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Ocular manifestations ofincontinentia pigmentiG. Holmstrom and K. Thoren

Department of Ophthalmology, Academic Hospital, Uppsala, Sweden

ABSTRACT.Purpose: The study aimed to evaluate the ocular manifestations in patients withincontinentia pigmenti (IP).Methods: Thirty patients from different parts of Sweden participated. Orthop-tic and ocular examinations were performed as well as evaluation of refractionand visual acuity.Results: Ocular manifestations, probably associated with IP, were found in 77%(23/30) of the patients. Thirteen had serious or vision-threatening eye manifes-tations in one eye, of whom 7 were totally blind in that eye from retinal detach-ments. Ten patients had minor retinal and/or corneal changes.Conclusion: Ocular lesions in patients with IP may be serious and lead to blind-ness because of retinal disease. Ophthalmological follow-up is essential in theneonatal period and such a programme is recommended.

Key words: Incontinentia pigmenti – ocular manifestations – retinal lesions – follow-up.

Acta Ophthalmol. Scand. 2000: 78: 348–353Copyright c Acta Ophthalmol Scand 1999. ISSN 1395-3907

Incontinentia pigmenti (IP), alsoknown as Bloch-Sulzberger syn-

drome, is a rare disorder, described at thebeginning of this century (Garrod 1906;Bloch 1926; Sulzberger 1928). It is in-herited as an X-linked dominant con-dition that is fatal in males. A fewaffected men have been described, prob-ably because of somatic mutations duringthe embryological period. The gene forIP has not yet been identified, but at leastone has been localized to the long arm ofthe X chromosome (Xq28) (Jouet et al.1997). This gene is probably the cause ofIP in most familial cases.

Incontinentia pigmenti is a multi-sys-temic disorder which affects ectodermalstructures with various dermatological,dental, ocular and neurological features.Cutaneous manifestations appear at birthor within a few weeks after. Four stagesare described, but not all of them necess-arily occur. They start as an erythema-tous vesicular rash associated witheosinophilia and followed by verrucouslesions, hyperpigmentation and finallypallor, atrophy and scarring. The diag-

nosis is made by a skin biopsy. Dentalmanifestations occur in 65%, accordingto Carney (1976), and include partial ortotal anodontia, late dentition, andpegged and otherwise malformed teeth.Various neurological features such asconvulsive disorders, cerebral palsy andretarded development occur in at least30% (Carney 1976).

Ocular manifestations, often asymmet-ric, are described in 35% (Carney 1976).Most characteristic are various retinallesions involving both the developing reti-nal vessels and the underlying pigmentepithelium (RPE). Retinal ischaemia andproliferation of new vessels with sub-sequent bleeding, exudation, preretinalgliosis and tractional detachment of adysplastic retina may be seen. As with re-tinopathy of prematurity, the processmay stop spontaneously at any stage,leaving various retinal sequelae, e.g. avas-cular areas, tortuous, irregular vessels,exudates, vitreous haemorrhages, prereti-nal fibrosis, RPE mottling or hypopig-mentation and retinal detachment(Rahi & Hungerford 1990; Goldberg &

Custis 1993). Apart from the retinal fea-tures, others are described including op-tic atrophy, foveal hypoplasia,microphthalmos, cataract, conjunctivalpigmentation, corneal changes, iris hypo-plasia, uveitis, phthisis, nystagmus, stra-bismus and myopia (Carney 1976; Fran-cois 1984; Goldberg & Custis 1993).

Several reports on selected groups ofcases with ocular manifestations in in-continentia pigmenti have been published(Watzke et al. 1976; Raab 1983; Eisen-haure et al. 1985; Spallone 1987; Gold-berg & Custis 1993) and also a few meta-analyses of the literature (Scott et al.1955; Carney 1976). The aims of the pres-ent study were to make an inventory ofthe disease in Sweden, to acquire betterknowledge of it from the genetic, dental,neurological and ophthalmologicalpoints of view, to give information to thepatients and their families, to promotecreation of an association for patientswith incontinentia pigmenti, and to sug-gest a programme for follow-up of thesepatients. The ophthalmological part ofthe study is presented here.

Material and MethodsWith the help of clinical geneticists, der-matologists, paediatric dentists and pae-diatric ophthalmologists, during theyears 1996–1997 we tried to find patientswith incontinentia pigmenti in Sweden.The criteria described by Landy andDonnai were used to confirm the diag-nosis of IP (1993). The patients were con-tacted and invited to take part in a thor-ough evaluation of the history as well asophthalmological and dental examina-tions. Thirty-eight patients were iden-tified, of whom 30 took part in the oph-thalmological and dental examinations.The mean age of the patients at the ex-amination was 22 years (range 16months–56 years). Fifteen were children

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(aged Æ18 years) and 15 adults (±18years). In eight of the patients, IP was theresult of a spontaneous mutation, whilethere was a heredity for the disease in 22patients who belonged to nine families.

All patients in this study were exam-ined by an orthoptist (K.T) and an oph-thalmologist (G.H.). The orthoptic evalu-ation included cover test for at least nearand distance, testing of motility and ofstereopsis (Lang’s stereotest). The bestcorrected visual acuity was evaluatedmonocularly with linear optotypes, usingthe Snellen chart at 5 metres, if possible,or HVOT or LH tests at 3 metres (Hedinet al. 1980; Hyvarinen et al. 1980). Thepreferential looking test (acuity cards)(Teller et al. 1986) was used in childrenunable to take part in the previous tests.The results of the latter test were con-verted from cycles/degree to linear acuity,for calculations.

In children, the refraction was deter-mined in cycloplegia with the help of reti-noscopy, after instillation of a mixture of

Table 1. Ocular findings in IP.

ID no. Age VA R VA L Refr R Refr L Anterior segment Retina R Retina L OA Strab

1 44 1 1 ª0.25 ª0.25 0 02 25 1 0 ª5.5 Corn degen, cat, phthisis left 0 3 exo left3 18 1 1 ª2.25 ª2.5 Corn subep opacity right 0 14 1 0.2 0.2 2.5 2.5 Corn subep opacity both eyes 0 05 27 1 1 0 0 1 06 4.5 0.8 1 1.75 2.5 2 07 44 1 1 0.5 0.5 1 18 17 1 1 0.5 0.25 0 19 27 0 1 ª0.25 Corn degen, cat, phthisis right 3 1 left exo right

10 39 1 1 ª0.75 ª0.5 0 111 2 0.8 0.8 0.5 0 Corn subep opacity both eyes 0 012 43 1 1 1 1 0 013 18 0 0.6 ª5.88 Corn degen, vessels, aphakia, phthisis right 3 0 left exo right14 13 0.7 0.8 ª10.13 ª9.25 0 0 eso right15 6.5 1 0.6 2.5 ª0.38 Corn subep opacity left 0 016 13 0.9 0 ª0.5 Corn degen, vessels, cat, phthisis left 0 3 exo left17 6.5 0.35 0 0.35 Synechiae, iris hypoplasia, cat left 0 3 exo left18 28 1 1 0.25 0 0 019 6.5 0.9 0 0.25 Corn degen, iris hypoplasia, cat, phthisis left 0 3 eso left20 38 1 1 ª9.63 ª9.75 1 121 7 1 1 1 1.25 0 022 25 0.0005 1 5.64 ª2.87 2 1 right exo right23 8 0.9 1 ª0.75 0.5 0 0 eso right24 32 1 1 ª0.75 ª0.75 1 125 9.5 1 1 0.75 0.5 0 026 24 1 0.7 ª0.63 ª4 0 2 eso left27 34 1 0.4 0 ª1 Corn subep opacity both eyes 0 0 exo left28 56 1 1 1.38 1.25 0 029 21 0 1 0.5 Enucleated right 3 0 exo right30 12 0.1 1 2.5 3 2 0 right eso right

Ocular findings in the study group of 30 patients with incontinentia pigmenti.(Abbreviations: ID no.-identification number, VA-visual acuity, R-right, L-left, refr-refraction (spherical equivalent), retina 0-no lesion, 1-mild, 2-moderate, 3-severe, OA-optic atrophy, strab-strabismus, exo-exotropia, eso-esotropia, corn degen-corneal degeneration, cat-cataract, subep-subepith-elial).

cyclopentholate hydrochloride 0.85% andphenylephrine hydrochloride 1.5%.Astigmatism was recorded as negativevalues. Spherical equivalents (π/ª sphereπ 0.5 x (-cylinder)) were calculated.

The anterior part of the eye was evalu-ated with a slitlamp and the fundus wasexamined with a binocular ophthalmo-scope and in many cases with biomicros-copy. Fundus photographs were taken ofall patients where possible and laterevaluated by the ophthalmologist (G.H.)together with a retinal specialist.

ResultsVisual acuityTwenty-eight patients were assessed withlinear optotype tests. One child wastested with the HVOT test, one child withthe LH test and 26 with the Snellen chart.Two children were tested with the prefer-ential looking test of whom one had cer-ebral palsy and retarded development

(no. 17, Table 1) and one was only 16months old (no. 4).

None of the patients tested with opto-types was bilaterally visually impaired(visual acuity Æ0.3). The visual acuity ofthe better eye was Ø0.8 in 27 patients and0.6 in one patient (no. 13), who had opticatrophy and nystagmus in her better eye,amaurosis of her other eye and epilepsy.The 16-month-old girl had normal acuityfor her age with the preferential lookingtest (4.8 cycles/degree at 55 cm ), whilethe 6-year-old girl with cerebral palsy didnot reach the level for her age (only man-aged 6.5 cycles/degree), probably second-ary to cerebral visual impairment (CVI).

Seven patients had amaurosis of theirworse eye. Another two patients (nos. 22,30) had a visual acuity of Æ0.1 in theirworse eye, both secondary to retinalpathology. Eight of these nine patientswith severe visual impairment (Æ0.1) intheir worse eye had good vision (Ø0.6) inthe other eye. The ninth patient did notreach normal level for her age with the

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preferential looking test, because of CVI(see above). Four other patients had a vis-ual acuity of 0.4 – 0.7 in their worse eye.In one of these (no. 26) the visual impair-ment was caused by a retinal lesion, intwo by amblyopia secondary to aniso-metropia and/or strabismus (nos. 15, 27),and in one it was probably caused by se-vere myopia (- 10 dioptres) (no. 14). Six-teen patients had a visual acuity of Ø0.8in their worse eye and the 16-month-oldgirl had normal vision for her age, meas-ured with the preferential looking test.

RefractionThe refraction was assessed in all eyes,apart from the amaurotic ones. One eyehad a hypermetropia of ±π3 dioptres, 30eyes were moderately hypermetropic(Æπ3 dioptres), while 10 right (10/27,37%) and 12 left (12/26, 46%) were my-opic (∞0 dioptres). Four of the right eyesand six of the left eyes had a myopia ofƪ2 dioptres. Altogether, seven patientshad a myopia of ƪ2 dioptres in eithereye, three bilaterally, of whom two pa-tients were severely myopic (∞ª9 di-optres) (nos. 14, 20).

Anterior segment of the eyeSuperficial, subepithelial, linear orrounded, corneal opacities were found in

Table 2. Ocular manifestations in 30 patients with incontinentia pigmenti.

n %

Retinal lesionsNone 12 (41%)Grade 1 (mild) 7 (23%)Grade 2 (moderate) 4 (13%)Grade 3 (severe) 7 (23%)

Other lesionsPhthisis, cataract, decompensated cornea 7 (23%)Mild corneal changes 5 (17%)Optic atrophy 4 (13%)Strabismus 13 (43%)Severe myopia (ƪ9 dioptres) 2 (7%)

Table 3. Vitreoretinal changes.

Grade 1 Minor and non-specific defects of the retinal pigment epithelium (RPE),not affect-ing the visual acuity, such as mottling of the PE, distinct pigmentations and depig-mented or hypopigmented areas.

Grade 2 Vascularized or non vascularized temporal ridge, with or without retinal or vascu-lar traction, gliosis or fibrosis, sometimes with avascular retinal areas peripheralof the ridge. See fig. 1 and 2.

Grade 3 Retinal detachment, retrolental membrane/mass, including the retina and vitreous.See fig. 3.

five patients, of whom three had bilateralchanges (Table 2). Only in one patient(no. 15) did the corneal opacity, being V-shaped and central, possibly affect the vi-sion. However, this patient also hadanisometropia, which probably was thereason for amblyopia in one eye.

Seven patients (all with grade 3changes in the posterior segment, see be-low) had widespread changes in the an-terior segment in one eye, i.e. cataract,shallow anterior chamber, decompen-sated cornea with band-shaped degenera-tion and calcium deposits. Iris hypoplasiaand synechiae from the iris to the lenswere seen in some of these eyes. Phthisiswas found in five of the seven amauroticeyes. One eye had been enucleated andwas replaced by a prosthesis (no. 29).

Posterior segment of the eyeVitreo-retinal changes were divided intothree grades, see Table 3.

Twelve patients had normal posteriorsegments with a clear vitreous and nor-mal retina, while 18 patients (18/30, 60%)had some kind of pathology, see Table 2.There was marked asymmetry and onlyfive patients had bilateral findings. Grade3 changes were present in seven patients(7/30, 23%) of whom one had grade 1 inthe other eye. Grade 2 was found in four

patients, of whom one had grade 1 in theother eye. Grade 1 alone occurred inseven patients, of whom three had bilat-eral changes.

Optic atrophy was found in one eye offour patients. Two of the patients (nos. 22and 30, Table 1) had grade 2 changes inthe posterior pole with temporal ridges,dragging of the central vessels, macularheterotopia, severe visual impairment(0.005 and 0.1, respectively) but noneurological defects. One patient (no. 9)with optic atrophy had normal vision inthat eye with only minor RPE defects inthe peripheral retina (grade 1), amaurosisof the other eye and minor cerebral palsy,while another patient (no. 13) had a vis-ual acuity of 0.6 in that eye, nystagmus,normal retina and epilepsy (see above).

StrabismusThirteen patients (13/30, 43%) had stra-bismus, five had esotropia and eight ex-otropia, of whom two (nos. 22, 27) hadpreviously been operated on for esotrop-ia. Retinal pathology was the most prob-able reason for strabismus in nine pa-tients, seven of whom had amaurosis inone eye and two had a severe visual im-pairment because of grade 2 changes. Inone more patient (no. 26) retinal changes(grade 2), resulting in a visual acuity of0.7, may have been the cause of strabis-mus, although an anisometropia of threedioptres cannot be excluded as a con-tributory cause. One patient (no. 27) hadsubtle bilateral subepithelial corneal opa-cities, which probably did not affect vis-ual acuity, slight anisometropia, left am-blyopia, but no neurological abnormali-ties. One patient (no. 23) had an infantileesotropia with no known neurological de-fects, while another patient (no. 14) hadminor cerebral palsy.

Onset of ocular manifestationsOf seven patients with monocular amaur-osis, ocular pathology had been discover-ed in the screening at two weeks of age intwo patients (nos. 16, 19), another twohad been detected because of uveitis atsix and five months of age (nos. 2, 13),one with strabismus at one and a halfyears (no. 17) and one had been exam-ined in the neonatal period and regardedas normal, but returned with strabismusat nine months (no. 29). One patient’scase notes from the first years could notbe found. In the fourth patient withgrade 2 changes in one eye (no. 6), theretinal pathology was detected on ourstudy examination.

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Fig. 1. Twenty-four-year old woman with an esotropic left eye with a Fig. 2. Twelve-year old girl (no. 30) with an esotropic right eye with atemporal ridge, vascular traction, macular heteroptopia and a vision of temporal ridge, vascular traction, macular heteroptopia, optic atrophy0.7 (no. 26). and a vision of 0.1.

Two patients (nos. 22, 30) with grade 2retinal changes and severe visual impair-ment (0.005 and 0.1) in one eye had beenreferred for ophthalmological examina-tion at one and a half years because ofstrabismus. Another patient (no. 26),with grade 2 changes and a final visualacuity of 0.7, was seen by an ophthalmol-ogist at one year of age because of stra-bismus ascribed to anisometropia. At sixyears of age, however, her retinal changeswere found.

Most of the minor eye manifestations,such as peripheral RPE defects and sub-epithelial corneal opacities, did not seemto affect vision and were first seen in thepresent study.

Follow-upsSome kind of screening with fundus ex-amination seems to have been performedin 15 patients. The examinations hadsometimes been scheduled at regular in-tervals up to a few years of age, but wereusually irregular and sporadic. A few pa-tients of whom one was a girl, whosemother, aunt and grandmother have in-continentia pigmenti, had been examinedonly once in the neonatal period. One pa-tient (no. 6) had been followed and re-garded as normal up to four years. Onthe study examination at four and a halfyears, she was noted to have a temporalridge (grade 2) in one eye, but without

dragging of the central posterior pole.Nine patients had no follow-ups at alland there was no information about sixpatients during the first years of life.

TreatmentIn five of seven patients who developedmonocular amaurosis, the ocular mani-festations were detected too late for treat-ment. Two of the children, however, wereexamined at two weeks of age, but oneof them already had widespread retinalchanges with haemorrhages and the otherone had a hazy and haemorrhagic vit-reous. At that stage, none of them wasregarded as suitable for cryo- or lasertreatment.

One patient (no. 13) had a cataract ex-traction at two years because of a swollen

Fig. 3. Six-year old girl (no. 17) with an amaurotic, exotropic left eye with detached fibrotic retina,retrolental mass, cataract, iris hypoplasia and synechiae.

lens. Another patient had her amauroticeye enucleated because of pain (no. 29).

Summary of resultsIn the entire group of 30 patients withincontinentia pigmenti, 30% (9/30) hadsevere visual impairment (Æ0.1) in oneeye. A further two patients had grade 2retinal changes, with a risk of developingtraction and retinal detachment, and an-other two patients had bilateral severemyopia (∞ª9 dioptres). Hence, alto-gether 43% (13/30) of this group had seri-ous or vision – threatening eye manifes-tations.

Another 10 patients had minor retinalchanges and/or subtle corneal opacities,without certain effects on visual acuity.Thirteen patients had strabismus.

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In summary, eye manifestations, prob-ably associated with incontinentia pig-menti, were found in 77% (23/30) of thepresent study group.

DiscussionOphthalmological manifestations werefound in 77% (23/30) of the patients withincontinentia pigmenti in the presentstudy. Two groups were identified, onewith serious and vision-threatening eyemanifestations (43%,13/30), and one withessentially non-specific findings with noobvious effect on visual function. Theserious changes were asymmetric and in-cluded retinal detachment, phthisis, reti-nal ridges with dragged retina and severemyopia. Optic atrophy was also found inthis group, as well as strabismus. Lessserious and non-specific findings werevarious RPE defects and subepithelialcorneal opacities.

Previous studies have reported ocularmanifestations in incontinentia pigmentiin 25–35% (Scott et al. 1955; Carney1976). The first was a review of 91 casesreported in the literature, and the secondstudy was a meta-analysis of 455 patientsin the literature. Our intention has beento describe various ocular manifestationsin patients with incontinentia pigmenti inSweden. Although it seems likely that wemissed several cases, they probably didnot have any major ocular manifes-tations. Therefore the true frequency ofserious manifestations may be lower thanwe found (43%).

Severe visual impairment (Æ0.1) of oneeye was found in nine patients in the pres-ent study. Two of these were seen by anophthalmologist at two weeks of age,while the others were referred for an eyeexamination between five months andthree years. At that time, it was too latefor any treatment. A screening pro-gramme is needed for infants with IP andknowledge of the natural history of theretinal disease and of different treatmentmodalities. This would permit early de-tection of the retinal disease and initia-tion of adequate treatment.

Since IP is a rare disease, it is perhapsnot surprising that little is known aboutits pathogenesis and natural history. Abasic pigmentary abnormality may affectthe RPE, leading to changes in the retinawith dysplasia and detachment (Men-sheha-Manhart et al. 1975). Nishimara etal. (1980) speculated that a primary ar-terial insufficiency might lead to obstruc-

tion, ischaemia and proliferation of ves-sels. On the other hand, Brown (1988)thought that the retinal ischaemia seen inIP could be the source of an angiogenicfactor. Retinal changes in IP have alsobeen ascribed to mutations in a gene onthe X-chromosome, which impairs theproduction of an enzyme or other proteinneeded for cell differentiation (Catalanoet al. 1990). An inflammatory responsemight then ensue which would stimulateabnormal fibro-vascular proliferation(Catalano et al. 1990) and contribute tothe development of retinal dysplasia(Heathcote et al. 1991).

The natural history of the retinalmanifestations is not very well under-stood. The vascular changes seem to startduring the first postnatal weeks and pro-gress during the following weeks or evenmonths (Brown 1988; Krey & Laux 1974;Nishimura et al. 1980). In the final stage,the retina becomes detached and includedin a retrolental fibrotic mass. The processcan stop at any time and spontaneouslyregress, leaving various sequaelae (Fran-cois 1984; Rosenfeldt & Smith 1985;Goldberg & Custis 1993). Experience oftreatment is also limited. Cryo- or lasertreatment is recommended when earlysigns of progression of retinal disease arepresent (Nishimura et al. 1980; Catalanoet al. 1990; Rahi & Hungerford 1990;Watzke et al. 1990; Wald et al. 1993).Treatment of the avascular, ischaemicareas has been the most common, al-though the success rate varies (Best &Rentsch 1974; Nishimura et al. 1980; Tor-nabe & Schochet 1981; Catalano et al.1990; Rahi & Hungerford 1990; Wald etal. 1993). A few authors have treated theabnormal vascular tissue directly (Watzkeet al. 1976; Nix & Apple 1981). This hasalso been recommended by Catalano etal. (1990), who base their view on the as-sumption that the neovascular responseis induced by the abnormal retinal tissue,rather than the avascular retina. In a fewadvanced cases of retinal detachment, vi-trectomy has been performed, but withvery poor results (Wald et al. 1993).

Retinal disease, sometimes leading todetachment and amaurosis, is the majorocular threat to patients with IP. Neo-natal eye screening of children with in-continentia pigmenti during the firstyears of life is mentioned by severalauthors (Rahi & Hungerford 1990; Gold-berg & Custis 1993; Landy & Donnai1993; Fekrat et al. 1998). In spite of theincomplete knowledge of the natural his-tory of retinal disease in IP as well as of

the indications and exact timing for treat-ment, we also advocate such screening.Based on previous papers, our presentstudy, and personal communications withProfessors Goldberg in Baltimore andTassman in Philadelphia, we recommendthe following schedule for detection andtreatment of children with retinal lesions,as well as of treatment of strabismus andrefractive errors. The eyes should beexamined as soon after birth as possible,at least monthly for three to four months,at three-month intervals for one year, andtwice yearly up to three years. The fre-quency of examinations should, ofcourse, be increased in children with reti-nal disease. If, at three years of age, noabnormalities, no refractive errors andno strabismus are found, the follow-upscan probably be stopped.

In conclusion, incontinentia pigmentiis a hereditary ectodermal condition withvarious skin, dental, neurological andocular manifestations. In neonates withobvious skin manifestations and a her-edity of IP, the diagnosis is easy and con-firmed by a skin biopsy. In older childrenand adults, the constellation of skinmanifestations, dental abnormalities,possible neurological problems and eyemanifestations is a help in the diagnosis.The ocular lesions in incontinentia pig-menti may be serious and lead to blind-ness. It is therefore essential to refer neo-nates to ophthalmologists as soon as thediagnosis is made. They must be familiarwith the disease and schedule thesechildren for screening and regular follow-ups, preferably as recommended.

AcknowledgementsWe are grateful to Niclas Dahl, M.D., Ph.D.,for advice about genetics, to Per Tornqvist,M.D., Ph.D., for advice and assistance inevaluation of the retinal photographs, and toBorje Nordh for performing the photography.

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Received on May 3rd, 1999.Accepted on September 16th, 1999.

Corresponding author:

G Holmstrom, M.D., Ph.D.Department of OphthalmologyAcademic HospitalUniversity of UppsalaS-751 85 UppsalaSweden.Tel: π46 18 663000.Fax: π46 18 665180.Email: gerd.holmstrom/ogon.uas.lul.se