J Med Genet 1993; 30: 53-59

Syndrome of the month

Incontinentia pigmenti (Bloch-Sulzbergersyndrome)

S J Landy, D Donnai

Incontinentia pigmenti (IP) is a rare genoder-matosis and was probably first described asearly as 1906 by Garrod,' but the credit isgiven to Bardach,2 Bloch,3 Siemens,4 and Sulz-berger5 for defining the condition during the1920s, although only the names of Bloch andSulzberger feature in the eponym. It is amultisystem, ectodermal disorder accompa-nied by dermatological, dental, and ocularfeatures and in a minority of cases may beassociated with neurological deficit.The typical phenotype is a result of func-

tional mosaicism, a phenomenon which occursin X linked dominant disorders because oflyonisation.The name incontinentia pigmenti describes

the characteristic, albeit non-specific, histolo-gical feature where there is incontinence ofmelanin from the melanocytes in the basal layerof the epidermis into the superficial dermis.

GeneticsExtensive pedigree review suggests X linkeddominance with lethality in males. This modeof inheritance is supported by the high fema-le:male ratio, female to female transmission,increased incidence of miscarriages and by theoccurrence of two reported cases of classicalIP in males with Klinefelter syndrome(47,XXY).6 The half chromatid mutationmodel and postzygotic mutation have beensuggested to explain the survival of occasionalsporadic males with IP.89

In 1985 linkage to Xpl 1 was suggested afterreports of five females with de novo X;auto-some translocations involving Xp 1 1 associatedwith phenotypes similar to IP.1'1" In 1987Happle14 suggested that these were cases ofpigmentary mosaicism rather than classical IP.Females with an IP phenotype and X;auto-some translocations raise several problems.The variegated phenotype of IP depends onrandom lyonisation, while the pathologicaleffects of X;autosome translocations dependon non-random lyonisation, the normal Xchromosome being preferentially inactivated.

Sefiani et all5 in 1988 excluded the possi-bility of linkage to Xpl 1 in a series of familialcases. In 1991, in a large linkage study involv-ing 12 families and nine terminal X long armmarkers, they confirmed linkage of familial IPto the Xq28 region with a lod score of 6-19 at arecombination fraction of 0.03.16 This is sup-

ported by linkage analysis, done by the auth-ors, in six pedigrees with lod scores of 3-2 fortwo terminal X long arm markers (unpub-lished data).

Clinical featuresThis information is based on several ac-counts17"33 and on an unpublished clinicalstudy involving 111 patients, with clinicalfeatures compatible with familial IP, under-taken by the authors (Landy et al, in prepara-tion). As would be expected in an X linkeddominant disorder the presentation in femalecarriers is variable, presumably a result oflyonisation.

SKINThe cutaneous manifestations of incontinentiapigmenti are diagnostic; however, their ab-sence does not exclude the diagnosis. Classi-cally the dermatological features are describedin four stages but all stages do not necessarilyoccur and several stages may overlap. Stage 1:erythema, vesicles, pustules. Stage 2: papules,verrucous lesions, hyperkeratosis. Stage 3:hyperpigmentation. Stage 4: pallor, atrophy,and scarring.

Stage 1The first stage is characterised by blisters,usually preceded by erythema, which occuranywhere on the body but usually spare theface (fig 1). The lesions of the first stagedevelop within the first few weeks of life.Typically the blisters appear at or soon afterbirth and often respect the midline (fig 2). Alinear distribution, along the limbs and cir-cumferentially around the trunk, is classicallydescribed although this is not absolute. Eachcrop of blisters clears within weeks and theymay or may not be replaced by new crops, atthe same or different sites. In general, stage 1has cleared completely by four months. It isnot uncommon for the blisters to recur duringacute febrile illness in childhood but theseeruptions are less severe than those seen in theneonatal period and are short lived. The initialinflammatory phase is accompanied by mas-sive infiltration of eosinophils into the epider-mis and marked peripheral blood leucocytosiswith up to 65% eosinophils.

Department ofMedical Genetics,St Mary's Hospital,Hathersage Road,Manchester M13 OJH.S J LandyD Donnai

Correspondence toDr Donnai.

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Figure I Stage I at 10 days showing linear streaks ofvesicles on the trunk and limbs but sparing the face.

Figure 2 Vesicular lesions on the trunk respecting themidline.

Stage 2The typical, hyperkeratotic lesions of stage 2may be present from an early stage. Theyusually appear on the distal limbs, as theblisters begin to heal, after several weeks (fig3). Sometimes these lesions do not occur ormay be so trivial that they go unnoticed. Theblisters on the distal limbs become dry andhyperkeratotic forming warty lesions whichmay persist (fig 4). These lesions rarely affectthe trunk or face but may occur on the scalp.They clear completely by six months in over80% of cases.

Stage 3Stage 3 is, classically, the hallmark of IP butagain its presence and extent are variable. Itranges from no or very little hyperpigmen-tation to extensive involvement of the skin.The hyperpigmentation fades and has disap-peared by the end of the second decade. Thishyperpigmentation is more often apparent onthe trunk than the limbs and occurs in streaksor whorls which respect Blaschko's lines (figs 5and 6). The nipples are frequently involved inthe increased pigmentation and the axillae andgroins are invariably affected. The timing ofthe pigmentary abnormalities varies but ingeneral the streaks gradually appear sometimeafter the blisters have disappeared and becomedarker over weeks or months. The distributionof these lesions is often unrelated to the distri-bution of the previous vesicular rash. Thepigmented lesions remain static for a period oftime until they fade during childhood andadolescence. By the age of 16 the majority ofthese pigmented lesions have disappeared. Oc-casionally they remain and can be a permanentfeature, usually in the groins. Sometimes there

is no delineation between the stages andseveral features occur concurrently (fig 6).

Stage 4The features of the fourth stage are those of'burnt out' IP and are often present before thehyperpigmentation has disappeared com-pletely. The typical lesions seen in adults andadolescents with IP are pale, hairless patches

Figure 4 Persistent hyperkeratotic lesion over thelateral malleolus at 6 months.

;$s ,Figure 3 Stage 2 at 4weeks showing verrucouslesions in a lineardistribution on the palm.

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I{Figure 5 Stage 3 at 3 years showing classical hyperpigmentation following Blaschko'slines.

Figure 7 Stage 4 showing pale, hairless, atrophiclinear lesions on the posterior lower leg. This patient alsohas a right hemiparesis.

Figure 6 At 18 months this patient had evidence ofstages 1, 2, and 3 with bullae, verrucae, andhyperpigmentation. There was also evidence of stage 4with pale, atrophic lesions elsewhere.

or streaks best seen on the lower leg (fig 7).Moss and Ince29 in 1987 first noticed thatalthough these lesions, seen best on the poster-ior calves, are usually described as hypopig-mented, in fact the contrast with normal skin isprobably because of the lack of hair folliclesand reduced vascularity and that the differencein pigmentation is a minor factor. Some sub-jects admit that these areas become moreobvious when the normal skin tans in sunlightbut some claim that the contrary is true. Wesupport the observation of Moss and Ince29and this may help our understanding of thepathogenesis of the lesions seen in this dis-order.

The skin covering the trunk in affectedadults may show atrophic linear or reticulatelesions with normal or increased pigmentation.These lesions, if present at all, tend to be lessatrophic than those seen on the limbs, reflect-ing the degree of damage to the dermis.

NAILSThe frequency of nail dystrophy may be ashigh as 40% but it is usually mild. The degreeof involvement is variable, ranging from mildridging or pitting to onychogryposis andsevere nail disruption not unlike onychomyco-sis (fig 8). Fortunately these episodes of naildisintegration seem to be temporary but mayrecur during childhood or adolescence. Thecause of this nail disruption is unknown. Ifonychodystrophy is present then it is seen inall or most of the nails on the hands and thefeet.

Subungual keratotic tumours associatedwith IP have been described by various

Figure 8 Severe nail dystrophy in a 3 year old girlwhich lasted six months and has resolved completely.

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authors.283436 The histology of these tumourscorresponds closely to that seen in the verru-cous cutaneous lesions of stage 2 and showshyperkeratosis, acanthosis, papillomatosis, andfocal dermal dyskeratosis. In addition, theselesions can be associated with bony deformitiesof the underlying phalanges.28 These tumoursare painful as well as unsightly and can beeradicated by desiccation and curettage.

HAIRMost subjects with IP consider their hair to benormal but almost 50% have had or do haveminor abnormal features when questionedspecifically. Alopecia, especially at the vertexand usually after blistering at this site, iscommon but in most cases it is partial and goesunnoticed. Thin or sparse hair early in child-hood does not seem to correlate with the qua-lity or quantity of the hair in later life. Abnor-mal hair in IP tends to be lustreless, wiry, andcoarse and occurs, more often than not, at thevertex. Wiklund et aP0 first described this,calling it the woolly-hair naevus. There arevery few patients with IP who have severeproblems with poor quality hair or alopecia.Hair colour shows a normal distribution.

EYEThe incidence of eye involvement is difficult toascertain as most ocular changes are not severeand might well be missed without very detailedexamination. Squints occur in over one-thirdof patients, often in association with refractiveerrors, and it is these features which are re-sponsible for most of the unilateral visualimpairment in IP, albeit of a mild degree. Thehallmark of ocular IP involves abnormalities ofthe developing retinal vessels and the underly-ing pigmented cells, and is present in over40% of patients. Areas of retinal ischaemiapromote new vessel proliferation with subse-quent bleeding and fibrosis, somewhat similarto that found in retinopathy of prematurity.This process generally aborts spontaneously atan early stage, but in 10% of patients mayprogress to gross intraocular scarring withsevere visual loss. Fortunately, this usuallyaffects only one eye and appears to be even lesscommon in those without neurological abnor-malities. Other notable associations includemicrophthalmos, cataract, and optic atrophy,but despite all this over 90% of patients havenormal vision.

DENTALThe dental features of IP occur in over 80% ofcases and are of considerable diagnostic im-portance because, in contrast to many of thedermatological features, they persist throughlife. Either or both deciduous and permanentdentition may be affected and the typicalfeatures include hypodontia, delayed eruption,impaction, and malformation of the crowns,especially conical forms and accessory cusps.28(fig 9). Delayed eruption seems to be consis-tent but the explanation for this is unclear.

Figure 9 This 26 year old shows hypodontia, conicallower incisors, and retained deciduous teeth. There areno enamel defects.

There is no increased incidence of enamelhypoplasia and the teeth are of normal quality.

BREASTBreast hypoplasia has been reported inconsis-tently, but breast anomalies are not mentionedin Carney's review."7 In the authors' experi-ence the incidence of breast anomalies, includ-ing (in order of frequency) supernumerarynipple, nipple hypoplasia, breast hypoplasia oraplasia (fig 10), and abnormalities in nipplepigmentation, is at least 10 times greater thanthe incidence in the general population.

NEUROLOGICALThe neurological features described are di-verse and Carney'7 found that 30% of thepatients (465) in the reports he reviewed, thathad adequate information, had notable CNSdisease. A list of the commoner features hefound includes convulsive disorders (13%),

Figure 10 Unilateral breast aplasia is a well recognisedbut uncommon feature of IP.

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Table 1 Diagnostic criteria for incontinentia pigmenti.

No evidence of IP in a first degree female relative

Major criteriaTypical neonatal rashErythemaVesiclesEosinophilia

Typical hyperpigmentationMainly trunkBlaschko's linesFading in adolescence

Linear, atrophic, hairless lesions

Minor criteria (supportive evidence)Dental involvementAlopeciaWoolly hair/abnormal nailsRetinal disease

At least one major criterion is necessary to make a firmdiagnosis of sporadic incontinentia pigmenti. The minorcriteria, if present, will support the diagnosis but because oftheir high incidence complete absence should induce a degreeof uncertainty

spastic paralysis (11%), motor retardation(7%), mental retardation (12%), and microce-phaly (4%). Some of these features occurredconcurrently. The clinical information in someof these reports is minimal with no mention ofthe typical skin manifestations or other ecto-dermal associations common in IP. It is pos-sible that there may be cases of pigmentarymosaicism or similar disorders included in thisreview. More recent figures from our ownstudy suggest that the incidence of CNS ab-normalities is considerably less in familial IPand in cases where strict diagnostic criteria areapplied (table 1). The overall incidence ofmental or motor retardation in our series ofover 100 subjects is less than 10%. Further-more, in familial cases the incidence of severemental retardation is only 3% compared to15% in the sporadic group.

OTHERSSkeletal anomalies, asymmetry, and ear anom-alies have been reported as associations of IPbut in our series all structural abnormalitieswere associated with severe neurological defi-cit and included contractures, dislocations,and scoliosis.

Patient managementSKINDuring the neonatal period, or whenever theblisters are present, strict attention to hygieneis paramount but specific treatment is notindicated. The lesions should be kept dry andprotected from trauma. Reassurance that therash will improve is most important. Later,when the rash is quiescent no special advice forskin care is necessary.

EYESRetinal vascular changes have been docu-mented as progressing during the first fewmonths of life, and perinatal screening,

Evidence of IP in a first degree female relative

The diagnosis of IP is likely in a first degree female relative ofan affected female if any of the following features aredemonstrable, alone or in combination

Suggestive history or evidence of typical rashSkin manifestations of IPHyperpigmentationScarringHairless streaksAlopecia at vertex

Anomalous dentitionWoolly hairRetinal diseaseMultiple male miscarriages

repeated monthly during this period, is recom-mended. Xenon photocoagulation37 or cryo-therapy23 have been shown to promote regres-sion of neovascular changes in IP. Despite thepaucity of data regarding this, such therapywould appear justified if the sight is threa-tened. In view of the high incidence of squintand amblyopia, screening should probably becontinued for several years, particularly wherethere is a family history of squint.

TEETHParents should be warned that delayed erup-tion is common and that special dental atten-tion may be necessary if teeth are missing orabnormal. Very few people with IP have majordental problems.

CENTRAL NERVOUS SYSTEMCNS involvement in the neontal period is apoor prognostic sign and potential long termproblems should be discussed. If there are nosuch features and no seizures (especially infamilial cases) the child should be kept undercareful review and the parents reassured. Inour study all of the subjects with CNS diseasehad seizures in the neonatal period. Onepatient, with no mental or motor retardation,developed epilepsy in adolescence.

Confirmation of the diagnosisThe diagnosis of IP is founded on the clinicalfeatures. The classical florid rash of IP isdiagnostic but unusual presentations can occurwhen skin biopsy may be necessary. In olderchildren and adults with 'burnt out' IP, or inthose who may be at risk of IP, designation ofcarrier status may be more difficult.

Features of IP in adults can be subtle andspecial techniques may be needed. A Wood'slight is useful to show minor pigmentary an-omalies.

Skin biopsy should always be considered inatypical or mentally retarded cases to look forchromosomal mosaicism.

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The diagnosis may be inferred in an 'at risk'subject if there are typical dental anomalies,nail dysplasia, patchy alopecia, or retinal dys-plasia without the typical skin involvement.X inactivation studies in several centres3740

(Curtis, personal communication) have shownpreferential inactivation of the maternal X incarriers of familial IP and skewed X inactiva-tion in sporadic cases. This may well provideaccurate prediction of carrier status in at risksubjects long before the gene is identified.

Differential diagnosisAny condition exhibiting Blaschko's lines maybe confused with IP and strict diagnostic cri-teria are crucial (tables 1 and 2). The skinchanges in early infancy must be distinguishedfrom epidermolysis bullosa, bullous impetigo,dermatitis herpetiformis, and herpes zoster.Focal dermal hypoplasia should not be con-fused with neonatal IP even in its severestform.

Table 2 Clinical features that may indicate analternative diagnosis.

Skeletal involvement (other than that secondary toneurological deficit)Gross neurological deficitAsymmetrySevere alopeciaAtypical hyperpigmentationGross hypopigmentationFollicular pitting

X linked chondrodysplasia punctata alsoexhibits Blaschko's lines but there are certain,relatively constant, features which also occur

in this disorder to distinguish it from IP,namely, skeletal dysplasia, congenital catar-act, and alopecia. The typical scarring withfollicular pitting seen in this condition is notseen in IP (fig 11). Naegli syndrome is a rare

disorder characterised by reticular pigmen-tation of the skin but has no inflammatoryphase. Other features include heat intolerance

Figure 11 Linear scarring with follicular pitting seen in X linked chondrodysplasiapunctata.

and palmar hyperkeratosis which are notfeatures of IP.The heterogeneous group of disorders

known as hypomelanosis of Ito (HI) or pig-mentary mosaicism, now known to be theresult of chromosomal mosaicism in somecases and assumed to be the result of singlegene mosaicism in others4146 may be confusedwith IP. The clinical findings in HI includedepigmentation (skin histology shows paucityof melanin granules in the basal layer of theepidermis) following Blaschko's lines and ahigh frequency of mental retardation, seizures,asymmetry, and skeletal abnormalities. Theconfusion with IP may be an important factorin the discrepancy between the previously pre-dicted complication rates in IP and the compli-cation rates found in our series.

Clearly, making a definitive diagnosis incases with pigmentary anomalies is difficultbut an important rule of thumb is to abide bystrict diagnostic criteria and to avoid labellinga condition without a degree of certainty.

This work has been funded by the North WestRegional Health Authority. We would like tothank Dr Jane Dickinson for her adviceregarding the ophthalmic features of inconti-nentia pigmenti, Dr A P Read for supervisingthe molecular aspects of the study, Dr A Curtisfor his help with laboratory techniques, and allof our colleagues who contributed cases for thestudy.

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