Clin Genet 2014: 85: 536–542Printed in Singapore. All rights reserved

© 2013 John Wiley & Sons A/S.Published by John Wiley & Sons Ltd

CLINICAL GENETICSdoi: 10.1111/cge.12223

Original Article

Incontinentia pigmenti diagnostic criteriaupdate

Minic S., Trpinac D., Obradovic M. Incontinentia pigmenti diagnosticcriteria update.Clin Genet 2014: 85: 536–542. © John Wiley & Sons A/S. Published byJohn Wiley & Sons Ltd, 2013

In 1993 diagnostic criteria for incontinentia pigmenti (IP), agenodermatosis in which skin changes are usually combined withanomalies of other organs, were established. Approximately a decade ago,IKBKG gene mutation was discovered as a cause for IP. This finding hasnot been included in IP diagnosis so far. In addition, literature data pointedout a few other clinical findings as possible IP diagnostic criteria.Literature facts concerning IP diagnosis were analyzed. Different organanomalies, their frequency and severity, were analyzed in the context ofapplicability as IP diagnostic criteria. Taking into account analyzed datafrom the literature, the proposal of updated IP diagnostic criteria waspresented. We propose as major criteria one of the stages of IP skinlesions. As updated IP minor criteria in our proposal we included: dental,ocular; central nervous system (CNS), hair, nail, palate, breast and nippleanomalies; multiple male miscarriages, and IP pathohistological findings.In the diagnosis of IP, the presence of IKBKG mutation typical for IP, andexistence of family relatives with diagnosed IP are taken into account.

Conflict of interest

None.

S. Minica, D. Trpinacb

and M. Obradovicb

aSchool of Medicine, University ofBelgrade and Clinics ofDermatovenerology, Clinical Center ofSerbia and bInstituteof Histology and Embryology, Schoolof Medicine, University of Belgrade,Belgrade, Serbia

Key words: anomalies – diagnosticcriteria – IKBKG gene – incontinentiapigmenti – molecular genetic testing

Corresponding author: Snezana Minic,Clinics of Dermatovenerology, ClinicalCenter of Serbia, School of Medicine,University of Belgrade, Deligradska 34,11000 Belgrade, Serbia.Tel.: +381 64 199 88 67;fax: +381 11 361 25 67;e-mail: dtrpinac@eunet.rs

Received 4 April 2013, revised andaccepted for publication 24 June 2013

Incontinentia pigmenti [IP (OMIM 308300),Bloch–Sulzberger syndrome] is a rare X-linkedgenodermatosis with an estimated prevalence of0.2/100,000 (1) in which changes of skin that arealways present are usually combined with anomaliesin skin appendages and in other organs (2). IP appearsalmost exclusively in females and is usually lethal inmales (3). The total number of IP patients registeredin the literature for the 1906–2012 period was 2291(91.83% females, 5.85% males, and 2.32% withunspecified sex) (4). IKBKG (Inhibitor of Kappa BKinase Gamma , previously NEMO ; OMIM 300248)is the only gene known to be associated with IP(2). Mutations of the IKBKG gene, localized on theX-chromosome, locus Xq28, are responsible for IP (5).The IKBKG gene product NEMO/IKKγ is required forthe activation of the nuclear factor-kappa B (NF-κB)transcription factor. As a consequence of IKBKGmutation in IP cells, its accurate gene product does not

arise and NF-κB activation does not occur (5). At theskin level, NF-κB appears to have a dual role in cellgrowth and apoptosis (6).

The phenotypic expression of IKBKG mutation ishighly variable, even among related patients withthe same mutation (5). In contrast, patients withdifferent IKBKG mutations may have the same clinicalphenotype (5). This variability is likely to be the resultof skewed X-chromosome inactivation and caused bythe pleiotropic role of the IKBKG gene product (7, 8). Itis hypothetically possible that a few different mutations(including IKBKG) are responsible for the completephenotypic characteristics of IP (4, 7).

In routine practice from 1993, established diag-nostic criteria for IP are Landy and Donnai’s (3)(Table 1). Anomalies are classified in the diagnostic cri-teria according to their frequency and severity. Besidesdermatological findings, IP criteria included dental andretinal anomalies and multiple male miscarriages (3).

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Table 1. Proposal for updates to Landy and Donnai’s IP criteria (3)

Major criteria Minor criteria (supportive evidence) Conditions for establishing IP diagnosis

Typical IP skin stages distributedalong Blaschko’s lines:

Vesiculo-bullous stageVerrucous stageHyperpigmented stageAtrophic/hypopigmented stage

Dental anomaliesOcular anomaliesa

CNS anomaliesb

AlopeciaAbnormal hair (sparse hair, wooly

hair, anomalies of eyebrows andeyelashes)

Abnormal nailsPalate anomaliesc

Nipple and breast anomaliesd

Multiple male miscarriagesTypical skin pathohistological findingsd

No evidence of IP in a first-degree female relative:If lacking genetic IKBKG mutation data, at least

two or more major criteria or one major andone or more minor criteria are necessary tomake a diagnosis of sporadic IP

In the case of confirmed IKBKG mutationtypical for IP any single major or minorcriterion is satisfactory for IP diagnosis

Evidence of IP in a first-degree female relative:Any single major or at least two minor criteria

In all cases eosinophilia and skewedX-chromosome inactivation supportsdiagnosise

a According to the authors.b According to Minic et al. (4).c According to Minic et al. (7, 9).d According to Hadj-Rabia et al. (10).e According to Parish et al. (44) and Donnai (11).

Original IP criteria did not include non-dental oralanomalies, non-retinal ocular anomalies, CNS anoma-lies, nipple anomalies, or pathohistological findings(3). Because the causative gene and type of muta-tion were not known yet, Landy and Donnai (3) couldnot consider the possibility of confirming IP diagno-sis by detecting IKBKG gene mutation using moleculargenetic testing. On the basis of several articles (4, 7–12)that considered some modifications of the existing cri-teria (3), we discussed the available literature, analyzedthe diagnostic criteria, and here propose their updating.

Phenotypic expression of disease

To obtain consistent and comparable data on thefrequency of hair and ocular anomalies in the IPliterature for the period 1993–2012, we carried out themeta-analysis of these anomalies in a manner similarto that used in systematic reviews of central nervoussystem (CNS), dental, and oral anomalies (4, 7). Themeta-analysis included IP patients from the period1993–2012 after IP diagnostic criteria were established(3). Details of analyses are presented in Appendix S1:meta-analysis of hair, nail, and ocular anomalies in theincontinentia pigmenti literature, Tables S1–S7.

Skin manifestations

Skin changes in IP represent IP major criteria (3).They typically occur at birth or during the first weeksof life to adulthood along Blaschko lines (2). Skinabnormalities are consistent IP features and usuallyoccur in four stages that evolve sequentially (2). Theonset, duration, and overlapping of IP stages varyamong patients, and not all patients experience all fourstages; stage 4 does not occur in all individuals (2).Each clinical stage has characteristic pathohistologicalfindings (10, 13). We present details of the clinical skin

changes for each stage, onset, and pathohistologicalfindings in Table 2. Because of the important diagnosticvalue of pathohistological findings in IP, Hadj-Rabiaet al. (10) proposed them as IP minor criteria.

Skin appendages anomalies

Anomalies of hairIP skin changes precede the appearance of hair changes.The complete absence of pilosebaceous units mayappear in IP stage 4 in affected skin areas (13, 14).Hair anomalies were classified as IP minor criteria (3).Almost 50% of IP patients have had or do have minorabnormal hair features (3, 15). In a recent study of198 IP patients, 66% reported hair abnormalities (16).Alopecia is a common hair anomaly in IP, especiallyat the vertex and often after blistering or verrucouslesions at the site (11). Most commonly, alopecia ismild and unnoticed (15). Besides the scalp, alopeciamay occur also on the trunk and extremities (2). Hairis often described as sparse early in childhood and aslusterless, wiry, or coarse later (11). Sparse eyelashesand eyebrows were also reported in 76% of 25 adultpatients (10). According to our investigation (AppendixS1, Tables S2 and S3), 24.83% (22.78% females and2.05% males) of 733 IP patients with investigated hairpresented different hair anomalies. All types of alopeciawere registered in 20.33% of investigated IP patients,and other non-alopecia hair anomalies were registeredin 4.50%. Vertex alopecia was found in 12.14% ofinvestigated IP patients, and non-vertrex alopecia wasfound in 8.18%. Non-alopecia hair anomalies includedsparse hair, wooly hair, and anomalies of eyebrows andeyelashes.

Anomalies of nailsThe age of onset of nail anomalies ranges from 3 to45 years of age, usually after puberty (17). The mean

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Table 2. Stages of skin changes evolution in IP: clinical findings (2, 3), stage onset (2, 3), pathohistological findings (10, 13) anddifferential diagnosis

StageClinical skinchanges Stage onset

Pathohistologicalskin findings

Differentialdiagnosis

Stage 1vesiculo-bullousstage

Erythema andblistering

Within the first fewweeks of life;generallydisappears byage 18 months

Eosinophilic spongiosisand intraepidermalvesicle containingeosinophils. Manyapoptotic keratinocytesin the epidermis

Dermatoses with blisteringin early infancy such asdifferent types ofepidermolysis bullosaand bullous bacterialinfection

Herpes simplexVaricella/herpes zoster

Stage 2 verrucousstage

Hypertrophic rash Within the first fewmonths of life;usually lasts for afew months

Papillomatosis,hyperkeratosis, andacanthosis of theepidermis. Manyapoptotic cells in theepidermis formingsquamous eddies.Major melaninincontinence

Verrucae vulgares (simplewarts)

Nevus verrucosusMolluscum contagiosumX-linked-dominant

chondrodysplasiapunctata

Linear epidermal nevi

Stage 3hyperpigmentedstage

Hyperpigmentation Usually begins asstage 2 starts toresolve; persistsinto adulthood

Marked melaninincontinence withnumerousmelanophages in thedermis. No moreepidermal hyperplasia.Scattered apoptoticcells in the epidermis

Hypomelanosis of ItoNaegeli syndromePigment mosaicism

Stage 4 atrophic/hypopigmentedstage

Hypopigmentationand alopecia

The hyperpigmen-tation usuallybegins to fade inthe teens andearly twenties;does not occur inall patients

An atrophic epidermis;massive reduction ofmelanin in the basallayer; the persistence ofapoptotic bodies in theepidermis or papillarydermis; the completeabsence ofpilosebaceous unitsand eccrine glands

Vitiligo with localizedalopecia

Different types ofectodermal dysplasia

age is 26.88 years of age (17). The reason for such lateonset of nail anomalies is still unknown. Nail changesmay involve all or most of the fingernails and toenails.The changes typically affect fingers more than toes (15),but the most common are on the first three digits of thehands (17). Nail changes were included in IP minorcriteria (3). In several reported series of IP patients,7.1–48% of them had nail anomalies (3, 12, 16, 18).According to our investigation (Appendix S1, TableS4), 8.7% (8.9% females, 7% males) of 723 IP patientswith investigated nails had different nail anomalies.Their manifestations ranged from mild ridging or pittingto severe nail dystrophy (11) or subungual or periungualtumors (3, 16). Biopsies and X-ray examination ofthe digits provide identification and diagnosis of suchsubungual tumors (17). The pathohistology of thesetumors corresponds closely to that seen in the verrucouscutaneous lesions of stage 2. These lesions can beassociated with bony deformities of the underlyingphalanges (3).

Anomalies of the breast and nipplesAbnormalities of the breast and nipples in IP have beenreported inconsistently in the literature (3). They werenot mentioned in Carney’s review (18). According toLandy and Donnai (3), the incidence of nipples andbreast anomalies was at least 10 times greater thanthe incidence in the general population. In order offrequency predominate supernumerary nipples, nipplehypoplasia, breast hypoplasia, and aplasia (3). BesidesLandy and Donnai (3), exceptions were studies ofBadgwell et al. (16) and Hadj-Rabia et al. (10), where11% and 30% of IP patients, respectively, with breastand nipple anomalies were presented. A possible reasonfor the discrepancy in the frequency of anomalies isthe fact that in the literature IP patients were usuallypresented as neonates or prepubescent children, whereasHadj-Rabia et al. (10) presented 25 adult IP patients.The prevalence of supernumerary nipples in the generalpopulation was 0.2–5% (19), lower than in IP patients.Differences in clinical phenotype of breast and nipple

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anomalies between prepubescent children and adultsarose from the fact that only after puberty are breastscompletely developed. Generally, before puberty it ispossible to notice only nipple numerical anomalies.

Dental and oral anomalies

Dental anomalies could be seen only after reaching thefirst year of life when tooth eruption starts, whereasoral anomalies can be detected immediately after birth.According to the reports with larger series of IP patients(9, 10, 12, 20–22), different percentages of IP patientswith dental and oral anomalies, from 30.86% (20)to 92% (10), as well as different numbers of dentaland oral anomaly types per patient, from 1.48 (21)to 2.48 (10), were found. In a systematic review inthe period 1993–2012 dental and/or oral anomalieswere observed in 54.38% of 513 stomatologicallyinvestigated IP patients (7). According to the frequency,dental and/or oral anomalies represent the most frequentand important IP minor diagnostic criteria (7). Ofall registered anomalies, 95.05% were dental, and4.95% were oral. The most frequent dental anomalieswere dental shape anomalies, hypodontia, and delayeddentition (36.42%, 31.22%, and 17.87%, respectively).Cleft and highly arched palate were the most frequentlyregistered oral anomalies (7, 9). Although the absolutenumber of palate anomalies is relatively small, thenumber is 25 times higher in IP patients than inthe general population (7). This fact indicates that itwould be useful for diagnostic purposes to consider oralanomalies, especially cleft and highly arched palate, asIP minor criteria because they are visible at birth, unlikedental anomalies, which are detectable only after 1 yearof age (7).

Ocular anomalies

Retinal anomalies were included in a list of IP diag-nostic criteria (3). It was also concluded that despiteall reported anomalies more than 90% of IP patientshave normal vision (3). Ocular anomalies occur fromthe neonatal period through the early infantile period(2). In IP patients ocular anomalies may be serious andmay lead to vision-threatening manifestations or evenblindness caused by retinal disease (23). Ophthalmo-logic findings of IP patients were published in severalretrospective studies with different results of IP patientswith ocular anomalies, from 16% to 77% (12, 18, 21,24–27). The majority of retinal anomalies in IP repre-sented vascular anomalies that included telangiectasia,ectasia, hemorrhage, arteriovenous anastomoses, neo-vascularization, and avascularity of retina (28). Theylead to a sequence of events, ending with retinaldetachment (23). Occasionally, the process can stopat any time and spontaneously regress, leaving varioussequelae (29, 30).

According to our investigation 37.24% of 831 IPpatients had different ocular anomalies (Appendix S1,Tables S5–S7). Retinal and non-retinal anomalies were

present in approximately the same ratio, 53.00% and47.00%, respectively. Vitreous anomalies and lensanomalies represented 3.38% and 2.61% of all anoma-lies. Microphthalmia and amaurotic eyes represented2.30% and 6.91%, respectively. The total number ofocular types of anomalies per patient was 2.11. A singleIP patient had different combinations of ocular anoma-lies: only retinal, only non-retinal, or a combinationof both types of anomalies. Serious vision-threateninganomalies represented 69.89% of all ocular anomalies.

Some of the aforementioned non-retinal, but serious,vision-threatening anomalies registered in IP patientswere present in the general population in much smallernumbers than in IP patients. Congenital cataracts werepresent in 0.3% (31) and microphthalmia in 0.02% ofthe general population (32). However, according to theetiologic classification of infantile and developmentalcataracts in dermatologic diseases, cataracts wereclassified as an IP feature (33). Although retinalanomalies are one of the IP diagnostic criteria (3), wefound non-retinal ocular anomalies in approximatelyhalf of IP patients registered (Appendix S1, Tables S6and S7). Some of the non-retinal anomalies were notincluded in actual IP diagnostic criteria (3). This waswhy we suggested modification of ‘retinal diseases’ inthe ‘ocular anomalies’ criterion that covers both retinaland non-retinal anomalies.

Central nervous system anomalies

CNS anomalies constitute the most serious compli-cations of IP (23). Similar to skin changes in IP,CNS anomalies occur from the neonatal period throughthe early infantile period (4). CNS abnormalities thatemerge in adulthood IP patients are unlikely to be aconsequence of IP. According to the several reportswith series of IP patients, 13–35% of the patients hadCNS anomalies (18, 20, 25). Landy and Donnai (3)omitted CNS anomalies as an IP criterion althougha high percentage of registered CNS anomalies thatthe authors stated (under 10%) for their unpublishedseries of 111 IP patients. Differences in findings arevery likely to originate from different sample sizes,and, because of the larger sample size, the results ofthe recent study were more reliable (4). In a system-atic review of CNS anomalies in IP during the period1993–2012, CNS anomalies were observed in 30.44%of 795 neurologically investigated IP patients (4). Themost frequent types of CNS anomalies were seizures,motor impairment, and mental retardation, which com-prise 41.98%, 25.70%, and 20.36%, respectively, ofall observed CNS anomaly types. Microcephaly wasregistered in 4.07% of IP patients (4). The majorityof neurologically investigated IP patients with CNSanomalies (18.86%) suffered from severe CNS anoma-lies (4). Moreover, IKBKG gene mutation involvementin mental retardation is generally recognized, and thegene was added to the list of mental retardation genes(34). Although limitations such as heterogeneity, differ-ent definitions, and criteria for their diagnosis, frequen-cies of seizures, motor impairment, mental retardation,

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and microcephaly were generally higher than in thecorresponding general population. For example, micro-cephaly for live births for the 2005–2009 period was1.67 per 10,000 births (35). In the general population,the prevalence of epilepsy was 0.005–0.01% (36), andthe prevalence of mental retardation was 1–3% (37).

On the basis of the collected and analyzed data, itis obvious that percentages of IP patients with CNS(30.44%) (4) and ocular anomalies (37.24%) (AppendixS1, Table S7) were high. Taking into account thefact that retinal anomalies were already recognized asIP minor criteria (3), the similar frequency of CNS(30.44%) (4) and retinal anomalies (23.58% accordingto our study, Appendix S1, Table S7), and the fact thatCNS anomalies represent the most important threat tothe normal lifespan of IP patients (14), CNS anomaliesshould be recognized as IP minor criteria (4).

Non-ectodermal IP manifestations

Under the influence of eotaxin expression in IP-affectedkeratinocytes (38) leukocytosis with eosinophilia mayoccur, particularly in stages 1 and 2 (2). In IP diagnosticcriteria (3), eosinophilia was classified as a majorcriterion. As eosinophilia is not pathognomonic for IP itmay only support IP diagnosis. Some unusual featuresin IP, such as ultrastructurally disordered leukocytes,were also observed (39).

Combination of different organ anomalies in IP

The relationship of the simultaneous occurrence ofthe most frequent IP extracutaneous anomalies: CNS,ocular, and dental and/or oral anomalies were investi-gated (4). According to this analysis of the literaturedata, 54.30% of IP patients with CNS anomalies hadassociated ocular anomalies. Dental and/or oral anoma-lies were present in 69.56% of IP patients with CNSanomalies. CNS, ocular, and dental and/or oral anoma-lies occurred in 36.93% of IP patients simultaneously.Different combinations of associated extracutaneousanomalies in IP are likely to be the result of skewed X-chromosome inactivation and caused by the pleiotropicrole of IKBKG gene product (20, 40).

Miscarriages

A history of multiple male miscarriages is one of theIP diagnostic criteria (3). Affected women have anincreased risk of miscarriage, most likely represent-ing affected male conceptions (11) that typically failto survive past the second trimester (15). It is advis-able to perform careful skin evaluation in women withrecurrent miscarriages and to perform IKBKG molecu-lar genetic testing (10).

IP in males

Although IP has been identified as a disease lethalfor males, approximately 120 males who meet the

diagnostic criteria for IP have been reported (7).Survival in a male is most often mediated throughsomatic mosaicism (41, 42). In some cases it ismediated through the 47,XXY karyotype (Klinefeltersyndrome) (41, 42).

Timetable of different organ anomalies appearance in IP

In establishing the diagnosis of IP, it is very importantto take into account the age at onset of some changesand age of the examinees. Usually skin changes appearfirst at birth (15), followed immediately by CNS (4)and eye (2) anomalies. Oral (not dental) anomaliesare visible at birth also (11). Hair anomalies aredetectable somewhat later, when the hair begins togrow. Dental anomalies can be seen only after reachingthe first year of life when tooth eruption starts (11).Numeric anomalies of the nipple are present at birth,and other breast anomalies develop after puberty (12).Nail anomalies occur usually after puberty (17).

Molecular genetic testing

Detecting IKBKG gene mutation responsible for IP (5),because of its high prevalence in IP, indicates that themutation detection has a high diagnostic relevance (43).Besides IP, several other phenotypes can be expressedthat are caused by different types of IKBKG genemutations (2).

IKBKG exons 4–10 deletion is common in individu-als with IP and is found in nearly 70–80% of IP patients(5, 8, 40). To date, 53 different (missense, frameshift,non-sense, and splice-site) mutations of IKBKG havebeen reported in IP patients (40). The rate of de novomutations is approximately 65% (40). These mutationsoriginate from different molecular mechanisms at theIKBKG locus (8).

When other IP major criteria are absent, detectionof positive IKBKG gene mutation typical for IP inthe presence of a single IP minor criterion wouldbe acceptable for making a diagnosis among femalefirst-degree relatives. Analytical methods for IKBKGmutation screening were discussed in detail recently byFusco et al. (8). In male patients with clinical signs ofIP, a diagnostic algorithm is proposed (42).

Although skewed X-chromosome inactivation is notunique for IP (2), some authors recommend addingevidence of skewed X-chromosome inactivation resultsto IP criteria (11, 44). Results of X-chromosomeinactivation studies are only supportive and need tobe carefully interpreted in the context of clinicalfindings and/or family history (2). Sometimes (e.g.when Klinefelter syndrome is suspected) karyotypeanalysis may be useful.

Identification of an IKBKG mutation allows carriersto make informed reproductive decisions, which takesinto account the risk of having an IP-affected child. Awomen with a mutation may decrease her risk of havingan IP-affected child by taking advantage of prenataldiagnosis (8). Preimplantation genetic diagnosis is alsopossible (8).

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Differential diagnosis

Any condition with skin manifestations in Blaschko’slines may be confused with IP (11). The age ofthe patient and the onset of changes are important.Differential diagnosis in the context of skin changesdepends on the IP stage. Numerous skin diseases couldbe considered (14) and are summarized in Table 2. Ifthere are no visible skin changes, differential diagnosisis far more difficult especially if no other familymembers have been diagnosed with IP.

Conclusion

Clinical features of IP are variable and are difficult todiagnose in cases with mild manifestations. Taking intoaccount all previously discussed aspects of clinical andlaboratory IP diagnostics, we present the proposal ofupdated IP diagnostic criteria.

Our proposal for updated IP major criteria includesany of four IP skin stages. For updated IP minor crite-ria, because of their frequency in IP compared with thefrequency in the general population and potential sever-ity, included the following: dental anomalies, ocular(instead of retinal) anomalies, CNS anomalies, alope-cia and abnormal hair, abnormal nails, palate, breastand nipple anomalies, multiple male miscarriages, andIP pathohistological findings. Eosinophilia and the evi-dence of skewed X-chromosome inactivation studiesmay be carefully considered as conditions that supportthe diagnosis of IP.

Besides IP major and minor criteria in establishingIP diagnosis presence of IKBKG mutation typical forIP, and existence of family relatives with diagnosedIP are taken into account. If there is no evidence ofIP in a first-degree female relative and genetic IKBKGmutation data are lacking, at least two or more majorcriteria or one major criterion and one or more minorcriteria are necessary to make a diagnosis of sporadicIP. If there is no evidence of IP in a first-degree femalerelative and the case is confirmed for IKBKG mutationtypical for IP, any single major or minor criterion issatisfactory for IP diagnosis. If there is evidence ofIP in a first-degree female relative, any single majorcriterion or at least two minor criteria are satisfactoryfor IP diagnosis.

Supporting Information

The following Supporting information is available for this article:

Appendix S1. Meta-analysys of hair, nail, and ocular anomalies inthe incontinentia pigmenti literature.Table S1. Number and percentage of IP patients according to sexin the period 1993–2012.Table S2. Number of IP patients according to sex with investigatedhair and presence of hair anomalies in the period 1993–2012.Table S3. Number of different hair anomaly types and theirpercentage in IP patients investigated for presence of hair anomaliesaccording to sex in the period 1993–2012.Table S4. Number of IP patients according to sex, investigatedpresence of nail anomalies and presence of nail anomalies in theperiod 1993–2012.

Table S5. Number of IP patients according to sex, ophthalmologicalinvestigation and presence of eye anomalies in the period1993–2012.Table S6. Number and percentage of single mild and serious visionthreatening nonretinal anomaly types according to sex in the period1993–2012.Table S7. Number and percentage of retinal, nonretinal, seriousvision threatening anomaly types with and without included retinalanomalies in IP patients according to sex in the period 1993–2012.

Additional Supporting information may be found in the onlineversion of this article.

Acknowledgements

This work was supported by Ministry of Education and Science ofthe Republic of Serbia grant number 175005.

References1. Orphanet Report Series. Prevalence of rare diseases: Bibliographic

data. 2012, from http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf. AccessedFebruary 20, 2013.

2. Scheuerle A, Ursini MV. Incontinentia pigmenti (Bloch–Sulzbergersyndrome). University of Washington, Seattle (WA): GeneReviews2008, from http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=i-p. Accessed February 20 2013.

3. Landy SJ, Donnai D. Incontinentia pigmenti (Bloch–Sulzbergersyndrome). J Med Genet 1993: 30: 53–59. DOI: 10.1136/jmg.30.1.53.

4. Minic S, Trpinac D, Obradovic M. Central nervous system anomaliesin incontinentia pigmenti. Orphanet J Rare Dis 2013: 8: 25. DOI:10.1186/1750-1172-8-25.

5. Smahi A, Courtois G, Vabres P et al. Genomic rearrangement in NEMOimpairs NF-κB activation and is a cause of incontinentia pigmenti.The International Incontinentia Pigmenti (IP) Consortium. Nature 2000:405: 466–472. DOI: 10.1038/35013114.

6. Kaufman CK, Fuchs E. It’s got you covered: NF-κB in the epidermis.J Cell Biol 2000: 149: 999–1004. DOI: 10.1083/jcb.149.5.999.

7. Minic S, Trpinac D, Gabriel H, Gencik M, Obradovic M. Dental andoral anomalies in incontinentia pigmenti: a systematic review. Clin OralInvest 2013: 17: 1–8. DOI: 10.1007/s00784-012-0721-5.

8. Fusco F, Pescatore A, Steffan J, Royer G, Bonnefont JP, Ursini MV.Clinical utility gene card for: incontinentia pigmenti. Eur J Hum Genet2013: 21. DOI: 10.1038/ejhg.2012.227.

9. Minic S, Novotny GEK, Trpinac D, Obradovic M. Clinical features ofincontinentia pigmenti with emphasis on oral and dental abnormalities.Clin Oral Invest 2006: 10: 343–347. DOI: 10.1007/s00784-006-0066-z.

10. Hadj-Rabia S, Rimella A, Smahi A et al. Clinical and histologicfeatures of incontinentia pigmenti in adults with nuclear factor-κBessential modulator gene mutations. J Am Acad Dermatol 2011: 64:508–515. DOI: 10.1016/j.jaad.2010.01.045.

11. Donnai D. Incontinentia Pigmenti. In: Cassidy S, Allanson JE, eds.Management of genetic syndromes, 2nd edn. Hoboken, NJ: Wiley-Liss,2005: 309–314.

12. Hadj-Rabia S, Froidevaux D, Bodak N et al. Clinical study of 40 casesof incontinentia pigmenti. Arch Dermatol 2003: 139: 1163–1170. DOI:10.1001/archderm.139.9.1163.

13. Fraitag S, Rimella A, de Prost Y, Brousse N, Hadj-Rabia S, BodemerC. Skin biopsy is helpful for the diagnosis of incontinentia pigmenti atlate stage (IV): a series of 26 cutaneous biopsies. J Cutan Pathol 2009:36: 966–971. DOI: 10.1111/j.1600-0560.2009.01206.x.

14. Berlin AL, Paller AS, Chan LS. Incontinentia pigmenti: a review andupdate on the molecular basis of pathophysiology. J Am Acad Dermatol2002: 47: 169–187. DOI: 10.1067/mjd.2002.125949.

15. Chen H. Atlas of genetic diagnosis and counseling. Totowa, NJ:Humana Press Inc, 2006: 539–544.

16. Badgwell AL, Iglesias AD, Emmerich S, Willner JP. The natural historyof incontinentia pigmenti as reported by 198 affected individuals.Abstract 38. American College of Medical Genetics Annual Meeting:Nashville, TN, 2007.

541

Minic et al.

17. Chun BS, Rashid R. Delayed onychodystrophy of incontinentiapigmenti: an evidence-based review of epidemiology, diagnosis andmanagement. J Drugs Dermatol 2010: 9: 350–354.

18. Carney RG. Incontinentia pigmenti: a world statistical analysis.Arch Dermatol 1976: 112: 535–542. DOI: 10.1001/archderm.1976.01630280059017.

19. Boyd E, Stevenson RE. Breasts. In: Stevenson RE, Hall JG, eds. Humanmalformations and related anomalies, 2nd edn. New York, NY: OxfordUniversity Press, 2006: 1049–1064.

20. Fusco F, Bardaro T, Fimiani G et al. Molecular analysis of the geneticdefect in a large cohort of IP patients and identification of novel NEMOmutations interfering with NF-κB activation. Hum Mol Genet 2004: 13:1763–1773. DOI: 10.1093/hmg/ddh192.

21. Phan TA, Wargon O, Turner AM. Incontinentia pigmenti case series:clinical spectrum of incontinentia pigmenti in 53 female patientsand their relatives. Clin Exp Dermatol 2005: 30: 474–480. DOI:10.1111/j.1365-2230.2005.01848.x.

22. Holmstrom G, Bergendal B, Hallberg G, Marcus S, Hallen A, DahlN. Incontinentia pigmenti – a rare disease with many symptoms.Lakartidningen 2002: 99: 1345–1350.

23. Goldberg MF. The skin is not the predominant problem in incontinentiapigmenti. Arch Dermatol 2004: 140: 748–750. DOI: 10.1001/arch-derm.140.6.748.

24. Holmstrom G, Thoren K. Ocular manifestations of incontinen-tia pigmenti. Acta Ophthalmol Scand 2000: 78: 348–353. DOI:10.1034/j.1600-0420.2000.078003348.x.

25. Kim BJ, Shin HS, Won CH et al. Incontinentia pigmenti: clinicalobservation of 40 Korean cases. J Korean Med Sci 2006: 21: 474–477.DOI: 10.3346/jkms.2006.21.3.474.

26. Pascual-Castroviejo I, Pascual-Pascual SI, Velazquez-Fragua R, Mar-tinez V. Incontinentia pigmenti: clinical and neuroimaging findings ina series of 12 patients. Neurologia 2006: 21: 239–248.

27. Minic S, Obradovic M, Kovacevic I, Trpinac D. Ocular anomalies inincontinentia pigmenti – literature review and meta-analysis. Srp ArhCelok Lek 2010: 138: 408–413. DOI: 10.2298/SARH1008408M.

28. Equi R, Bains HS, Jampol LM, Goldberg MF. Retinal tears occurringat the border of vascular and avascular retina in adult patients withincontinentia pigmenti. Retina 2003: 23: 574–576.

29. Fekrat S, Humayun MS, Goldberg MF. Spontaneous retinal reattach-ment in incontinentia pigmenti. Retina 1998: 18: 75–77.

30. Goldberg MF, Custis PH. Retinal and other manifestations ofincontinentia pigmenti (Bloch–Sulzberger syndrome). Ophthalmology1993: 100: 1645–1654. DOI: 10.1016/S0161-6420(93)31422-3.

31. Yee KT. The Special Senses. In: Keeling JS, Yee Khong T, eds.Fetal and neonatal pathology, 4th edn. London: Springer-Verlag, 2007:825–850.

32. Centers for Disease Control and Prevention (CDC). Improved nationalprevalence estimates for 18 selected major birth defects – United

States, 1999–2001. MMWR Morb Mortal Wkly Rep 2006: 54:1301–1305.

33. Traboulsi EI. Eye. In: Stevenson RE, Hall JG, eds. Human malforma-tions and related anomalies, 2nd edn. New York: Oxford UniversityPress, 2006: 297–325.

34. Ropers HH, Hamel BC. X-linked mental retardation. Nat Rev Genet2005: 6: 46–57. DOI: 10.1038/nrg1501.

35. EUROCAT Prevalence Data Tables, 2013 from http://www.eurocat-network.eu/prevdata/resultsPdf.aspx?title=B3&allanom=false&allregf=true&allrega=true&anomalies=8&winx=1256&winy=894.Accessed on February 20, 2013.

36. Theodore WH, Spencer SS, Wiebe S et al. Epilepsy in North America:a report prepared under the auspices of the global campaign againstepilepsy, the International Bureau for Epilepsy, the InternationalLeague Against Epilepsy, and the World Health Organization. Epilepsia2006: 47: 1700–1722. DOI: 10.1111/j.1528-1167.2006.00633.x.

37. Galasso C, Lo-Castro A, El-Malhany N, Curatolo P. ”Idiopathic”mental retardation and new chromosomal abnormalities. Ital J Pediatr2010: 36: 17. DOI: 10.1186/1824-7288-36-17.

38. Jean-Baptiste S, O’Toole EA, Chen M, Guitart J, Paller A, ChanLS. Expression of eotaxin, an eosinophil-selective chemokine, paral-lels eosinophil accumulation in the vesiculobullous stage of incon-tinentia pigmenti. Clin Exp Immunol 2002: 127: 470–478. DOI:10.1046/j.1365-2249.2002.01755.x.

39. Minic S, Trpinac D, Obradovic M, Novotny GE, Gabriel HD, KuhnM. Incontinentia pigmenti with ultrastructurally disordered leucocytes.J Clin Pathol 2010: 63: 657–659. DOI: 10.1136/jcp.2009.074203.

40. Fusco F, Paciolla M, Napolitano F et al. Genomic architecture atthe Incontinentia Pigmenti locus favours de novo pathological allelesthrough different mechanisms. Hum Mol Genet 2012: 21: 1260–1271.DOI: 10.1093/hmg/ddr556.

41. Kenwrick S, Woffendin H, Jakins T et al. Survival of male patients withincontinentia pigmenti carrying a lethal mutation can be explained bysomatic mosaicism or Klinefelter syndrome. Am J Hum Genet 2001:69: 1210–1217. DOI: 10.1086/324591.

42. Gregersen PA, Sommerlund M, Ramsing M, Gjørup H, RasmussenAA, Aggerholm A. Diagnostic and molecular genetic challenges inmale incontinentia pigmenti: a case report. Acta Derm Venereol 2013.DOI: 10.2340/00015555-1593.

43. Fusco F, Pescatore A, Bal E et al. Alterations of the IKBKG locus anddiseases: an update and a report of 13 novel mutations. Hum Mutat2008: 29: 595–604. [Epub ahead of print]. DOI: 10.1002/humu.20739.

44. Parrish JE, Scheuerle AE, Lewis RA, Levy ML, Nelson DL. Selectionagainst mutant alleles in blood leukocytes is a consistent feature inincontinentia pigmenti type 2. Hum Mol Genet 1996: 5: 1777–1783.DOI: 10.1093/hmg/5.11.1777.

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