Miljana Obradović

Incontinentia pigmenti diagnostic criteria update

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.

Systematic review of central nervous system anomalies in incontinentia pigmenti

The objective of this study was to present a systematic review of the central nervous system (CNS) types of anomalies and to consider the possibility to include CNS anomalies in Incontinentia pigmenti (IP) criteria. The analyzed literature data from 1,393 IP cases were from the period 1993–2012. CNS anomalies were diagnosed for 30.44% of the investigated IP patients. The total number of CNS types of anomalies per patient was 1.62. In the present study there was no significantly higher number of anomalies per patient in females than males. The most frequent CNS types of anomalies were seizures, motor impairment, mental retardation, and microcephaly. The most frequently registered CNS lesions found using brain imaging methods were brain infarcts or necrosis, brain atrophies, and corpus callosum lesions. IKBKG exon 4–10 deletion was present in 86.00% of genetically confirmed IP patients. The frequency of CNS anomalies, similar to the frequency of retinal anomalies in IP patients, concurrent with their severity, supports their recognition in the list of IP minor criteria.

Dental and oral anomalies in incontinentia pigmenti: a systematic review

ObjectivesIncontinentia pigmenti (IP) is an X-linked genodermatosis caused by a mutation of the IKBKG gene. The objective of this study was to present a systematic review of the dental and oral types of anomalies, to determine the total number and sex distribution of the anomalies, and to analyze possible therapies.Materials and methodsWe analyzed the literature data from 1,286 IP cases from the period 1993–2010.ResultsDental and/or oral anomalies were diagnosed for 54.38% of the investigated IP patients. Most of the anomaly types were dental, and the most frequent of these were dental shape anomalies, hypodontia, and delayed dentition. The most frequent oral anomaly types were cleft palate and high arched palate. IKBKG exon 4–10 deletion was present in 86.36% of genetically confirmed IP patients.ConclusionsAccording to the frequency, dental and/or oral anomalies represent the most frequent and important IP minor criteria. The most frequent mutation was IKBKG exon 4–10 deletion. The majority of dental anomalies and some of the oral anomalies could be corrected.Clinical relevanceBecause of the presence of cleft palate and high arched palate in IP patients, these two anomalies may be considered as diagnostic IP minor criteria as well.

Clinical features of incontinentia pigmenti with emphasis on oral and dental abnormalities

One of interesting aspects in dermatology is the fact that skin may reflect the presence of anomalies in other organs and tissues. One such example is incontinentia pigmenti (IP), a rare, complex, X-linked genodermatosis. Clinical manifestations of IP according to evolution and prognosis can be considered as skin, as well as dental, eye, and central nervous system, changes. We have investigated a total of nine families with 25 subjects, 23 females and 2 males. In 12 female and 2 male subjects, all of them with clinical characteristics of IP, we observed the following abnormalities: teeth-shape anomalies (coni- or peg-like teeth), the presence of numerous cariotic teeth, early dental loss, delayed eruption, partial anodontia, and gothic palate. To our knowledge, this is the first time that the presence of gothic palate in patients with IP has been documented. As we found out, in two female subjects and one male subject, in which nonrandomed X inactivation did not occur, gothic palate could be supposed as characteristic of IP.

DMCM, a benzodiazepine site inverse agonist, improves active avoidance and motivation in the rat.

There are several modulatory sites at GABA(A) receptors, which mediate the actions of many drugs, among them benzodiazepine. Three kinds of allosteric modulators act through the benzodiazepine binding site: positive (agonist), neutral (antagonist), and negative (inverse agonist). The goal of the present study was to examine the influence of the inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) acting on α GABA(A) receptor and compare its dose-response effects on memory and depression-like behavior. We independently studied the effects of DMCM (0.05-1.0 mg/kg) on retention versus acquisition of active avoidance and depression-like behavior in the forced swim test. Throughout the study, drugs were given intraperitoneally, 30 min before testing. ANOVA has showed that treatment with DMCM significantly affected retrieval of avoidance response (p<0.05), exerted promnesic effects in inverted U-shape manner. Dunnetts test indicated that the DMCM avoidance-facilitatory dose was 0.1mg/kg. At the dose facilitating retrieval of avoidance memory, DMCM significantly (p<0.05, comparison of regression coefficients by Students t-test) and progressively increased acquisition rate during 5 days training, compared to the saline group. In forced swim test, ANOVA indicated statistically significant effects of DMCM (p<0.05). Dunnetts analysis showed that DMCM significantly decreased immobility time at the dose of 0.1mg/kg, exerted acute antidepressant-like effects. Our results experimentally support the findings that under certain circumstances, nonselective benzodiazepine site inverse agonists, produce memory-enhancing and antidepressant-like effects. The molecular and neuronal substrates linking the actions of specific GABA-benzodiazepine receptor complex subunits remains to be further elucidated.

Antidepressant effects of an inverse agonist selective for α5 GABA-A receptors in the rat forced swim test

Abstract It has been shown in electrophysiological studies that the ligand L-655,708 possesses a binding selectivity and a moderate inverse agonist functional selectivity for α5-containing GABA-A receptors. The present study is aimed to investigate the antidepressant effects of the ligand L-655,708 in the forced swim test (FST) and its impact on locomotor activity in rats. The behavior of the animals was recorded with a digital camera, and the data were analyzed by one-way ANOVA, followed by Dunnett’s test. In FST, L-655,708 significantly decreased immobility time at a dose of 3 mg/kg after a single and repeated administration (p<0.05), exerting acute and chronic antidepressant effects. However, it did not induce significant differences in the time of struggling behavior during FST. Furthermore, L-655,708 did not show a significant effect on locomotor activity (p>0.05). These data suggest that negative modulation at GABA-A receptors containing the α5 subunit may produce antidepressant effects in rats. These effects were not confounded by locomotor influences.

Incontinentia pigmenti with ultrastructurally disordered leucocytes

Incontinentia pigmenti (IP) is a rare X-linked genodermatosis in which skin changes are combined with anomalies of other tissues, mainly of ectodermal origin. Mutations of the IKBKG gene are responsible for IP. Haematological disorders among IP patients are rare. Four female patients from a single family, with typical clinical characteristics of IP, are reported. In addition, all affected family members show a distinct haematological phenotype: hypogranular granulocytes, leucocytes with pseudoplatelets, and different anomalies of nuclei. Pseudoplatelets are a typical finding in patients with leukaemia. As there is dysfunction of the IKBKG gene in leukaemia, it is hypothesised that mis-regulation of the NEMO pathway may cause the appearance of pseudoplatelets in acute leukaemias as well as in IP. These observations suggest that IP may not be only linked to skin and organs of the ectodermal origin.

The acidophilic nature of neuronal Golgi impregnation.

The mechanisms of Golgi impregnation of neurons has remained enigmatic for decades. Recently, it was suggested that divalent (di)chromate anions play a role in the Golgi impregnation process. Therefore, we incubated slices of (para)formaldehyde-fixed rat brain tissue in solutions of potassium (di)chromate, phosphate, chloride or nitrate at pH 6 or 7. Slices were then immersed in solutions of silver nitrate and processed for light microscopical analysis. At pH 6, dichromate probes resulted in dense and homogeneous impregnation of neuronal cytoplasm (typical impregnation). At pH 7, chromate probes showed solely partial cytoplasmic and heavy nuclear-region neuron impregnation (atypical impregnation). Phosphate probes at pH 6 resulted in typical impregnation, whereas at pH 7 phosphate probes gave atypical impregnation. Both at pH 6 and 7, chloride and nitrate probes did not yield any Golgi impregnation. These findings confirmed the pH-dependence of silver-chromate Golgi impregnation as well as the correctness of corresponding acidic silver-phosphate impregnation. Our study revealed a previously unknown, strong anion-dependence of Golgi impregnation, suggesting that hydrogenated monovalent anions are carriers of the neuron impregnation.

Blaschko line analogies in the central nervous system: A hypothesis

In X-chromosome-linked skin disorders the pattern of involvement follows Blaschko lines. Patterns of changes analogous to cutaneous Blaschko lines in different X-linked diseases existed in other organs. There is no commonly accepted analogy to Blaschko lines in the central nervous system (CNS). The objective of this study was to consider a hypothesis of the existence of Blaschko lines in the CNS in the example of incontinentia pigmenti (IP). Articles were analyzed in which brain imaging methods were used in IP patients with CNS anomalies. In IP patients with neurological signs brain lesions usually were localized and extended radially. Affected areas did not correspond to territories vascularized by any determined artery. Radially distributed brain lesions morphologically match the radial unit model of cortical development. It can be proposed that in IP in CNS Blaschko line analogies, similar to those in the skin, represent the trace of development of the clone of neurons arising from the cell marked with IKBKG mutation. The hypothesis of the existence of Blaschko line analogies in CNS is supported by radially distributed CNS image findings in IP, the radial unit model of CNS development, and the common embryonic origin of skin, CNS, and eyes.

Ophthalmological findings in series of incontinentia pigmenti patients from Serbia.

INTRODUCTION Incontinentia pigmenti (IP) is a rare complex X-linked genodermatosis in which skin changes are combined with anomalies of other organs. Mutations of the NEMO gene localized on chromosome Xq28 are responsible for IP. Clinical manifestations of IP according to evolution and prognosis can be considered as skin changes and dental, eye and central nervous system changes. OBJECTIVE The aim of our study was to investigate type and frequency of ocular features in Serbian population. METHODS We investigated the total of 9 families with 22 subjects, 20 females and 2 males, at the Institute of Dermatovenerology, Clinical Centre of Serbia, in the period from 1989 to 2009. Our subjects were diagnosed clinically by a dermatologist and the diagnosis confirmed by cutaneous histopathology and ultrastructural analysis. The pedigrees, karyotype analyses, routine laboratory findings, additional specialized clinical examinations were done for all subjects. RESULTS Among 22 IP patients from our study, different ophthalmological anomalies were observed in 16% of subjects. In female subjects, all of them with clinical characteristics of IP, we observed the following anomalies: retinal detachment, microphthalmia, cataract, strabismus and nystagmus. CONCLUSION Compared to available literature data, our percentage of IP patients with anomalies was lower. It may be due to differences in examined populations or due to the fact that the patients in our study were firstly admitted to the Institute of Dermatology. Ophthalmological findings may be often considered as very severe anomalies in IP. It is very important to detect IP as early as possible, medically help and monitor these patients.