Causes of Optic Atrophy in Children

The prenatal visual system injury may exist as a spectrum ranging from optic nerve hypoplasia (signifying early gestational injury) to atrophy (signifying late gestational injury) (Fig. 4.5), with a mixture of atrophy and hypoplasia occurring with midgestational injuries (Fig. 4.6). This deve­ lopmental response to injury has been invoked to explain the pseudoglaucomatous cupping seen commonly in children with periventricular leukomalacia.401 The critical periods for developing hypoplasia vs. atrophy in response to prenatal injury have not been defined. The role of other factors, such as the nature of injury (e.g., ischemic vs. toxic) and its duration (acute vs. sustained), is also unclear.

Causes of Optic Atrophy in Children

Compressive/Infiltrative Intracranial Lesions

Bilateral optic atrophy diagnosed in the first 2 years of life is an ominous sign that may portend recurrent shunt dysfunction, in a hydrocephalic child, or anterior visual pathway compression from a congenital suprasellar tumor. These tumors include craniopharyngiomas, nonfunctional pituitary tumors, gliomas, meningiomas, arteriovenous malformations, aneurysms, metastatic tumors, and arachnoid cysts.

Rarely, optic atrophy is associated with suprasellar tumors of maldevelopmental origin, such as lipomas or lipodermoids,339 suprasellar aneurysms,382 or with ipsilateral compression, by an ectatic internal carotid artery.397 Bilateral band atrophy may be recognized when compression primarily involves the chiasm. Band atrophy is best detected with the red-free light on direct ophthalmoscopy, which shows selective loss of the nasal and temporal nerve fiber layer.369,683 Because the temporal nerve fiber layer is poorly visible on direct ophthalmoscopy, the selective absence of the nasal nerve fiber bundle relative to the superior and inferior nerve fiber bundles is used to establish the diagnosis. In the case of chiasmal compression, OCT measurement of the preoperative retinal nerve fiber layer thickness can be predictive of the degree of postoperative visual rehabilitation.766a

In addition to optic atrophy, children with congenital suprasellar tumors may display congenital nystagmus (from bilateral sensory visual loss), nystagmus simulating spasmus nutans, see-saw nystagmus, or signs of dorsal midbrain syndrome. Systemic examination may provide some clues to the diagnosis in the form of café au lait spots or signs of emaciation in children with suprasellar glioma, signs of hypopituitarism in craniopharyngioma, and an abnormally large head size in hydrocephalus. Ipsilateral proptosis in a child with unilateral optic atrophy is highly suggestive of orbital optic glioma.

The finding of nystagmus in an older child with bilateral optic atrophy is an important diagnostic sign that confirms that visual loss was present in the first 2 years of life. A suprasellar lesion should be excluded in this setting. Unilateral optic nerve compression generally presents with proptosis or sensory esotropia in the preschool years. Optic tract lesions (compressive or otherwise) produce homonymous hemianopia with contralateral band atrophy, but no associated nystagmus. Noncompressive retrogeniculate lesions that are congenital in origin can also produce this constellation of findings. For example, arteriovenous malformations, including those involving the vein of Galen, can present with band atrophy in combination with homonymous hemianopia.432 Macular thickness measurements using optical coherence tomography may prove useful in the evaluation of the amount of ganglion cell loss in patients with band atrophy.584

In compressive lesions of the anterior visual pathways, the degree of optic atrophy is a good predictive sign of the potential restoration of vision following neurosurgical decompression.

Patients with neurofibromatosis type 1 have a predilection to develop CNS astrocytomas and to show a frequency of optic pathway gliomas of about 15%510 (Fig. 4.7). Most of these tumors are asymptomatic, with visual impairment in only about 20% of affected individuals. The frequency of neurofibromatosis type 1 in patients with optic pathway glioma varies in different series, from 10 to 70%. About onehalf of the tumors are intraorbital and the other half are intracranial. Café au lait spots are often absent or less conspicuous in young children. In patients with neurofibromatosis type 1, optic glioma is

Optic Glioma

Optic glioma is largely a tumor of childhood, with a mean age at presentation of 9 years (range: birth to old age).223 No gender predilection appears to exist. Seventy-five percent of cases present during the first decade of life, and 90% present during the first two decades.

Fig. 4.7  Optic nerve glioma in neurofibromatosis. Left: Bilateral optic glioma in child with NF1. Axial MR image shows characteristic fusiform enlargement of left right optic disc and kiniking of left optic disc. Area of high signal intensity (corresponding to perineural arachnoidal gliomatosis) surrounds core of low signal intensity (optic nerve). Used with permission from Seiff et al782. Right: Sagittal oblique MR shows characteristic fusiform enlargement and superior kinking of the nerve in another child with NF1. Area of high signal intensity (corresponding to perineural arachnoidal gliomatosis) surrounds core of low signal intensity (optic nerve). Used with permission from Brodsky95

more often multifocal, occasionally affecting both optic nerves without apparent connection at the chiasm.223

Optic pathway glioma may exist in the absence of anterior visual pathway dysfunction. The absence of optic atrophy or papilledema, therefore, does not rule out chiasmal glioma in the child with neurofibromatosis. Lewis et al504 reviewed the ocular and intracranial features of neurofibromatosis in 217 patients, 15% of whom had tumors of the anterior visual pathways. In two-thirds of these, the tumors were not detected by ophthalmologic examination, underscoring the importance of neuroimaging studies in these patients.

Due to the heterogeneity of optic pathway gliomas and their varying locations along the anterior visual pathway, a variety of clinical presentations have been noted. However, regardless of the location, most patients eventually develop some degree of visual loss. The visual loss is usually due to astrocytic proliferation, separation of longitudinal axonal bundles, axonal compression with subsequent demyelination, and mechanical disruption of axons.303 There is generally poor correlation between tumor growth and visual acuity.373

Optic nerve tumors commonly present as orbital mass lesions with axial proptosis, painless unilateral proptosis associated with disc edema, neoplastic infiltration of the disc, or optic atrophy. Optic atrophy is eventually noted in most, if not all, cases.

Rarely, a congenital suprasellar glioma may be associated with optic disc dysplasia.846 An afferent pupillary defect is usually noted in unilateral or asymmetric cases. Visual field examination usually reveals a central scotoma or, with chiasmal involvement, temporal field defects. Temporal field defects are associated with loss of ganglion cells and nerve fiber layer nasal to the fovea. Optic atrophy is thus noted on the nasal and temporal sides of the disc in the classic “band” or “bowtie” distribution (Fig. 4.1). Proptosis is generally absent in chiasmal and hypothalamic tumors.

Chiasmal gliomas usually present in childhood, with unilateral or bilateral (often asymmetric) optic atrophy and visual loss. Hypothalamic or endocrine dysfunction from hypothalamic involvement is also frequently present. This includes precocious puberty, obesity, panhypopituitarism, and dwarfism. Children with early invasion of the hypothalamus, present within the first several years of life with the diencephalic syndrome. Less commonly, hydrocephalus, seizures, cerebrospinal fluid (CSF) rhinorrhea, increased CSF protein, and tumor cells in the CSF have been reported with chiasmal gliomas. Occasionally, untreated patients with chiasmal gliomas may show spontaneous visual improvement despite the absence of tumor shrinkage on neuroimaging studies.512 If the chiasmal lesion expands to involve the nearby third ventricle, obstructive hydrocephalus may result. Spasmus nutans may occur, which may be distinguishable clinically from the benign variety by the presence of an afferent pupillary defect and/or optic atrophy. See saw nystagmus may also occur.

Previously, plain skull X-rays show classic enlargement of the optic foramen and a J-shaped sella turcica. Computed tomography (CT) shows isodense enlargement of the optic nerve or chiasm, with variable enhancement. Fusiform enlargement of the optic nerve is characteristic. MR studies are now obtained in young children, in order to avoid exposure to ionizing radiation, and may be superior for imaging the intracanalicular and intracranial spaces.393

Optic nerve gliomas arise from astrocytes surrounding optic nerve axons. Histopathology of optic glioma usually reveals juvenile pilocytic astrocytoma with a benign cytologic appearance although mixed and malignant cases occur. An exuberant reactive proliferation of the surrounding meningeal tissues (termed arachnoidal gliomatosis) may accompany those gliomas associated with neurofibromatosis, occasionally causing diagnostic confusion with optic nerve sheath meningioma (Fig. 4.7). In addition to neoplastic growth and arachnoidal gliomatosis, the tumor mass may show enlargement as a result of intralesional hemorrhage, cyst formation, or accumulation of extracellular Periodic Acid Shiff (PAS)- positive mucosubstance secreted by the glial cell.223 The malignant form of glioma occurs primarily in adults.

Alvord and Lofton23 extensively reviewed the topic of optic glioma. In a review of optic pathway gliomas in neurofibromatosis type 1, Hoyt and Imes375 concluded that “It is agreed that the main bulk of an optic pathway glioma is a low grade neoplasm with unpredictable growth potential. It is not possible to demonstrate clear histological differences between tumors with limited growth and tumors that will grow.”

Because most gliomas are benign and enlarge slowly, affected children generally show long-term survival,375 and treatment is controversial. Surgical amputation is considered when there is disfiguring proptosis in a blind eye. When the tumor is confined to the optic nerve, complete surgical excision with clear margin is curative, but many such children have sufficiently useful vision to suggest that conservative management with simple observation is a viable option. Removal or debulking of the orbital portion of the glioma is usually possible while leaving the globe in place. In this situation, the orbital portion of the tumor can be resected without adverse effect, even when the tumor involves the intracranial optic nerves or chiasm.

In 1980, Stern and colleagues823 reviewed the histopathologic results of 34 tissue specimens from orbital optic gliomas. In 17 of 18 gliomas from patients with neurofibromatosis, a circumferential perineural pattern of growth in the subarachnoid space with minimal involvement of the intraneural compartment was found. They termed this pattern arachnoidal gliomatosis to signify that there was a marked proliferation of astrocytes over meningoepithelial cells and fibroblasts. In 14 of 16 gliomas from patients without neurofibromatosis, astrocytic proliferation was strictly intraneural with intact pial boundaries. The authors concluded that the perineural pattern of astrocytic proliferation was highly characteristic of neurofibromatosis-associated gliomas.

Magnetic resonance imaging can often predict tumor histopathology in vivo, since gliomatosis tissue has a long T1 and T2 relaxation time due to its high water content, causing it to appear bright on T2-weighted images and dark on T1-weighted images. Because gliomatosis tissue is primarily perineural (confined to the subarachnoid space surrounding the optic nerve) in neurofibromatosis, MR imaging imparts a double signal to the contents of the expanded dural sheath, with an outer signal that is indistinguishable from CSF and a sharply demarcated inner signal corresponding to the optic nerve (Fig. 4.7). The peripheral CSF intensity signal in orbital optic glioma correlates with the histopathological finding of peripheral arachnoidal gliomatosis and serves as a neuroimaging marker for neurofibromatosis.95,782

When the tumor involves the optic chiasm, the overall prognosis for life diminishes due to hypothalamic or third ventricular involvement. Surgical intervention at this point does not appear to improve survival. Neurosurgical debulking of the tumor and/or ventriculoperotineal shunting procedures are necessary in children with large diencephalic tumors that produce obstructive hydrocephalus. The efficacy of radiation and chemotherapy in these tumors is a subject of debate. Any potential benefit of radiation should be weighed against the potential risks of irradiation to the developing brain. Reported complications after cranial irradiation in children include volume loss and atrophy of normal brain parenchyma, progressive calcification, white matter abnormalities,189,264 abnormalities in behavior, cognitive dysfunction, hypothalamic–pituitary dysfunction, growth retardation, acute lymphoblastic leukemia and other neoplasms,731 visual loss, ocular motor nerve palsy, neuromyotonia, and Moyamoya syndrome.646

Following surgical resection of an orbital optic glioma, several poorly understood phenomena may be observed. Ophthalmoscopic examination and fluorescein angiography may show a normal central retinal arterial circulation,502 and CT scanning and MR imaging may show an optic nerve-like structure that is normal in size and configuration (termed the “phantom” optic nerve).99,793

As detailed in Chap. 11, many optic gliomas have been reported to undergo spontaneous regression.665

Craniopharyngioma

Craniopharyngioma is by far the most common supratentorial tumor as well as the most common nonglial intracranial tumor of childhood. It affects primarily children and young adults, but the age range extends from the neonatal period to the eighth decade of life.148 Craniopharyngioma is a histologically benign epithelial neoplasm thought to arise from epithelial vestiges found at the junction of the lower infundibular stem and the pars distalis. These tumors bear resemblance to

Rathke's pouch cysts and epidermoid cysts of the region, and the three tumors may be related. They frequently exhibit invasive, aggressive local growth. Despite the histological appearance of craniopharyngioma, its intimate association with the visual apparatus, the hypothalamus, and the ventricular system frequently predisposes children with these tumors to anterior visual pathway compression and endocrine dysfunction.921 Children often develop signs and symptoms of increased intracranial pressure and dysfunction of the hypothalamic–pituitary axis, manifesting as growth failure, delayed sexual development, infantilism, obesity, diabetes insipidus, disturbances in heat regulation, thalamic crises characterized by spontaneous pain, and vasomotor disturbances.47,57,118,190,546,956 Rarely, precocious puberty occurs.

These tumors grow slowly and rarely present before 3–4 years of age. Craniopharyngioma is a particularly devastating tumor with respect to its long-term effects on the visual system. Most patients are admitted with visual problems as their presenting complaint.763 Children with craniopharyngioma develop gradual, progressive visual loss from compression of one or both optic nerves, chiasm, tract or, less commonly, as a result of chronic papilledema. Occasionally, visual loss may be rapid, and the child may be thought to have retrobulbar neuritis. It is not unusual for children with craniopharyngioma to complain of nonspecific symptoms and be assigned the diagnosis of psychogenic visual loss prior to the developing optic atrophy.576 The diagnostic goal is to detect neuro-ophthalmologic signs of craniopharyngioma before permanent injury to the visual system whenever possible. Therefore, in the examination of the preschool child with headaches, short stature, decreased visual acuity, diminished stereopsis, or symptoms of hemifield slide (described by young children as objects disappearing or suddenly appearing where they do not belong), or postfixational blindness (described as objects disappearing in the distance),926 we carefully examine pupil size (to look for increased diameter, afferent papillary defect, or light-near dissociation),270 color vision to look for dyschromatopsia, which is an early sign of compression, and confrontation visual fields to look for bitemporal desaturation. In our experience, Hand–Hardy–Rittler plates provide better sensitivity to acquired dyschromatopsia than Ishihara color plates. Difficulty with depth perception is often described in patients with chiasmal lesions, and diminished stereopsis has been shown to be a sensitive, albeit nonspecific, indicator of chiasmal dysfunction.362

Unfortunately, many children with craniopharyngioma already have profound optic atrophy by the time they are examined.3,576 Optic atrophy may occur consequent to compression by the tumor, surgical resection, or radiation therapy.260,332 In one series, optic atrophy developed in 81% of eyes.3,546 Poorer visual outcome was seen in children who were less than 6 years of age at presentation. Another recent

study found ophthalmological problems in 96% of children at the time of diagnosis, with decreased acuity in 51%, strabismus in 27.6%, papilledema in 34.4%, and optic atrophy in 37.9%.195 Band atrophy is best detected with direct ophthalmoscopy, which shows selective loss of the nasal and temporal nerve fiber layer. Because the temporal nerve fiber layer is poorly visible on direct ophthalmoscopy, the selective absence of the nasal nerve fiber bundle relative to the superior and inferior nerve fiber bundles is used to establish the diagnosis, which can now be confirmed by OCT.584 Papilledema, secon­ dary to extension of the tumor into the third ventricle, may also occur in children and young adults with craniopharyngioma. Other presentations include see-saw nystagmus from compression of the mesencephalon and the interstitial nucleus of Cajal,450 sensory exotropia,3 and excessive tearing.915

The rare association of anomalous optic discs with craniopharyngioma and other congenital suprasellar tumors846 is attributed to the tumor’s proximity to the anterior visual pathways and its potential for disrupting optic axonal migration during embryogenesis. Associated signs include hypopituitarism (e.g., short stature, retarded sexual development, obesity, infantilism) and signs of hypothalamic involvement (e.g., thermolability), which are much more common after treatment. Diabetes insipidus is rare as a presenting sign, but it commonly develops following tumor resection.

Craniopharyngiomas are uniformly located, at least partially, in the suprasellar cistern. The symptoms and signs produced depend on the age of the patient, the size of the tumor, the direction of its growth, and the location of the optic chiasm (i.e., prefixed, fixed, and postfixed). The location of the chiasm determines whether the tumor compresses the optic nerves, the anterior chiasm (junctional syndrome), the chiasm, or the optic tract, each with its attendant visual consequences. The tumor may project into the third ventricle, causing hydrocephalus. Although craniopharyngioma usually occupies the suprasellar cistern in location, it may rarely originate beneath the sella, within the third ventricle, or even within the chiasm.100 Posterior extension of the tumor may compress the ventral brainstem and cerebellum. CT scanning often shows a lesion that is calcified, cystic, and suprasellar (Fig. 4.8).109,119 In the absence of calcification, however, the tumor can be isodense with CSF and easily go unrecognized unless the suprasellar cistern is enlarged and its normal pentagonal shape is distorted.915 On MR imaging, signal characteristics of craniopharyngioma may vary depending on the tumor composition, with high signal intensity on T1-weighted images correlating with high cholesterol content or the presence of methemoglobin, and low signal intensity on T1or T2-weighted images, correlating with a bony trabecular network (Fig. 4.8).233,696

Fig. 4.8  Craniopharyngioma. (a) Axial CT scan shows low density suprasellar mass with calcification. (b) Coronal MR image of the same lesion shows an inhomogenous signal, reflecting both solid and cystic

components of the suprasellar mass. The calcification cannot be directly demonstrated on MR images

Craniopharyngioma is a congenital tumor that may be solid, cystic, or both. The cyst is often filled with fluid that resembles machine oil, but the fluid may be straw colored. The fluid contains cholesterol crystals. Characteristic calcification within the tumor is readily demonstrated with plain skull films. CT is excellent for demonstrating the characteristic areas of calcification and cyst formation. On MR imaging, the calcification can be indirectly inferred (Fig. 4.8).

The treatment of craniopharyngioma remains somewhat controversial. Surgical resection remains the treatment of choice for craniopharyngioma, but the issue of whether to attempt complete removal, with its potential morbidity and mortality or subtotal resection followed by radiotherapy, is not completely resolved. In a clinicopathological analysis of 56 patients operated on for craniopharyngioma, Weiner et al921 found that gross total resection was associated with a lower recurrence rate (17%) than subtotal resection with or without radiation therapy (58%). In this study, the histopathological subtype did not significantly influence the surgical outcome. Some tumors are extremely difficult to eradicate because of their adherence to the optic nerves, hypothalamus, and the vessels of the circle of Willis, necessitating local irradiation therapy. Interstitial irradiation (interstitial brachytherapy) is an additional option.892

Many patients enjoy a significant return of vision after treatment. Repka and colleagues717 assessed 30 patients with craniopharyngioma preoperatively and postoperatively to evaluate the degree of visual recovery. At the time of presentation, visual acuity was reduced in 42% of eyes; 20% of eyes had normal visual fields. One week postoperatively, acuity was reduced in 23% of eyes; 48% of eyes had normal fields, with a slight decrease to 44% on long-term follow-up. Patients with visual defects that were present after the first postoperative month showed no long-term improvement in acuity or field. Stark et al820 described a 9-year-old girl who recovered from no light perception vision to 20/25 in the right eye after subtotal surgical resection. The diagnosis of craniopharyngioma should be considered in patients with psychogenic visual loss and in those with amblyopia, particularly when no amblyogenic factors, such as anisometropia or strabismus, are present.3

The differential diagnosis of craniopharyngioma in children includes meningioma, pituitary adenoma, 595 dysgerminoma, Rathke's pouch cyst, and suprasellar epidermoid cyst.

Uncommon Compressive Lesions Causing Optic

Atrophy in Children

Pituitary adenoma is uncommon in childhood and adolescence.266a,489a,919a Most pediatric pituitary adenomas present after the onset of puberty with frequent headaches, changes in visual acuity, and, in girls, menstrual dysfunction.

Similarly to adults, 70% of children have evidence of pituitary hypersecretion at presentation,721 with prolactinomas being most common.266a,489a,919a A common presenting complaint is failure of sexual maturation. Pituitary adenomas in the prepubertal period may be more likely to exhibit extrasellar extension or invasiveness.266a,489a,919a Visual symptoms and signs may appear less commonly in children than in adults with pituitary adenomas. In a series of 25 children with pituitary adenomas,266a three showed optic atrophy, with two of these having visual failure as a part of the presenting symptoms. Pituitary apoplexy has been reported in children.688,787,833

Optic nerve sheath meningioma is rare in children.182,490

The diagnosis is suggested by the triad of optociliary shunt vessels, optic atrophy, and visual loss although this triad may less commonly be encountered in optic nerve glioma.576 Other features, common to both glioma and sheath meningioma, include proptosis, afferent pupillary defect, strabismus, limitations of eye movements, and visual field defects.404 These overlapping features and the purported rarity of optic nerve sheath meningioma in children may lead to diagnostic confusion with optic nerve glioma. The presence of optociliary shunt vessels may be a helpful diagnostic sign; they were present in only 1 of 22 patients with optic nerve glioma, but were identified in 10 of 47 patients with nerve sheath meningioma in one series.404

Neuroimaging findings may help differentiate optic nerve glioma from sheath meningioma. CT scans of orbital gliomas reveal fusiform enlargement and kinking of the optic nerve, with erosion and enlargement of the optic canal. The CT scans of meningiomas reveal diffuse enlargement, shaggy borders, frequent calcification, and hyperostotic thickening of the optic canalicular bone along with intraorbital “railroad tract sign” on axial images, representing abnormal enhancement of the periphery of the nerve. Gadolinium-enhanced MR may be particularly suited to delineate the extent of intracranial involvement of nerve sheath meningioma.960 In equivocal cases, a direct biopsy may be needed to establish the diagnosis. It is important to biopsy both the sheaths and the nerve itself to avoid a false-positive diagnosis on the basis of finding arachnoid hyperplasia that may surround a glioma, imparting a histological appearance of a meningioma.

It is particularly important to establish the correct diagnosis of optic nerve sheath meningioma in children, as many authors consider this lesion to be more aggressive in children than in adults.182,490,941,942 There is some evidence that the childhood tumors have a higher propensity to show intracranial, intraneural, intraorbital, and intraocular spread than their adult counterparts. The treatment of optic nerve sheath meningioma is controversial.182

Dysgerminoma should be suspected in a child who presents with diabetes insipidus and who is found to have bitemporal hemianopia. With the exception of histiocytosis X, it is rare for children with other compressive lesions in this location

to present with diabetes insipidus. These usually solid tumors show similar histological features to pinealomas, but present in the perichiasmatic region. They occur in the first or second decade of life and may present with diabetes insipidus, visual loss, visual field defects, optic atrophy, or pituitary dysfunction. Similar lesions may be a part of the trilateral retinoblastoma syndrome. Suprasellar germinomas are divided equally between the sexes, unlike those in the pineal location, of which about 90% are in boys. Dermoids, epidermoids, and hamartomas are more uncommon and constitute the bulk of the remaining suprasellar masses.

Osteopetrosis is an inherited metabolic bone disease characterized by a generalized increase in bone density due to reduction in osteoclast function. The disease is associated with narrowing of the foramina of the base of the skull, with resultant compressive neuropathy. Visual loss may arise from either optic nerve or retinal dysfunction. Optic atrophy may result secondarily either from papilledema or from compressive neuropathy due to narrowing of the optic foramen.335,371 Visual loss with optic atrophy may occasionally be the presenting symptom.655 Optic nerve decompression may result in stabilization or even improvement of vision.556 It is important to perform electroretinography to exclude an associated retinal degeneration before undertaking optic nerve decompression.371,655

Craniosynostoses (e.g., Crouzon syndrome, Pfeiffer syndrome, Apert syndrome, plagiocephaly) are not uncommonly associated with visual failure due to optic atrophy.43,323,614 One retrospective study found optic atrophy in 16.7% of patients with craniosynostosis,845 whereas others have found optic atrophy in 7% with Crouzon disease315 and 5% of patients with Apert syndrome.442 The pathogenesis of optic atrophy in craniosynostosis may be related to (1) increased intracranial pressure and papilledema, (2) kinking and stretching of the optic nerve due to abnormal cranial and brain growth, (3) narrowed optic canals, or (4) a complication of craniofacial surgery.111 Papilledema may occur in otherwise asymptomatic patients.54,188 One study found that a 40% prevalence of visual loss from a combination of optic atrophy ametropia, exposure keratitis, and strabismic and anisometropic amblyopia continues to complicate this condition.845 When present, papilledema resolves after decompressive craniofacial surgery.682 Over the past decade, mutations in the fibroblast growth factor receptors (FGFR 1,2, and 3) genes, the TWIST gene, and the EFNB1 gene have been identified in craniosynostotic syndromes.597,882

Premature fusion of cranial sutures is commonly associated with optic atrophy in GAPO syndrome.769,773,912 GAPO is an acronym for the manifestations of growth retardation, alopecia, pseudoanodontia, and progressive optic atrophy.391,596 It is a rare autosomal recessive disorder that also shows a peculiar geriatric facial appearance, short stature resembling rhizomelic dwarfism, muscular habitus, and a large fontanel

in infancy. The hair is lost within the first few years of life, and the teeth are normal, but unerupted. Aside from progressive alopecia, these children may develop growth and mental retardation, large fontanelles, a puffy face, and swollen eyelids.493 As these findings are also seen in hypothyroidism, thyroid status should be examined in these children.493 Optic atrophy has been reported in 30% of affected children. The nature of the optic atrophy is unclear, with possible contributions from concurrent glaucoma or intracranial hypertension.588 Patients appear to have a shortened life expectancy, with death occurring in midlife. Craniodiaphysial dysplasia is another rare sclerosing bone disorder that is due to modeling errors of the long bones and the skull bones. Patients display widening and flattening of the nasal bridge, malformation of nasal cartilage, hypertelorism, and enlargement of the skull.106 Optic atrophy can result from narrowing of the optic canals due to sphenoidal boney overgrowth.447

Fibrous dysplasia is an abnormal fibro-osseous disorder of bone of unknown etiology. The disorder is considered to be a maturational arrest at the woven bone stage, with abnormal development of bony tissue, resulting in fibrous tissue proliferation and defective osteogenesis. Normal bone is gradually replaced with fibrous tissue. The process occurs primarily during childhood, but may continue into adulthood. Histological analysis shows areas of fibrous tissue interwoven with newly formed bone.585 The disorder most commonly involves a single bone (monostotic), but it may be disseminated throughout the body (polyostotic). Polyostotic fibrous dysplasia occurs in association with café au lait spots and precocious puberty in girls with Albright syndrome.

In most patients, the lesions in fibrous dysplasia grow slowly and then stabilize in early adulthood. The most commonly affected calvarial bone is the frontal bone, then the sphenoid, temporal, parietal, and occipital bones, in that order. The most common presentation is a painless enlargement of the involved bone, causing facial asymmetry, orbital dystopia, or unilateral proptosis.703 Involvement of the bones at the base of the skull may cause narrowing of the neural foramina with compression of cranial nerves, causing hearing loss, tinnitus, and cranial nerve palsies. If the disorder affects the lesser wing of the sphenoid bone, the optic canal may become narrowed, with compression of the optic nerve and subsequent optic atrophy.585,686 Initially, such patients may be misdiagnosed as having retrobulbar optic neuritis, with the correct diagnosis subsequently suggested by neuroimaging studies obtained when spontaneous visual improvement fails to occur.922 Involvement of the sella turcica may compress the optic chiasm, leading to chiasmal syndrome and optic atrophy.928 Trigeminal neuralgia and increased intracranial pressure have also been described. Prompt surgical decompression of the optic canal in patients with compressive neuropathy may restore some optic nerve function and halt progression of the optic atrophy.703 Other rare causes