2013 John Wiley & Sons A/S.

Published by John Wiley & Sons Ltd

Clin Genet 2013

Printed in Singapore. All rights reserved

CLINICAL GENETICS
doi: 10.1111/cge.12223

Original Article

Incontinentia pigmenti diagnostic criteria

update
Minic S, Trpinac D, Obradovic M. Incontinentia pigmenti diagnostic
criteria update.
Clin Genet 2013. John Wiley & Sons A/S. Published by John Wiley &
Sons Ltd, 2013
In 1993 diagnostic criteria for incontinentia pigmenti (IP), a
genodermatosis in which skin changes are usually combined with
anomalies of other organs, were established. Approximately a decade ago,
IKBKG gene mutation was discovered as a cause for IP. This finding has
not been included in IP diagnosis so far. In addition, literature data pointed
out a few other clinical findings as possible IP diagnostic criteria.
Literature facts concerning IP diagnosis were analyzed. Different organ
anomalies, their frequency and severity, were analyzed in the context of
applicability as IP diagnostic criteria. Taking into account analyzed data
from the literature, the proposal of updated IP diagnostic criteria was
presented. We propose as major criteria one of the stages of IP skin
lesions. As updated IP minor criteria in our proposal we included: dental,
ocular; central nervous system (CNS), hair, nail, palate, breast and nipple
anomalies; multiple male miscarriages, and IP pathohistological findings.
In the diagnosis of IP, the presence of IKBKG mutation typical for IP, and
existence of family relatives with diagnosed IP are taken into account.
Conflict of interest

None.

Incontinentia pigmenti [IP (OMIM 308300),

BlochSulzberger syndrome] is a rare X-linked
genodermatosis with an estimated prevalence of
0.2/100,000 (1) in which changes of skin that are
always present are usually combined with anomalies
in skin appendages and in other organs (2). IP appears
almost exclusively in females and is usually lethal in
males (3). The total number of IP patients registered
in the literature for the 19062012 period was 2291
(91.83% females, 5.85% males, and 2.32% with
unspecified sex) (4). IKBKG (Inhibitor of Kappa B
Kinase Gamma, previously NEMO; OMIM 300248)
is the only gene known to be associated with IP
(2). Mutations of the IKBKG gene, localized on the
X-chromosome, locus Xq28, are responsible for IP (5).
The IKBKG gene product NEMO/IKK is required for
the activation of the nuclear factor-kappa B (NF-B)
transcription factor. As a consequence of IKBKG
mutation in IP cells, its accurate gene product does not

S Minic a , D Trpinacb
and M Obradovic b
a
School of Medicine, University of
Belgrade and Clinics of
Dermatovenerology, Clinical Center of
Serbia and b Institute
of Histology and Embryology, School
of Medicine, University of Belgrade,
Belgrade, Serbia

Key words: anomalies diagnostic

criteria IKBKG gene incontinentia
pigmenti molecular genetic testing

Corresponding author: Snezana

Minic,

Clinics of Dermatovenerology, Clinical

Center 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 and
accepted for publication 24 June 2013

arise and NF-B activation does not occur (5). At the

skin level, NF-B appears to have a dual role in cell
growth and apoptosis (6).
The phenotypic expression of IKBKG mutation is
highly variable, even among related patients with
the same mutation (5). In contrast, patients with
different IKBKG mutations may have the same clinical
phenotype (5). This variability is likely to be the result
of skewed X-chromosome inactivation and caused by
the pleiotropic role of the IKBKG gene product (7, 8). It
is hypothetically possible that a few different mutations
(including IKBKG) are responsible for the complete
phenotypic characteristics of IP (4, 7).
In routine practice from 1993, established diagnostic criteria for IP are Landy and Donnais (3)
(Table 1). Anomalies are classified in the diagnostic criteria according to their frequency and severity. Besides
dermatological findings, IP criteria included dental and
retinal anomalies and multiple male miscarriages (3).

Minic et al.
Table 1. Proposal for updates to Landy and Donnais IP criteria (3)
Major criteria
Typical IP skin stages distributed
along Blaschkos lines:
Vesiculo-bullous stage
Verrucous stage
Hyperpigmented stage
Atrophic/hypopigmented stage

Minor criteria (supportive evidence)

Conditions for establishing IP diagnosis

Dental anomalies
Ocular anomaliesa
CNS anomaliesb
Alopecia
Abnormal hair (sparse hair, wooly
hair, anomalies of eyebrows and
eyelashes)
Abnormal nails
Palate anomaliesc
Nipple and breast anomaliesd
Multiple male miscarriages
Typical 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 and
one or more minor criteria are necessary to
make a diagnosis of sporadic IP
In the case of confirmed IKBKG mutation
typical for IP any single major or minor
criterion 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 skewed
X-chromosome inactivation supports
diagnosise

According to the authors.

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).
b

Original IP criteria did not include non-dental oral

anomalies, non-retinal ocular anomalies, CNS anomalies, nipple anomalies, or pathohistological findings
(3). Because the causative gene and type of mutation were not known yet, Landy and Donnai (3) could
not consider the possibility of confirming IP diagnosis by detecting IKBKG gene mutation using molecular
genetic testing. On the basis of several articles (4, 712)
that considered some modifications of the existing criteria (3), we discussed the available literature, analyzed
the diagnostic criteria, and here propose their updating.
Phenotypic expression of disease

To obtain consistent and comparable data on the

frequency of hair and ocular anomalies in the IP
literature for the period 19932012, we carried out the
meta-analysis of these anomalies in a manner similar
to that used in systematic reviews of central nervous
system (CNS), dental, and oral anomalies (4, 7). The
meta-analysis included IP patients from the period
19932012 after IP diagnostic criteria were established
(3). Details of analyses are presented in Appendix S1:
meta-analysis of hair, nail, and ocular anomalies in the
incontinentia pigmenti literature, Tables S1S7.
Skin manifestations

Skin changes in IP represent IP major criteria (3).

They typically occur at birth or during the first weeks
of life to adulthood along Blaschko lines (2). Skin
abnormalities are consistent IP features and usually
occur in four stages that evolve sequentially (2). The
onset, duration, and overlapping of IP stages vary
among patients, and not all patients experience all four
stages; stage 4 does not occur in all individuals (2).
Each clinical stage has characteristic pathohistological
findings (10, 13). We present details of the clinical skin

changes for each stage, onset, and pathohistological

findings in Table 2. Because of the important diagnostic
value of pathohistological findings in IP, Hadj-Rabia
et al. (10) proposed them as IP minor criteria.
Skin appendages anomalies
Anomalies of hair

IP skin changes precede the appearance of hair changes.

The complete absence of pilosebaceous units may
appear 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 minor
abnormal hair features (3, 15). In a recent study of
198 IP patients, 66% reported hair abnormalities (16).
Alopecia is a common hair anomaly in IP, especially
at the vertex and often after blistering or verrucous
lesions at the site (11). Most commonly, alopecia is
mild and unnoticed (15). Besides the scalp, alopecia
may occur also on the trunk and extremities (2). Hair
is often described as sparse early in childhood and as
lusterless, wiry, or coarse later (11). Sparse eyelashes
and eyebrows were also reported in 76% of 25 adult
patients (10). According to our investigation (Appendix
S1, Tables S2 and S3), 24.83% (22.78% females and
2.05% males) of 733 IP patients with investigated hair
presented different hair anomalies. All types of alopecia
were registered in 20.33% of investigated IP patients,
and other non-alopecia hair anomalies were registered
in 4.50%. Vertex alopecia was found in 12.14% of
investigated IP patients, and non-vertrex alopecia was
found in 8.18%. Non-alopecia hair anomalies included
sparse hair, wooly hair, and anomalies of eyebrows and
eyelashes.
Anomalies of nails

The age of onset of nail anomalies ranges from 3 to

45 years of age, usually after puberty (17). The mean

Incontinentia pigmenti diagnostic criteria update

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

Clinical skin
changes

Stage onset

Pathohistological
skin findings

Differential
diagnosis
Dermatoses with blistering
in early infancy such as
different types of
epidermolysis bullosa
and bullous bacterial
infection
Herpes simplex
Varicella/herpes zoster
Verrucae vulgares (simple
warts)
Nevus verrucosus
Molluscum contagiosum
X-linked-dominant
chondrodysplasia
punctata
Linear epidermal nevi

Stage 1
vesiculo-bullous
stage

Erythema and
blistering

Within the first few

weeks of life;
generally
disappears by
age 18 months

Eosinophilic spongiosis
and intraepidermal
vesicle containing
eosinophils. Many
apoptotic keratinocytes
in the epidermis

Stage 2 verrucous
stage

Hypertrophic rash

Within the first few

months of life;
usually lasts for a
few months

Stage 3
hyperpigmented
stage

Hyperpigmentation

Usually begins as
stage 2 starts to
resolve; persists
into adulthood

Stage 4 atrophic/
hypopigmented
stage

Hypopigmentation
and alopecia

The hyperpigmentation usually

begins to fade in
the teens and
early twenties;
does not occur in
all patients

Papillomatosis,
hyperkeratosis, and
acanthosis of the
epidermis. Many
apoptotic cells in the
epidermis forming
squamous eddies.
Major melanin
incontinence
Marked melanin
incontinence with
numerous
melanophages in the
dermis. No more
epidermal hyperplasia.
Scattered apoptotic
cells in the epidermis
An atrophic epidermis;
massive reduction of
melanin in the basal
layer; the persistence of
apoptotic bodies in the
epidermis or papillary
dermis; the complete
absence of
pilosebaceous units
and eccrine glands

age is 26.88 years of age (17). The reason for such late
onset of nail anomalies is still unknown. Nail changes
may 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 the
hands (17). Nail changes were included in IP minor
criteria (3). In several reported series of IP patients,
7.148% of them had nail anomalies (3, 12, 16, 18).
According to our investigation (Appendix S1, Table
S4), 8.7% (8.9% females, 7% males) of 723 IP patients
with investigated nails had different nail anomalies.
Their manifestations ranged from mild ridging or pitting
to severe nail dystrophy (11) or subungual or periungual
tumors (3, 16). Biopsies and X-ray examination of
the digits provide identification and diagnosis of such
subungual tumors (17). The pathohistology of these
tumors corresponds closely to that seen in the verrucous
cutaneous lesions of stage 2. These lesions can be
associated with bony deformities of the underlying
phalanges (3).

Hypomelanosis of Ito
Naegeli syndrome
Pigment mosaicism

Vitiligo with localized

alopecia
Different types of
ectodermal dysplasia

Anomalies of the breast and nipples

Abnormalities of the breast and nipples in IP have been

reported inconsistently in the literature (3). They were
not mentioned in Carneys review (18). According to
Landy and Donnai (3), the incidence of nipples and
breast anomalies was at least 10 times greater than
the incidence in the general population. In order of
frequency predominate supernumerary nipples, nipple
hypoplasia, breast hypoplasia, and aplasia (3). Besides
Landy and Donnai (3), exceptions were studies of
Badgwell et al. (16) and Hadj-Rabia et al. (10), where
11% and 30% of IP patients, respectively, with breast
and nipple anomalies were presented. A possible reason
for the discrepancy in the frequency of anomalies is
the fact that in the literature IP patients were usually
presented as neonates or prepubescent children, whereas
Hadj-Rabia et al. (10) presented 25 adult IP patients.
The prevalence of supernumerary nipples in the general
population was 0.25% (19), lower than in IP patients.
Differences in clinical phenotype of breast and nipple

Minic et al.
anomalies between prepubescent children and adults
arose from the fact that only after puberty are breasts
completely developed. Generally, before puberty it is
possible to notice only nipple numerical anomalies.
Dental and oral anomalies

Dental anomalies could be seen only after reaching the

first year of life when tooth eruption starts, whereas
oral anomalies can be detected immediately after birth.
According to the reports with larger series of IP patients
(9, 10, 12, 2022), different percentages of IP patients
with dental and oral anomalies, from 30.86% (20)
to 92% (10), as well as different numbers of dental
and oral anomaly types per patient, from 1.48 (21)
to 2.48 (10), were found. In a systematic review in
the period 19932012 dental and/or oral anomalies
were observed in 54.38% of 513 stomatologically
investigated IP patients (7). According to the frequency,
dental and/or oral anomalies represent the most frequent
and important IP minor diagnostic criteria (7). Of
all registered anomalies, 95.05% were dental, and
4.95% were oral. The most frequent dental anomalies
were dental shape anomalies, hypodontia, and delayed
dentition (36.42%, 31.22%, and 17.87%, respectively).
Cleft and highly arched palate were the most frequently
registered oral anomalies (7, 9). Although the absolute
number of palate anomalies is relatively small, the
number is 25 times higher in IP patients than in
the general population (7). This fact indicates that it
would be useful for diagnostic purposes to consider oral
anomalies, especially cleft and highly arched palate, as
IP minor criteria because they are visible at birth, unlike
dental anomalies, which are detectable only after 1 year
of age (7).
Ocular anomalies

Retinal anomalies were included in a list of IP diagnostic criteria (3). It was also concluded that despite
all reported anomalies more than 90% of IP patients
have normal vision (3). Ocular anomalies occur from
the neonatal period through the early infantile period
(2). In IP patients ocular anomalies may be serious and
may lead to vision-threatening manifestations or even
blindness caused by retinal disease (23). Ophthalmologic findings of IP patients were published in several
retrospective studies with different results of IP patients
with ocular anomalies, from 16% to 77% (12, 18, 21,
2427). The majority of retinal anomalies in IP represented vascular anomalies that included telangiectasia,
ectasia, hemorrhage, arteriovenous anastomoses, neovascularization, and avascularity of retina (28). They
lead to a sequence of events, ending with retinal
detachment (23). Occasionally, the process can stop
at any time and spontaneously regress, leaving various
sequelae (29, 30).
According to our investigation 37.24% of 831 IP
patients had different ocular anomalies (Appendix S1,
Tables S5S7). Retinal and non-retinal anomalies were

present in approximately the same ratio, 53.00% and

47.00%, respectively. Vitreous anomalies and lens
anomalies represented 3.38% and 2.61% of all anomalies. Microphthalmia and amaurotic eyes represented
2.30% and 6.91%, respectively. The total number of
ocular types of anomalies per patient was 2.11. A single
IP patient had different combinations of ocular anomalies: only retinal, only non-retinal, or a combination
of both types of anomalies. Serious vision-threatening
anomalies represented 69.89% of all ocular anomalies.
Some of the aforementioned non-retinal, but serious,
vision-threatening anomalies registered in IP patients
were present in the general population in much smaller
numbers than in IP patients. Congenital cataracts were
present in 0.3% (31) and microphthalmia in 0.02% of
the general population (32). However, according to the
etiologic classification of infantile and developmental
cataracts in dermatologic diseases, cataracts were
classified as an IP feature (33). Although retinal
anomalies are one of the IP diagnostic criteria (3), we
found non-retinal ocular anomalies in approximately
half of IP patients registered (Appendix S1, Tables S6
and S7). Some of the non-retinal anomalies were not
included in actual IP diagnostic criteria (3). This was
why we suggested modification of retinal diseases in
the ocular anomalies criterion that covers both retinal
and non-retinal anomalies.
Central nervous system anomalies

CNS anomalies constitute the most serious complications of IP (23). Similar to skin changes in IP,
CNS anomalies occur from the neonatal period through
the early infantile period (4). CNS abnormalities that
emerge in adulthood IP patients are unlikely to be a
consequence of IP. According to the several reports
with series of IP patients, 1335% of the patients had
CNS anomalies (18, 20, 25). Landy and Donnai (3)
omitted CNS anomalies as an IP criterion although
a high percentage of registered CNS anomalies that
the authors stated (under 10%) for their unpublished
series of 111 IP patients. Differences in findings are
very likely to originate from different sample sizes,
and, because of the larger sample size, the results of
the recent study were more reliable (4). In a systematic review of CNS anomalies in IP during the period
19932012, CNS anomalies were observed in 30.44%
of 795 neurologically investigated IP patients (4). The
most frequent types of CNS anomalies were seizures,
motor impairment, and mental retardation, which comprise 41.98%, 25.70%, and 20.36%, respectively, of
all observed CNS anomaly types. Microcephaly was
registered in 4.07% of IP patients (4). The majority
of neurologically investigated IP patients with CNS
anomalies (18.86%) suffered from severe CNS anomalies (4). Moreover, IKBKG gene mutation involvement
in mental retardation is generally recognized, and the
gene was added to the list of mental retardation genes
(34). Although limitations such as heterogeneity, different definitions, and criteria for their diagnosis, frequencies of seizures, motor impairment, mental retardation,

Incontinentia pigmenti diagnostic criteria update

and microcephaly were generally higher than in the
corresponding general population. For example, microcephaly for live births for the 20052009 period was
1.67 per 10,000 births (35). In the general population,
the prevalence of epilepsy was 0.0050.01% (36), and
the prevalence of mental retardation was 13% (37).
On the basis of the collected and analyzed data, it
is obvious that percentages of IP patients with CNS
(30.44%) (4) and ocular anomalies (37.24%) (Appendix
S1, Table S7) were high. Taking into account the
fact that retinal anomalies were already recognized as
IP minor criteria (3), the similar frequency of CNS
(30.44%) (4) and retinal anomalies (23.58% according
to our study, Appendix S1, Table S7), and the fact that
CNS anomalies represent the most important threat to
the normal lifespan of IP patients (14), CNS anomalies
should be recognized as IP minor criteria (4).
Non-ectodermal IP manifestations

Under the influence of eotaxin expression in IP-affected

keratinocytes (38) leukocytosis with eosinophilia may
occur, particularly in stages 1 and 2 (2). In IP diagnostic
criteria (3), eosinophilia was classified as a major
criterion. As eosinophilia is not pathognomonic for IP it
may only support IP diagnosis. Some unusual features
in IP, such as ultrastructurally disordered leukocytes,
were also observed (39).
Combination of different organ anomalies in IP

The relationship of the simultaneous occurrence of

the most frequent IP extracutaneous anomalies: CNS,
ocular, and dental and/or oral anomalies were investigated (4). According to this analysis of the literature
data, 54.30% of IP patients with CNS anomalies had
associated ocular anomalies. Dental and/or oral anomalies were present in 69.56% of IP patients with CNS
anomalies. CNS, ocular, and dental and/or oral anomalies occurred in 36.93% of IP patients simultaneously.
Different combinations of associated extracutaneous
anomalies in IP are likely to be the result of skewed Xchromosome inactivation and caused by the pleiotropic
role of IKBKG gene product (20, 40).
Miscarriages

A history of multiple male miscarriages is one of the

IP diagnostic criteria (3). Affected women have an
increased risk of miscarriage, most likely representing affected male conceptions (11) that typically fail
to survive past the second trimester (15). It is advisable to perform careful skin evaluation in women with
recurrent miscarriages and to perform IKBKG molecular genetic testing (10).
IP in males

Although IP has been identified as a disease lethal

for males, approximately 120 males who meet the

diagnostic criteria for IP have been reported (7).

Survival in a male is most often mediated through
somatic mosaicism (41, 42). In some cases it is
mediated through the 47,XXY karyotype (Klinefelter
syndrome) (41, 42).
Timetable of different organ anomalies appearance in IP

In establishing the diagnosis of IP, it is very important

to take into account the age at onset of some changes
and age of the examinees. Usually skin changes appear
first at birth (15), followed immediately by CNS (4)
and eye (2) anomalies. Oral (not dental) anomalies
are visible at birth also (11). Hair anomalies are
detectable somewhat later, when the hair begins to
grow. Dental anomalies can be seen only after reaching
the 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 the
mutation detection has a high diagnostic relevance (43).
Besides IP, several other phenotypes can be expressed
that are caused by different types of IKBKG gene
mutations (2).
IKBKG exons 410 deletion is common in individuals with IP and is found in nearly 7080% of IP patients
(5, 8, 40). To date, 53 different (missense, frameshift,
non-sense, and splice-site) mutations of IKBKG have
been reported in IP patients (40). The rate of de novo
mutations is approximately 65% (40). These mutations
originate from different molecular mechanisms at the
IKBKG locus (8).
When other IP major criteria are absent, detection
of positive IKBKG gene mutation typical for IP in
the presence of a single IP minor criterion would
be acceptable for making a diagnosis among female
first-degree relatives. Analytical methods for IKBKG
mutation screening were discussed in detail recently by
Fusco et al. (8). In male patients with clinical signs of
IP, a diagnostic algorithm is proposed (42).
Although skewed X-chromosome inactivation is not
unique for IP (2), some authors recommend adding
evidence of skewed X-chromosome inactivation results
to IP criteria (11, 44). Results of X-chromosome
inactivation studies are only supportive and need to
be carefully interpreted in the context of clinical
findings and/or family history (2). Sometimes (e.g.
when Klinefelter syndrome is suspected) karyotype
analysis may be useful.
Identification of an IKBKG mutation allows carriers
to make informed reproductive decisions, which takes
into account the risk of having an IP-affected child. A
women with a mutation may decrease her risk of having
an IP-affected child by taking advantage of prenatal
diagnosis (8). Preimplantation genetic diagnosis is also
possible (8).

Minic et al.
Differential diagnosis

Any condition with skin manifestations in Blaschkos

lines may be confused with IP (11). The age of
the patient and the onset of changes are important.
Differential diagnosis in the context of skin changes
depends on the IP stage. Numerous skin diseases could
be considered (14) and are summarized in Table 2. If
there are no visible skin changes, differential diagnosis
is far more difficult especially if no other family
members have been diagnosed with IP.
Conclusion

Clinical features of IP are variable and are difficult to

diagnose in cases with mild manifestations. Taking into
account all previously discussed aspects of clinical and
laboratory IP diagnostics, we present the proposal of
updated IP diagnostic criteria.
Our proposal for updated IP major criteria includes
any of four IP skin stages. For updated IP minor criteria, because of their frequency in IP compared with the
frequency in the general population and potential severity, included the following: dental anomalies, ocular
(instead of retinal) anomalies, CNS anomalies, alopecia and abnormal hair, abnormal nails, palate, breast
and nipple anomalies, multiple male miscarriages, and
IP pathohistological findings. Eosinophilia and the evidence of skewed X-chromosome inactivation studies
may be carefully considered as conditions that support
the diagnosis of IP.
Besides IP major and minor criteria in establishing
IP diagnosis presence of IKBKG mutation typical for
IP, and existence of family relatives with diagnosed
IP are taken into account. If there is no evidence of
IP in a first-degree female relative and genetic IKBKG
mutation data are lacking, at least two or more major
criteria or one major criterion and one or more minor
criteria are necessary to make a diagnosis of sporadic
IP. If there is no evidence of IP in a first-degree female
relative and the case is confirmed for IKBKG mutation
typical for IP, any single major or minor criterion is
satisfactory for IP diagnosis. If there is evidence of
IP in a first-degree female relative, any single major
criterion or at least two minor criteria are satisfactory
for IP diagnosis.
Supporting Information
The following Supporting information is available for this article:
Appendix S1. Meta-analysys of hair, nail, and ocular anomalies in
the incontinentia pigmenti literature.
Table S1. Number and percentage of IP patients according to sex
in the period 19932012.
Table S2. Number of IP patients according to sex with investigated
hair and presence of hair anomalies in the period 19932012.
Table S3. Number of different hair anomaly types and their
percentage in IP patients investigated for presence of hair anomalies
according to sex in the period 19932012.
Table S4. Number of IP patients according to sex, investigated
presence of nail anomalies and presence of nail anomalies in the
period 19932012.

Table S5. Number of IP patients according to sex, ophthalmological

investigation and presence of eye anomalies in the period
19932012.
Table S6. Number and percentage of single mild and serious vision
threatening nonretinal anomaly types according to sex in the period
19932012.
Table S7. Number and percentage of retinal, nonretinal, serious
vision threatening anomaly types with and without included retinal
anomalies in IP patients according to sex in the period 19932012.
Additional Supporting information may be found in the online
version of this article.

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

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