Unilateral buphthalmos may be the mode of presentation to the ophthalmologist of a patient with neurofibromatosis.'-5 The most common clinical setting in which buphthalmos is seen in association with neurofibromatosis has been referred to as the Francois syndrome.3'4 The syndrome is comprised of the triad of unilateral buphthalmos and hydrophthalmos, homolateral plexiform neuroma of the eyelid, and homolateral facial hemihypertrophy. The underlying cause of the buphthalmos has been ascribed to glaucoma since association with neurofibromatosis is almost always unilateral, and is thought to be secondary to obstruction of aqueous outflow by neurofibromatous tissue or as the result of congenital anomalies of the iridocorneal angle associated with neurofibromatosis.6 The possibility that the enlargement of the globe in neurofibromatosis might be due to factors other than ocular hypertension has received little attention although cases of buphthalmos with normal intraocular pressures have been reported.7,8
In this paper we document a case of buphthalmos and regional giantism associated with neurofibromatosis in which the enlargement of the globe could not be completely explained as the result of ocular hypertension. We suggest that ocular hyperplasia contributed to the buphthalmos in our case, and may play a more significant role in the genesis of buphthalmos associated with neurofibromatosis than has been reported previously.
N.B. is a White male born after a normal pregnancy and delivery of a 31-year-old mother on July 14, 1972. At birth it was noted that the left eye was more prominent than the right and the left side of the face was thought by some observers to be slightly fuller than the right. There was no family history of congenital glaucoma or buphthalmos. Physical examination was normal except for the ocular and facial asymmetry. In particular, no café au lait spots were seen.
Examination under anesthesia (halothane) documented the prominence of the left eye. Corneal diameters were: OD 10 mm and OS 12 mm. Both corneae were clear and lustrous. There were no splits in Descemet's membrane. Gonioscopy of the left eye revealed a deep angle in which garlands of vessels were suspended in abnormal tissue. The right optic cup size was estimated to be .2 and the left ,3. A diagnosis of congenital glaucoma was made, but the intraocular pressures (OD 12 mm Hg; OS 20 mm Hg by applanation) and the general status of the eye did not justify immediate surgical intervention. The patient was begun on pilocarpine two percent QID in the left eye.
The patient was followed over the next four months and monthly examinations under anesthesia (halothane) confirmed that the intraocular pressure of the left eye never exceeded 20 mmHg. Optic nerve cupping of the left eye did not increase. However, the left corneal diameter continued to enlarge to 15 mm despite the fact that no edema or splits in Descemet's membrane were ever observed. By this time the left facial hemihypertrophy was much more evident and noted to be due to both bony and soft tissue changes (Fig. 1). There were masses to be felt below the left ear, angle of jaw, and cheek extending from the infraorbital nerve to the side of the nose and lip. Biopsy confirmed these to be plexiform neuromas. It was also obvious that the left upper eyelid had thickened and drooped 2-3 mm below the level of the right. The left eye was proptosed as well' as enlarged. Café au lait spots did not appear until about the age of nine months.
Plain skull and facial films revealed hypertrophy of the left maxillary region and alveolar margin with distorted tooth growth as well as significant expansion of the left middle cranial fossa. The left optic foramen was larger than the right. Bilateral carotid arteriography was performed because of suspected intracranial tumor in continuity with the orbit. The left ophthalmic artery was much larger than the right with no aneurysmal dilation of the vessel being seen. A diagnosis of neurofibromatosis with leftsided buphthalmos, lid neuroma, and facial hemihypertrophy was made. Even though the enlarged left cornea was regarded as out of proportion to the intraocular pressure recorded (20-24 mm Hg) a goniotomy was performed in the hope that control of the intraocular pressures would slow the progression of ocular size.
During the next 12 months the intraocular pressure was monitored regularly with repeated examinations under anesthesia (halothane or ketamine). The pressure in the left eye never exceeded 16 mm Hg. The cornea remained clear but the buphthalmos increased to 16.5 mm.
Fig. 1. The patient at six months of age. Note the facial asymmetry, enlarged but lustrous left cornea, and slight ptosis of left lid.
Fig. 2. The patient at two years of age. The IeH sided facial hemihypertrophy and ptosis are much more pronounced than before. The ten globe has continued to enlarge but the cornea remains clear.
By the age of two and one-half years the patient's left sided facial hypertrophy had become grotesquely disfiguring (Fig. 2). The weight of the tissue mass on the left side of the face hampered the patient's balance and ability to hold his head erect and mechanically interfered with speech. The left lid completely covered the grossly enlarged globe and the patient was unable to elevate the lid at all. Skull and facial films showed an increase in the width of the left optic foramen (Fig. 3). Films of the long bones were taken and bowing of both tibiae was documented and the characteristic feature of fibrous dysplasia noted (Fig. 4).
Progressive enlargement of the left facial structures continued, so that by the age of four years the patient had developed chronic discomfort around the left eye. The eye was virtually blind and the principal problem had become the gross cosmetic deformities as well as the psychological problem of the father who found it difficult to look at the patient.
After consultation with the plastic surgeons, enucleation of the grotesquely enlarged left eye was performed by one of us (F.A.B.). The residual orbital plexiform neuroma rapidly grew and six months later a modified exenteration of the orbit was performed by the same surgeon. The orbital periosteum was preserved to permit maxillary reconstruction at a later date.
Fig. 3. Plain x-rays of the orbits reveal the left orbit to be enlarged and the left middle cranial fossa expanded.
Fig. 4. X-rays of the lower extremities reveal marked bowing of the right tibia with evidence of fibrous dysplasia.
The globe measured 35 x 28 x 34 mm. The corneal diameter was 16.5 mm (the right cornea at this time measured 11.5 mm) (Fig. 5).
The optic nerve appeared normal but was surrounded by a mass of grey lobulated tissue. The inferior oblique and inferior rectus muscle were enlarged to 4-5 times normal dimensions (Figs. 5 and 6).
On microscopic examination the tissue surrounding and compressing the optic nerve was identified as typical plexiform neuroma in characteristic rounded masses. It infiltrated the retrobulbar connective tissue and sclera. Neurofibromatous formations were present in the sheath of the optic nerve without actually infiltrating it. The choroid was thickened by neurofibromatous involvement (Fig. 7). The anterior chamber was deep and open. The corneoscleral meshwork was compressed and distorted, and normal structures were difficult to identify. No synechiae, neovascularization, or forward displacement of the iris was seen. The optic nerve was atrophic but without a targe cup. The findings confirmed the presence of plexiform neuroma compressing the optic nerve and infiltrating the retrobulbar tissues. Plexiform neuromas were identified in the sclera, choroid, and ciliary body.
The history of this case demonstrates the typical evolution of the various lesions of the Francois syndrome. The buphthalmos was noted at birth and made more prominent by orbital involvement with neurofibromatous tissue. The lid involvement and facial hem i hypertrophy only became obvious after the first few months of life. Café au lait spots did not become obvious until about the ninth month of life. Within two years the lid lesion had advanced to such a degree that the ptosis produced completely occluded the buphthalmic globe. The facial hemihypertrophy became so disfiguring that it caused serious psychological problems for both the patient and his family and eventually became the central problem in management.
The ocular involvement in patients with neurofibromatosis most commonly is seen as a diffuse hyperplasia of the neuroectodermal cell elements in the iris and choroid,12 sclera,13 cornea,11 optic nerve,2,13 and orbit13 Isolated lid neuromas in neurofibromatosis are associated with glaucoma in the homolateral eye in 50 percent of cases.3,4
There is no question of the diagnostic significance of unilateral buphthalmos, Ud plexiform neuroma, and facial hemihypertrophy since these features are a pathognomic presentation of neurofibromatosis. In the newborn with buphthalmos, the associated lid neuroma and hemihypertrophy of the facial structures may be subtle findings and falsely attributed to the facial asymmetry commonly seen in the newborn, but their correct recognition establishes the diagnosis. Where doubt exists a biopsy may be necessary to confirm the diagnosis. Café au lait spots may not be seen initially, but they should be searched for on subsequent examinations.
Fig. 5. The enucleated left globe is shown with the optic nerve being compressed by the plexiform neuromatous tissue.
Fig. 6. A portion of the residual orbital plexiform neuroma removed at the time of exenteration.
Fig. 7. A cross section of the grossly enlarged left globe.
Of particular interest in this case was the enlargement of the globe in spite of only moderate elevation of intraocular pressure, an enlargement which continued even after intraocular pressure was controlled. This suggests that some factoKs) other than elevated intraocular pressure caused the globe enlargement There was evidence of abnormal tissue in the iridocorneal angle and choroidal involvement with neurofibromatous tissue confirmed on histological examination. The enlargement of the globe reached extraordinary dimensions in this patient Although the patient suffered from a mild elevation in intraocular pressure during the first few months of his life the degree of buphthalmos seen in this case is completely out of proportion with that which we have seen in even the most severe cases of congenital glaucoma. Furthermore, the enlargement of the globe continued unrestrained after successful control of the intraocular pressure.
The frequent occurrence of buphthalmos in those cases in which the choroid is involved has been emphasized.3»4'13 The cause of the buphthalmos in these cases has been ascribed to a variety of different abnormalities - all of which ultimately produce increased levels of intraocular pressure. The ocular hypertension associated with neurofibromatosis is usually detected at birth, or very soon thereafter. However, there are exceptions to this rule. A case reported by Weber and Bode14 did not demonstrate any elevation in intraocular pressure until the age of four years.
Sachsalber15 proposed that the buphthalmos in neurofibromatosis resulted from disturbances in lymphatic circulation which, in turn, lead to an impedance of aqueous outflow. Collins11 reported that he found adhesions between the iris and posterior surface of the cornea which he suggested were the result of incomplete embryogenesis of these structures. This proposal implies that the pathogenesis of buphthalmos in neurofibromatosis is akin to that of congenital glaucoma. However, other authors5'16 have insisted that these adhesions are secondary changes occurring as the result of anterior displacement of the uveal tract by the neurofibromatosis involvement in the choroid and ciliary body. Development of new fibrovascular tissue in the iridocorneal angle leading to angle closure and a type of hemorrhagic glaucoma has also been reported in cases of ocular neurofibromatosis.5'17 Francois3'4 has insisted that obstruction of aqueous outflow by neurofibromatosis tissue compromising the angle structures accounts for most cases of buphthalmos in neurofibromatosis. The partial or complete absence of Schlemm's canal has been commented on in reviewing histological sections of some of these eyes.11'15·18»19 However, in these severely affected endstage buphthalmic globes the absence of normal structures may be secondary to tissue distortion rather than a primary structural defect.6 All of the above theories invoke a common thesis that the buphthalmos in neurofibromatosis is secondary to uncontrolled elevations of intraocular pressure.
In some cases, the possibility exists that the buphthalmos represents ocular giantism in a similar way that regional giantism affects the orbit and other surrounding tissues.
This has received little attention in the ophthalmic literature because of the emphasis on ocular hypertension as the cause. Babel and Younessian7 reported a case of neurofibromatosis with buphthalmos and posterior marginal dysplasia of the cornea in which no ocular hypertension was documented. Earlier, Wiener8 had postulated that an enlarged globe in neurofibromatosis may representa manifestation of generalized hyperplasia of the orbit and its contents. He suggested that two factors might contribute to the buphthalmos (1) fibrosis of the globe, and (2) increased tissue tension due to local circulatory disturbances. In other words, the buphthalmos may represent ocular giantism in a similar way that regional giantism affects the orbit and surrounding tissues.
We do not deny that abnormal tissue was identified in the iridocorneal angle of our patient In fact, it was comparable to that documented in previous reports3-6'15'19 of ocular neurofibromatosis. However, we wonder if the presence of abnormal tissue in the vital iridocorneal angle has not misled ophthalmologists in their conclusion that thè buphthalmos in neurofibromatosis results from obstruction of aqueous outflow. It is conceivable that the abnormal tissue identified within the iridocorneal angle of our case, and other cases of ocular neurofibromatosis, is part of a hyperplastic process similar to that described in the bony and vascular abnormalities associated with neurofibromatosis. It may be that Verhoeff's original proposal20 that metabolic disturbances lead to alterations of the growth of the globe in neurofibromatosis should be reconsidered. The recognition of the role which hyperplasia of other tissues affected by neurofibromatosis plays in various pathologic processes lends weight to the thesis that the buphthalmos may be, at least in part, the result of ocular hyperplasia.
Abnormalities of the orbit in neurofibromatosis are well known.21"" The most common findings are enlargement of the orbit and partial loss of the walls, ceilings, or apex.2''22 Less extensive bony abnormalities involve small gaps in the orbital walls or enlargement of normal fissures and foramenae.3 Some controversy continues concerning the etiology of these bony abnormalities, but it is established that many of them are not the consequence of direct involvement by neurofibromatous tissue. Rovit and Sosman22 have asserted that the enlarged orbit is part of a hemicranial dysplasia of diffuse elements. Other nonorbital skeletal changes which occur in neurofibromatosis, such as fibrous dysplasia and pseudoarthrosis, add support to the notion that many of the bony changes associated with neurofibromatosis are the result of a diffuse neuroectodermal dysplasia (with some mesodermal elements) rather than a consequence of direct involvement with neurofibromatous tissue." In our patient, in addition to diffuse enlargement of the left orbit, facial bones, and pseudoarthrosis of both tibiae, there was diffuse enlargement and dilation of the left ophthalmic artery without features of aneurysmal change.
Although less widely recognized as associated manifestations of neurofibromatosis the vascular malformation in von Recklinghausen's disease have been the subject of several recent reports.2*"26 A study26 of the pathologic features of the systemic vascular lesions demonstrated that the pathogenesis of both occlusive and aneurysmal changes is initiated by proliferation of Schwann cells within the arteries. In our case, the dilatation of the ophthalmic artery was extensive and did not have aneursymal features. Whether it resulted from a dysplasia of Schwann cells as suggested by Salyer and Salyer,26 or from some other form of tissue hyperplasia is not certain. Nonetheless, it too, like the bony changes in this case, can be considered part of a process of regional giantism.
The central question of this paper is the role of regional giantism in producing the buphthalmos associated with neurofibromatosis. Clearly, cases of buphthalmos are recorded where glaucoma was not detected. Our own case cannot be explained purely in terms of glaucoma. Furthermore, we contend that even where ocular hypertension is significantly higher than that recorded in our case a major dynamic force in the evolution of the buphthalmos is hyperplasia of ocular tissues, and a resulting abnormal distensability of the globe quite similar to the condition of aneurysmal formation of vessels in neurofibromatosis. In this respect, the buphthalmos associated with neurofibromatosis can be considered an expression of regional giantism and has important implications in respect to treatment of these cases which, for the most part, is disappointing in contrast to primary infantile glaucoma where the prognosis for surgical intervention is excellent.
A case of buphthalmos and regional giantism in neurofibromatosis with the characteristics of the Francois syndrome is reported. Difficulties of early diagnosis are emphasized. A discussion of the mechanisms which may produce buphthalmos in neurofibromatosis is presented. We propose that buphthalmos in neurofibromatosis may be primarily an expression of regional giantism rather than a consequence of uncontrolled intraocular pressure.
'This work was performed between 1972-1976 at the Royal Childrens Hospital. Melbourne, and the support and assistance of the staff of that hospital are gratefully acknowledged.
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