sex-linked hereditary bilateral...

Sex-Linked Hereditary Bilateral AnophthalmosPathologic and Radiologic CorrelationPhilip J. Brunquell, MD; John H. Papale, MD; Jonathan C. Horton, PhD; Roger S. Williams, MD;Michael J. Zgrabik, MD; Daniel M. Albert, MD; E. Tessa Hedley-Whyte, MD

\s=b\A 27-year-old man had X-linked trueanophthalmos. No evidence of opticglobe, nerves, or chiasm was found. Rudi-mentary structures suggesting optictracts were present. Lateral geniculatenuclei were present but gliotic. Calcarinecortex was thinner but had usual lamina-tion. The normal patches of cytochromeoxidase activity in layers II and III of visualcortex were absent.

(Arch Ophthalmol 1984;102:108-113)

rprue anophthalmos is a rare clinical*- entity, and the diagnosis can only

be made by histologie examination ofthe orbital contents. Cases withpathologic substantiation of both theintraorbital and the intracranial com¬

ponents of the visual system are stillrare.13 We present herein the radio-logic and postmortem follow-up in acase of an X-linked recessive form ofanophthalmos originally reported byHoefnagel et al.4 In addition to serialsections of both orbital contents, the

left lateral geniculate nucleus, and theleft calcarine cortex, the functionalstate of the right visual cortex was

investigated with the use of thecytochrome oxidase reaction.5

REPORT OF A CASEThe report that follows is a brief sum¬

mary. For additional details, see the reportof Hoefnagel et al.4

The patient was born (weighing 2.7 kg atterm) to a 26-year-old mother (gravida 3,para 2). Parents were nonconsanguineousand of normal intelligence. The pedigree ofthe family updated from the previousreport includes another maternal malecousin with unilateral anophthalmia andcontralateral microphthalmia and isshown in Fig 1.

The patient had clubbed feet, small head,and no eyes. He sat at 1 year, stood withassistance at 5 years, and was never able tostand or walk independently. His firstwords were uttered at 3 to 4 years.

At the age of 7 Vi years, his head circum¬ference was 49 cm (second percentile). Hisears were large and outstanding. The eye¬balls were absent, but eyelids, cilia, eye¬brows, lacrimal puncta, and tarsal carti¬lages were present. Epicanthal folds werenoted bilaterally, and palpebrai fissureswere 20 mm in width. Conjunctival mem¬branes of normal appearance lined theorbital cavities, which were 15 mm in theirgreatest depth. Vigorous lid-closure fol¬lowed touching the membranes. The lacri¬mal glands were enlarged, and tearing wasnormal. There was reactive blinking totouch and loud noise. Cranial nerves otherthan II, III, IV, and VI were normal. Mus¬cle tone was normal; bulk was diffuselydiminished. Sensation to noxious stimuliwas intact. Muscle stretch reflexes were 1 +bilaterally with flexor plantar responses.The right testis was undescended. Karyo-

type was normal. An EEG showed absenceof a posterior «-rhythm and no drivingresponse to photic stimulation. Skull x-rayfilms were normal, except for showingshallow orbits and small optic foramina.

At the age of 11 years, he was ad¬mitted to a state institution, at which timeheight, weight, and head circumferencewere all less than the second percentile.

When he was 15 years old, a grand malseizure lasting five minutes was witnessedfor the first time. His CSF was normal. AnEEG showed, in addition to absent -rhythm, generalized low-voltage fastactivity and intermittent bilateral sharpwaves, most prominent posteriorly. Sei¬zures were controlled with phénobarbitaland phenytoin (Dilantin). An examinationwhen the patient was 16 years old showedspastic paraparesis, flexion contractures,and a severe scoliosis.

When he was 25 years old, computedtomography (CT) showed densities withinthe orbits having the appearance of rudi¬mentary extraocular muscles. Ovoid lucen¬cies anteriorly in both orbits were believedto be rudimentary eye tissue (Fig 2). Opticforamina were present bilaterally. Theventricles were slightly enlarged, and cra¬nial asymmetry was noted. Large accesso¬ry bony sinuses were present in the frontalregions (Fig 3).

After an episode of hypothermia at theage of 26 xk years, he was found to have alow thyroxine level (3.7 Mg/dL) and anelevated thyrotropin level (14 µ /mL) andwas begun on levothyroxine sodium (Syn-throid) therapy. At the age of 26 years,hydrocortisone therapy was started forhypoadrenalism.

He died of aspiration pneumonia at theage of 27 years.

PATHOLOGIC FINDINGS

Postmortem examination revealed

Accepted for publication Jan 5, 1983.From the Charles S. Kubik Laboratory for

Neuropathology, Massachusetts General Hospi-tal (Drs Brunquell, Williams, and Hedley-Whyte); Howe Laboratory, Massachusetts Eyeand Ear Infirmary (Drs Papale, Zgrabik, andAlbert); and the Departments of Neurology (DrsBrunquell and Williams), Ophthalmology (DrsPapale and Zgrabik), Neurobiology (Dr Horton),and Pathology (Dr Hedley-Whyte), HarvardMedical School, Boston.

Presented in part at the American Academy ofNeurology meeting, San Diego, April 30, 1983.

Reprint requests to Department of Pathology,Massachusetts General Hospital, Boston, MA02114 (Dr Hedley-Whyte).

at University of California - San Francisco, on December 1, 2009 www.archophthalmol.comDownloaded from

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Mental Retardation

1929, etc = Year of Birth (·) = Carrier

# Anephric, Heal Atresia, Clubbed Feet, Perinatal Death

Fig 1.—Pedigree of family updated from Hoefnagel et al."

bilateral bronchopneumonia, kypho-scoliosis, muscular wasting, bilateralcryptorchidism, and atrophy of thethyroid, adrenal glands, and testes.

The calvarium was asymmetric,with a right parietal protuberance.Head circumference was 54 cm, withthickened cranial sutures. Largeaccessory bony sinus cavities superiorto the orbital contents did not commu¬nicate with the frontal sinuses (Fig 3).The pituitary fossa was small, withmarked thickening of the anterior andposterior clinoids and the petroclinoiddura.

The orbits were unroofed throughthe accessory frontal sinuses and con¬tained no identifiable eye tissue. Theextraocular muscles were in their nor¬mal positions. The anterior portion ofthe orbital contents in the left eyecontained a firm nubbin of connectivetissue. Tissue removed from the orbit¬al cavities measured 40 mm in length,27 mm in width, and 30 mm verticallyon the right, and 70 mm in length, 35mm in width, and 23 mm vertically onthe left.

Step sections of both orbital con¬tents revealed similar constituents,including peripheral nerve, autonomieganglion cells, connective tissue, stri¬ated muscle, blood vessels, fat, non-keratinized stratified epithelium,

areas of mild chronic nongranuloma-tous inflammation, and lacrimalglands (Fig 2). There was pigmentalong some nerve fibers. No trace ofcornea, lens, uveal tissue, retina, pig¬ment epithelium, or optic nerve wasfound.

The brain weighed 1,050 g. Opticnerves and chiasm were absent (Fig4). The third and sixth cranial nerveswere present but smaller than nor¬mal. The frontal lobes were particu¬larly small. All primary gyri and sulciwere identified, although the calcar¬me fissures were shorter than normal(Fig 5).

Although medial geniculate nucleiwere well defined in coronal section,lateral geniculate nuclei and optictracts were not grossly visible. Thesubcortical white matter of the cere¬bral hemispheres was diffusely firm,and the ventricles were slightly di¬lated. The brain stem, cerebellum, spi¬nal cord, and blood vessels were nor¬mal.

The sites of the optic tracts werevisible microscopically, more appar¬ent on the left than the right, as smallgliotic structures without myelinatedfibers. The lateral geniculate bodiesoccupied their normal position (Fig 6)but were small, measuring 0.3 X 0.2mm, with an anteroposterior extent of

only 2.5 mm. The nucleus was severelygliotic, with a few, both small andlarge, neurons, but normal laminationwas completely lacking (Fig 6). Theoptic radiations were much thinnerthan normal.

In serial sections through the leftcalcarine cortex, primary visual cor¬tex (area 17) could be clearly identi¬fied by the boundary between areas 17and 18 (Fig 7). The basic layeringpattern of area 17 was preserved,although several anomalies werenoted. Area 17 seemed less richly lam¬inated than usual. Layer IVb was notvisible as the usually cell-poor gapbetween IVc and the supragranularlayers. Myelin stains confirmed theabsence of a well-myelinated line ofGennari. Finally, with the use ofNissl's staining method, the densityand size of cells seemed generallyreduced throughout striate cortex.Superior colliculi appeared normal incell stains, but the myelinated fiberbundles of the stratum opticum, theretinocollicular afférents in the nor¬mal brain, were absent.

In specimens of normal human stri¬ate cortex, regular patches ofenhanced cytochrome oxidase activityare visible, particularly in layers IIand III5 (Fig 8). In this case of anoph¬thalmia, no cytochrome oxidase



Fig 2.—Left, Axial section through orbitsshowing ovoid areas of low density (arrow¬heads) surrounded by tissue of medium densi¬ty suggesting presence of globes. Right, His¬tologie section of right orbital contents showscentral coalescence of fat surrounded bymuscle (M), peripheral nerve (N), and lacrimalgland (L). Eye tissue is conspicuously absent(trichrome, X2.5).

Fig 3.—

Left, Axial section revealing largeaccessory sinuses (A) in frontal bone. Right,Enlarged left frontal sinus partially overlyingorbit. Note orbital roof (O), crista galli (C), andfrontal bone (F).

Fig 4.—

Inferior surface of brain showingabsence of optic nerves and chiasm. Thirdand sixth cranial nerves are present.

Fig 5.—

Posteromedial surface of cerebralhemisphere showing shortened calcarine fis¬sure (arrowheads) that does not reach occipi¬tal pole. Primary gyri and sulci are otherwisenormal.

patches were present, as shown in Fig8, a tangential section through layersII and III. In addition, the thick bandof dark enzyme staining usuallypresent in layer IVc was very weak.

The small neurons of neocorticallayer IV appeared diminished in num¬ber in inferior frontal and temporalareas. The inferior olives were gliotic,with marked decrease in cell numbers,increased numbers of astrocytes, anddiminution of myelinated fibers in thehilum. The cerebellum showed diffusedecrease of granule cells and Purkin-je's cells. There were numerous spher¬oids in the cunéate nuclei bilaterallywithout demyelination in the posteri¬or cord.

COMMENT

Although Lycosthenes referred toanophthalmos in 1557,6 it was notuntil a century later that Bartholinprovided the first medical descrip¬tion.7 Briggs,8 in the early 19th centu¬ry, called attention to the possiblefamilial occurrence of the disease. Thefirst large clinical series, albeit with¬out histologie verification, was byTreacher-Collins in 1887.' Numerousreports followed, with little attemptto delineate the precise nature of anyintraorbital tissue until Mann10 subdi¬vided this heterogeneous group intothree distinct entities: primaryanophthalmos resulting from failure

of development of the optic vesicles;secondary anophthalmos, where fail¬ure of eye formation occurs as a com¬

ponent of more generalized abnormalforebrain development; and degenera¬tive or consecutive anophthalmos dueto complete regression or involutionof a previously formed optic vesicle. Inall cases there is virtual absence ofany neuroectodermal derivativeswithin the orbit. When such deriva¬tives are present in a patient with no

grossly evident eye structures, ex¬treme microphthalmos is a more

appropriate designation. Despite theapparent ease of this classification, itoffers little insight into pathogenesis,since cases with no residual eye tissue



Fig 6.—Left, Lateral geniculate body is small but well defined (arrow¬heads) and in normal proximity to medial geniculate nucleus (M). Itshows lack of lamination and neuronal depopulation (Nissl's method,X22). Right, Close-up view of lateral geniculate nucleus showsnonlaminated neuronal population (30-^m-thick section; Nissl's meth¬od, X64).

Fig 7.—Calcarine fissure (C) with striate cor¬tex above and junction between areas 17 and18 below (arrowhead). Note well-laminatedstriate cortex with thinner than usual layer IVb(20-/jm-thick section; Nissl's method, X26).

Fig 8.—

Left, Tangential section through superficial layers I, II, and III of normal visual cortexstained for cytochrome oxidase activity showing regular patches of cytochrome oxidase activity(X10). Right, Comparable section of patient's visual cortex showing uniform distribution ofcytochrome oxidase activity with no patches (X10).

may not always be ascribable to agen¬esis or degeneration. Furthermore,extrapolation to experimental modelsis limited as these are not character¬ized by complete failure of optic cupevagination.

In 1963, Duke-Elder" acknowledgedthe difficulty in distinguishing thenature of orbital contents on clinicalgrounds alone and pointed out thatthe true form of anophthalmos wasrare and that most cases showed some

intraorbital representation of neuro-ectodermal structures. This observa¬tion is strengthened by the fact thatonly 13 cases of primary anophthal¬mos had been tabulated as of 1980.12Newer noninvasive techniques, suchas orbital ultrasound13 and CT scan,may suggest a premortem diagnosisbut must be interpreted with caution.In this case, for instance, the centralcollection of orbital fat (low absorp¬tion) surrounded by muscle, peripher¬al nerves, and connective tissue (medi¬um absorption) suggested the pres¬ence of globes.

The heredity of familial anophthal¬mos is heterogeneous. Most cases aredistributed in an autosomal recessivepattern,1418 but a dominant patternhas also been reported.19 However,when anophthalmia is associated with

mental retardation and/or multiplecongenital malformations, case distri¬bution is more consistent with a sex-

linked recessive pattern of inheri¬tance.1722 Anophthalmos has also beenassociated with drugs,2325 congenitalinfection,26 vitamin A deficiency,27mechanical trauma to the fetus,28chromosomal aberrations,2933 and id¬iopathic multiple malformation syn¬dromes.3436 Animal models exist formany of these37 and also suggest a fewothers, such as radiation38 and alteredimmunity.39 The association of anoph¬thalmos with parasellar mass lesionssuggests that local pressure may de¬stroy the developing visual sys¬tem.1·40·41

Typically, as in this patient, thestructures that are not derived fromneuroectoderm are present, that is,



the eyelids, cilia, lacrimal apparatus,conjunctival lining, and extraocularmuscles. The absence of the lensseems to be due to the failure of theoptic cup to make proper contact withthe lens placode,37 suggesting that thecritical period is the development ofthe optic vesicle and cup. This hasbeen demonstrated in the mutantanophthalmic mouse ZRDCT/An,which serves as a suitable animalmodel for the human disorder.4243 Theconformation of the optic cup mayalso be a critical factor in determiningthe ultimate presence or absence ofeyes.43 The mutant mouse (ZRDCT/Ch) initially develops optic vesicles,which induce a small and poorly ori¬ented lens that cannot be assimilatedinto the optic cup, and ultimately bothdegenerate. The small orbits in ourcase seem to be a result of the failureof normal eye development.44

In the anophthalmic mouse, thedorsal lateral geniculate nucleusshows a loss of both neurons and gliaand a failure to develop a laminarpattern.45 These changes are moresevere in the mice enucleated postna-tally than in the anophthalmic mice.The degree of gliosis in the lateralgeniculate nucleus and the apparentremnants of optic tracts in our patientsuggest that the optic cup develop¬ment had proceeded to the retinoge-niculate interaction with subsequentdegeneration as in the mutant strain(ZRDCT/Ch).

In the anophthalmic mouse, genicu¬late neurons establish contact nor¬mally with area 17 of the neocortex.46Striate cortical efferente to lateralgeniculate nucleus47 and superior col-liculus,47 with increased connectionsto posterior thalamus,42 are alsoestablished. These connections mayensure the survival of lateral genicu¬late neurons, in contrast to theirdegeneration following postnatal eyeenucleation.45

In adult human beings, monocularenucleation causes anterograde trans-neuronal degeneration in the lateralgeniculate nucleus48·49; but the changesin striate cortex are less impres¬sive.50·51 Our findings in this case ofbilateral anophthalmia are analogous.Apparently the visual cortex can stillsurvive, develop, and organize cell lay¬ers in the absence of a retinogenicu-late pathway. Nevertheless, judgingfrom the depletion of neurons in thegeniculate body, the geniculocorticalpathway was seriously disrupted. Thisconclusion was supported by the evi¬dence obtained using the cytochromeoxidase stain. The patches of strongercytochrome oxidase activity present

in normal monkeys5·52 and humanbeings were lacking.51 In the macaquemonkey, these patches receive a directprojection in layers II and III fromthe lateral geniculate body.52 54 Follow¬ing eye removal in the macaque mon¬

key, the patches innervated by genicu¬late laminae, corresponding to themissing eye, turn pale and shrink.5 Inview of the appearance of the genicu¬late body (Fig 6), it was not surprisingthat the patches were absent alto¬gether in this case. Finally, connec¬tions within striate cortex were alsoprobably abnormal, since the densetangential fiber plexus in layer IVbwas extremely faint.

Our findings can be compared withthose in three reports in the Englishliterature that included gross andmicroscopic descriptions of all partsof the visual system.13 All three caseswere characterized by completeabsence of eye tissue, optic nerves,chiasm, and tracts. The lateral genic¬ulate nuclei were not found in onecase1 and were small and nonlami-nated in the other two.2·3 In one case,the calcarine cortex was normalgrossly with normal cellular lamina¬tion, save for absence of the myeli¬nated line of Gennari.2 The other twohad small striate areas, one with1 andone without 3 a line of Gennari, thelatter case showing grossly mal¬formed calcarine fissures.

It is possible that this patient'sgrowth retardation is due to a singlegene defect that affects the develop¬ment of multiple areas, including thehypothalamus and the eye. A multi-variate analysis of the pleiotropiceffects caused by WhWh (anophthal¬mic white) in the Syrian hamstershowed a high correlation with sixhypothalamically mediated indica¬tors.55 They included growth retarda¬tion, thyroid dysfunction, adrenalatrophy, and sterility, all findingsthat were present in this patient.Studies of some anophthalmic micerevealed pathologic changes in thehypothalamus, including alterationsof the suprachiasmatic nuclei thatwere deprived of normal retinal affér¬ents.56 Rats that are blinded or

deprived of visual stimulation showgrowth retardation,57 delayed puber¬ty,58 and reduced pituitary stores ofgrowth hormone.57 Although this sug¬gests an interdependence of hypotha-lamic and visual function, no histolog¬ie hypothalamic alterations were rec¬

ognized in this case. Serial sections ofthe hypothalamus were not done, andin the absence of an optic chiasm, thesuprachiasmatic nucleus could not bereliably identified.59

Russell Kerschmann, MD, performed the non-

neurophthalmologic portion of the autopsy.

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