A novel frameshift mutation of the IKBKG gene causing typical incontinentia pigmenti

Introduction. Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis. Mutations of the IKBKG gene are responsible for IP. A deletion of exons 4-10 can be found in 80% of patients with IP. There are 69 different mutations of the IKBKG gene that have been reported. Case Outline. A proband, female patient from a family without previously diagnosed IP is reported. She had skin and dental changes typical of IP. The diagnosis was made according to updated IP criteria. Pathohistological and ultrastructural analysis of skin biopsy confirmed the diagnosis. However, the common deletion of exons 4-10 in the IKBKG gene could not be detected. Sequencing revealed the indel (deletion/insertion) mutation c.641_647delGCATGGAinsAT (p.Arg214HisfsX38) in exon 5 of the IKBKG gene. Because this mutation could not be detected in the unaffected mother of the proband, it seems to be a de novo mutation. Conclusion. The registered novel frameshift IKBKG mutation c.641_647delGCATGGAinsAT (p.Arg214HisfsX38) can be considered to be the cause of IP in this case. [Projekat Ministarstva nauke Republike Srbije, br. 175005

Systematic review of central nervous system anomalies in incontinentia pigmenti

<p>Abstract</p> <p>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. <it>IKBKG</it> 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.</p

First IKBKG gene mutation study in Serbian incontinentia pigmenti patients

Introduction. Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis. Mutations of the IKBKG gene are the only known cause of IP. The presence of other than skin changes is important in the diagnosis of atypical IP cases when skin changes are discrete. Objective. The study was designed to analyze clinical manifestation, family histories and the frequency of IKBKG gene mutation in IP patients in Serbia for the first time and to compare them with other reported findings. Methods. Two Serbian unrelated families with eight female subjects were investigated. Blood samples were used for IKBKG exon 4-10 deletion testing using modified PCR protocol. For probands pathohistological and ultrastructural analyses of skin biopsies were done. Results. Positive clinical diagnosis according to IP criteria was present in seven cases. In six of them, including probands, positive molecular gene testing for IKBKG exon 4-10 deletion was present. Conclusion. This is the first report of genetically confirmed IP in two Serbian families. The IP patients presented a common IKBKG exon 4-10 deletion. The frequency and type of IKBKG mutation found in investigated IP patients in Serbia were similar to results of other studies. Various clinical features of investigated patients have allowed us to demonstrate that molecular genetic testing which specifically detects the common IKBKG mutations, the only known cause of IP, is useful in diagnosing IP especially in mild or atypical cases. The molecular genetic testing of the IKBKG mutations may be helpful for rapid confirmation of IP diagnosis, prenatal diagnosis and carrier detection

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

The Impact of the <i>IKBKG</i> Gene on the Appearance of the Corpus Callosum Abnormalities in Incontinentia Pigmenti

Incontinentia pigmenti (IP) is a rare skin disease combined with anomalies of the teeth, eyes, and central nervous system (CNS). Mutations of the IKBKG gene are responsible for IP. Among the most frequent CNS abnormalities found in IP using magnetic resonance imaging (MRI) are corpus callosum (CC) abnormalities. The aim of the study was to determine the presence of CC abnormalities, their relationship with the IKBKG mutations, and the possible presence of mutations of other genes. A group of seven IP patients was examined. Analyses of the IKBKG gene and the X-chromosome inactivation pattern were performed, as well as MRI and whole exome sequencing (WES) with the focus on the genes relevant for neurodegeneration. WES analysis showed IKBKG mutation in all examined patients. A patient who had a mutation of a gene other than IKBKG was excluded from further study. Four of the seven patients had clinically diagnosed CNS anomalies; two out of four had MRI-diagnosed CC anomalies. The simultaneous presence of IKBKG mutation and CC abnormalities and the absence of other mutations indicate that IKBKG may be the cause of CC abnormalities and should be included in the list of genes responsible for CC abnormalities

Challenges in Rare Diseases Diagnostics: Incontinentia Pigmenti with Heterozygous GBA Mutation

Rare diseases represent a diagnostic challenge due to their number, variety of clinical phenomena, and possibility of a simultaneous presence of two or more diseases. An illustration of this challenge is an occurrence of a late diagnosis of a proband initially diagnosed with West syndrome, later revealed to be caused by Incontinentia pigmenti (IP). Furthermore, 20 years later, it was discovered that the proband was also a carrier of a heterozygous GBA gene mutation. The methods used in diagnostics were as follows: IKBKG gene analysis, the X-chromosome inactivation assay, analyses of the genes relevant for neurodegeneration, WES analysis, analysis of biochemical parameters typical for Gaucher disease (GD), and autoantibodies including IFN-&alpha;2a and IFN-&omega;. To avoid overlooking IP and other possible rare disease diagnoses, carefully searching for dermatological signs in these conditions is recommended. It is important that the diagnostic criteria are based on quality and extensive data from multiple studies of each rare disease. Establishing precise diagnostic criteria for as many rare diseases as possible and establishing a publicly accessible database of rare diseases with a search possibility according to phenotypic abnormalities and genetic mutations would greatly facilitate and speed up the establishment of an accurate diagnosis

Immunohistochemical study of pathological alterations of peritoneum in patients with terminal renal insufficiency and on peritoneal dialysis

Background/Aim. During peritoneal dialysis (PD) an exchange of substances between blood and dialysate takes place through specific histological structures of peritoneum. Peritoneal double-layered serous membrane has, so far, mostly been studied with electron microscopy on experimental animals. The aim of this study was to assess integrity of peritoneal tissue in end-stage renal disease (ESRD) and PD patients using standard light microscopy and immunohistochemical methods. Methods. Peritoneal tissue biopsies were performed on 25 persons: 8 healthy donors during nephrectomy, 9 ESRD patients upon insertion of PD catheter, and 8 PD patients upon removal of the catheter for medical indications. The samples were fixed and prepared routinely for immunocytochemical staining by standardized streptavidin biotin AEC method using a LSAB2® HRP kit (Dako®, Denmark) for collagen IV and analyzed by light microscopy. Results. We observed mesothelial detachment from lamina propria, duplicated basement membrane and much thicker blood vessel walls in ESRD and PD patients, compared to healthy subjects. Differences in histological structure, emphasized with immunostaining, indicated pathological alterations of peritoneal tissue in the renal patients. Conclusions. Imunohistochemistry can be used in studying histological alterations of peritoneal tissue in ESRD and PD patients. This method may indicate possible problems in filtration and secretion processes in this tissue