The results of this investigation presented the distribution by sex similar to the results of other studies
]. The percentage of IP patients with CNS anomalies was similar to the results of Carney
] and Hadj-Rabia et al.
], 30.5% and 32%, respectively. However, Fusco et al.
] identified 13% and Kim et al.
] identified 35% IP patients with CNS anomalies. These discrepancies could be explained by the differences in the IP patients’ cohort. The results of present statistical analysis of data by sex showed that there was no significant difference in the number of CNS anomaly types per patient or in the distribution of seizures, mental retardation, and motor impairment.
Besides limitations such as heterogeneity, different definitions, and criteria for their diagnosis, frequencies of seizures, motor impairment, mental retardation, and microcephaly were generally higher than in the corresponding general population. For example, according to Eurocat Prevalence Data Tables
] microcephaly for live births for the 2005–2009 period was 1.67 per 10,000 births. In the general population the prevalence of epilepsy was 0.005-0.01%
], and the prevalence of mental retardation was 1-3%
In the present study there was no significantly higher number of anomalies per patient in females than males. Fusco et al.
] found higher values, 2.25 CNS anomaly types per patient in females and 2.40 in males, whereas Kim et al.
] found only one CNS anomaly type per patient. Fusco et al.
] found 13.55% in female and 35.71% in male IP patients with CNS anomalies. These differences in findings very likely originate from different sample sizes, and, because of the larger sample size, the results of the present study were more reliable.
Because pathoanatomical findings in IP patients were very rare
], brain imaging methods gave the majority of data concerning the morphological aspects of CNS lesions
]. The most frequently registered CNS lesions with the brain imaging method were brain infarcts or necrosis, brain atrophy, and corpus callosum lesions.
Besides the fact that IP results from enhanced apoptosis due to mutations in the IKBKG
], pathogenesis of CNS lesions in IP is still controversial issue. The CNS lesions may share a common pathophysiologic state with the vascular occlusive disease seen in the retinas of IP patients
]. However, other brain imaging and pathoanatomical studies fail to show a relationship between brain abnormalities and vascular patterns
]. Brain infarcts found in IP patients
] supported the hypothesis of vascular pathogenesis of CNS lesions in IP, whereas findings of brain atrophy
], corpus callosum lesions
], disorder of myelination
] and lack of relationship between brain abnormalities and vascular patterns
] supported the hypothesis of disorder of the NF-κB metabolic pathway in neurons and glia cells as a pathogenetic mechanism.
CNS lesions in IP can result from the same pathogenesis as skin
], by inducing apoptosis of IKBKG
mutated cells because the CNS, such as the skin, is of ectodermal origin. The evolution of the lesions can be interpreted as representing the death of cells that have the IKBKG
mutation-bearing X-chromosome as the active one and their replacement by cells in which the normal X-chromosome is active
]. Considering the similarities between IP retinopathy and retinopathies of prematurity
] and in diabetes
], the fact that apoptosis in the diabetic rat retina occurred before changes in microcirculation
] indicates that a similar process may occur in the retina and the CNS of IP patients. One must bear in mind the fact that apoptosis is a process defined by manifesting specific morphological and molecular features, visible only in histological sections under microscope
], not visible directly and clinically in patient. It is possible that in the CNS, as in the retina, apoptotic changes precede vascular changes, but the first clinically noticeable signs in IP patients are vascular changes. In the experimental model of retinopathy of prematurity occurred apoptosis of endothelial cells in the developing retina, leading to vaso-obliteration followed by proliferative retinopathy
]. It is possible to speculate that, besides parenchymal cells, apoptosis occurs in blood vessel walls’ cells of affected organs. For the time being there is no evidence for such a hypothesis.
Besides apoptosis, some other processes occurred in IKBKG
mutation affected tissue. IKBKG
mutation leads to expression of eotaxin, chemokine chemotactic for eosinophils
] responsible for eosinophil infiltration
]. Eotaxin is abnormally expressed in epidermis affected by IKBKG
mutation and in vascular endothelial cells, findings which correlate with eosinophil infiltration in the skin
]. Perivascular eosinophil deposition has been observed along with endothelial cell degeneration within retinal blood vessels
]. It was proposed that apoptotic keratinocytes act leading to inflammatory responses inducing synthesis and release of different chemokines including eotaxin and sequent eosinophil infiltration
]. There is also proposal that vascular endothelial growth factor (VEGF) receptor is involved in the vascular changes in IP
]. As NF-κB is involved in the transduction system of the messages received by the VEGF receptor, disorder of the transmission of this message in IP might influence cerebral microvascularization
Taking into account all the facts presented, identical pathophysiological mechanisms of IP development with apoptosis as a key event occur in all affected tissues, skin, retina, and CNS while the vascular changes in IP appear secondary to apoptosis.
A group of 50 IP patients from the literature with CNS anomalies that were positive tested for IKBKG
mutations was independently analyzed. The percentage of IP patients with common exon 4–10 deletion is similar to the results (80%) of Smahi and The International Incontinentia Pigmenti Consortium
]. Although the number of CNS anomaly types was higher for common IKBKG
exon 4–10 deletion, the difference was not significant. Fusco et al.
] found a similar distribution: 2.00 CNS anomaly types per IP patient with IKBKG
exon 4–10 deletion and 2.50 CNS anomaly types per IP patient with other than IKBKG
exon 4–10 deletion. However, because of the low number of documented patients with other than IKBKG
exon 4–10 mutations this can be also the result of a statistical bias. The correlation between type of IKBKG
mutation and IP phenotype expression was not found up to date.
We investigated the relationship of the simultaneous occurrence of the most frequent IP extracutaneous anomalies: CNS, ocular, and dental and/or oral anomalies. Based on literature data of a selected series of 29 IP patients with MRI confirmed CNS anomalies, from which 20 (68.96%) had associated ocular anomalies, it was speculated that ocular anomalies increase the chance of CNS anomalies in IP patients
]. However, Fusco et al.
] in a series of 59 genetically confirmed IP females found eight patients with CNS anomalies, only four of whom had associated ocular anomalies. In the Hadj-Rabia et al.
] study only three of 13 IP patients with CNS anomalies had associated ocular anomalies. In the present analyses of literature data 101 (54.30%) of the IP patients had associated ocular anomalies. In extensive meta-analyses 37.44% (289/772) of IP patients with diagnosed eye anomalies were found
]. The assumption that ocular anomalies increase the chance of CNS anomalies in IP patients
] was made based on a very specific and relatively small sample. The high number of accompanying ocular anomalies reflected primarily common embryonic origin of eyes and CNS. Besides ocular anomalies, dental and/or oral anomalies were analyzed. They were present in 80 (69.56%) IP patients with CNS anomalies. There was a higher correlation between CNS and dental and/or oral anomalies than CNS and ocular anomalies. In an extensive systematic review dental and/or oral anomalies were diagnosed for 54.38% (279/513) of the investigated IP patients
]. A total of 41 IP patients had CNS, ocular, and dental and/or oral anomalies simultaneously. Different combinations of associated extracutaneous anomalies in IP are likely to be the result of skewed X-chromosome inactivation and due to the pleiotropic role of IKBKG
Because the epidermis, a key substrate of IP, and CNS had same embryonic origin, it was supposed that IP CNS changes are in accordance with their origin
]. However, besides the fact that IKBKG
gene mutations were considered as the only cause of IP phenotype
], one must consider that other possibilities for their origin may exist. This problem is related not only to CNS anomalies associated with IP. A similar situation with dental and oral anomalies was recently discussed in detail
]. Because IKBKG
is involved in a complex NF-κB signaling pathway that regulates the expression of hundreds of genes
], its mutation can produce different disorders in organisms, and the entire spectrum of anomalies seen in IP usually is attributed to IKBKG
mutations. Statistical data indicate that incidences of typical CNS anomalies in IP were much higher than in the general population. However, there are no absolute facts that exclude the possibility that some other gene mutations in IP patients besides IKBKG
]. There are a great number of genes whose mutations are responsible for different anomalies, including some CNS anomalies found in IP: mental retardation, seizure, and microcephaly. Besides involvement of IKBKG
gene mutation in mental retardation that is generally recognized
], there are more than 290 other genes involved in mental retardation
]. Thus, it is hypothetically possible that cutaneous manifestations in IP originate from IKBKG
mutation, whereas extracutaneous anomalies in IP patients originate from some gene mutation other than IKBKG
. According to this hypothesis there is an option that combinations of mutations of IKBKG
and some other gene(s) are responsible for final IP phenotype expression – skin changes and associated extracutaneous anomalies. In the available literature there are no facts to confirm or reject such a hypothesis. So the possibility of the existence of a few different mutations (including IKBKG
) responsible for the complete phenotypic characteristics of IP is still open.
According to Landy and Donnai’s IP diagnostic criteria
], skin lesions were classified as IP major criteria, whereas dental, hair, nail, and retinal anomalies were classified as IP minor criteria. Landy and Donnai
] registered a high percentage of CNS anomalies (<10%) in their unpublished series of 111 IP patients, but omitted CNS anomalies as IP minor criteria. Histological features of affected skin and nipple anomalies as well as oral anomalies, especially palate anomalies, were also omitted so far as minor criteria
]. To establish the possibility to include CNS anomalies as IP minor criteria, percentages of severe CNS anomalies and retinal anomalies in IP were compared. In our meta-analysis of eye anomalies in IP patients for the 1976–2010 period, 37.44% of IP patients with diagnosed eye anomalies were found
]. Retinal anomalies were present in 17.52% of IP patients
]. Based on collected and analyzed data it is obvious that the total percentage of IP patients with CNS (30.44%) and ocular anomalies (37.44%)
] is similar, as is the percentage of IP patients with vision-threatening retinal (17.52%)
] and severe CNS (18.86%) anomalies. Taking into account that vision-threatening retinal anomalies, already recognized as IP minor criteria
], were registered in a smaller percentage than severe CNS anomalies and the fact that CNS anomalies represent the most important threat to the normal life span of patients with IP
], CNS anomalies should be included as IP minor criteria.
Currently causative therapy for IP, including associated CNS anomalies, does not exist. CNS anomalies are life threatening and are the most severe consequences of IP. Because CNS anomalies usually occur from the neonatal through the early infantile period, fast referral of neonates with IP to pediatric neurologists should be routinely considered.