe cases that are associated with ipsilateral microphthalmia or anophthalmia.570

Goldenhar syndrome may be associated with a broad array of CNS abnormalities, including hydrocephalus, Arnold–Chiari malformation, unilateral arhinencephaly, occipital and frontal encephalocele, intracranial arachnoid cyst, intracranial lipoma, holoprosencephaly, callosal hypoplasia, lissencephaly, and intracranial lipoma.791 An intracranial dermoid cyst has also been reported in a patient with Goldenhar syndrome.622 Various bony defects may also be present, including microcephaly, cranial asymmetry, platybasia, hypoplasia of the petrous and ethmoid bones, and absence of the internal auditory canals.791,946

The Wildervanck (cervico-oculo-acoustic) syndrome may be difficult to distinguish from the Goldenhar syndrome. It consists of sensorineural deafness, Klippel–Feil anomaly, and Duane syndrome (Fig. 11.32). Wildervanck syndrome is much more common in girls than in boys.127 As Duane syndrome is much more common in the Wildervanck than in the Goldenhar syndrome, its presence necessitates a search for the associated Klippel–Feil anomaly.69,209 Because many patients have overlapping features, the syndromes of Goldenhar and Wildervanck may represent different ends of a spectrum.209

Delleman (Oculocerebrocutaneous)

Syndrome

In 1981, Delleman and Oorthuys235 described two children with multiple intracranial cysts, orbital cysts, agenesis of the corpus callosum, periorbital skin appendages, punchlike skin defects, and skin atrophy or hypoplasia (Fig. 11.33). Numerous cases have since been described as the Delleman, or oculocerebrocutaneous, syndrome. Additional anomalies in this condition include seizures, generalized asymmetry, skull defects, rib anomalies, and mental retardation.11,947 Unilateral anophthalmos with ipsilateral orbital hypoplasia and hypoplasia of the corresponding intracranial optic nerve may also be seen.129 In some children, the clinical features of Delleman syndrome overlap those of Goldenhar spectrum, making the clinical distinction between these two entities difficult.129

Encephalocraniocutaneous Lipomatosis

Encephalocraniocutaneous lipomatosis is a rare neurocutaneous syndrome characterized by lipomas of the cranium and CNS, alopecia of the scalp, and a broad range of CNS abnormalities, including unilateral intracranial cysts, cerebral migration anomalies, and cortical atrophy.480,546 Affected children have seizures, spasticity, and mental retardation. Epibulbar choristomas and small skin nodules are the most common ophthalmologic manifestations, but neuro-ophthalmologic findings including papilledema and optic disc pallor have also been reported.480 Encephalocraniocutaneous lipomatosis should be considered, along with Goldenhar syndrome and linear sebaceous nevus syndrome in the differential diagnosis of conditions with epibulbar choristomas.480

Incontinentia Pigmenti

(Bloch–Sulzberger Syndrome)

Incontinentia pigmenti is a rare neurocutaneous disease that affects the skin, bones, teeth, CNS, and eyes. Its almost exclusive occurrence in females is attributed to an X-linked dominant mutation that is lethal in males. Linear lesions appear at birth or soon afterward. These lesions subsequently resolve to leave a linear pattern of pigmentation. Retinal abnormalities most commonly involve the temporal equator and include vascular dilation, arteriovenous anastamosis, preretinal fibrosis, vascular proliferation, and nonperfusion of the retina temporal to the vascular abnormalities.332 These vascular changes, which resemble those of retinopathy of prematurity and sickle

Fig. 11.32  Wildervanck syndrome. (a) Facial photograph showing minimal esotropia in primary gaze. (b) Secondary positions of gaze showing bilateral Duane syndrome. (c) Sagittal MR image demonstrating

diffuse hypoplasia of pons and medulla. (d) Parasagittal MR imaging demonstrating foreshortening of neck and severe thoracic kyphosis. With permission from Brodsky et al127

cell disease, may lead to retinal detachment. Dragging of the retinal vessels, macular heterotopia, retinal folds, foveal hypoplasia, and retinal pigment epithelium mottling may also occur.332,350 Other ophthalmologic abnormalities may include cataract, optic atrophy, retinal dysplasia, a retrolental mass (termed pseudoglioma) secondary to extensive retinal detachment, nystagmus, and esotropia.753

Pascual-Castroviejo et al677 found MR abnormalities, including focal atrophy of the cerebrum, cerebellum, and hypoplasia of the corpus callosum, in four of eight patients with

incontinentia pigmentia. The MR abnormalities were seen only in patients who had neurological abnormalities. The CNS manifestations in incontinentia pigmenti may be ischemic in origin secondary to intracranial small vessel disease.516 Lee et al516 found the severity of retinal vascular occlusions to correlate with the degree of CNS involvement on MR imaging and suggested that retinal vascular occlusions may eventually prove to be a marker for CNS disease. The finding of optic atrophy in some children with incontinentia pigmentia may also reflect ischemic white matter injury.350