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Incontinentia pigmenti (IP; OMIM# 308300) is a rare inherited disease caused by a mutation of IKBKG, which is also known as NEMO, located on Xq28. IP patients usually present with abnormalities of skin, eyes, nails and central nervous system. The neurological damege, which occur usually from neonatal through the early infantile period, leads to neulogical complication such as development retardation, motor paralysis and epilepsy. However, there has been little study done concerning the effect of therapy for the neural abnormalities. We have investigated the clinical findings in a female IP case with a novel mutation of IKBKG for six years due to disclosing the neurological prognosis and the immunological features. It is hoped that the present study will contribute to a better management of IP patients.

Summary Introduction Incontinentia pigmenti (IP) is an X-linked genodermatosis caused by mutation of the NEMO/IKBKG gene. While lethal in male foetuses, heterozygous females survive because of X-inactivation mosaicism. Herein we discuss 9 male patients with IP. Materials and methods This is an observational, descriptive, retrospective, multicentre, French study carried out with the help of the SFDP research group. Statistical analysis was performed both on our own patients and on those reported in the literature. Results Nine boys with no family history of IP but with typical neonatal skin reactions were included. Genetic analysis of blood (n = 8) and skin biopsy (n = 3) confirmed the diagnosis of IP by identification of common deletion of the IKBKG/NEMO gene (exons 4 to 10) in the state of somatic mosaic in 6 and 2 cases respectively. Where analysed, the karyotype was normal (n = 6). Over a median follow-up period of 48 months (3 months to 10 years), 3 patients had neurological abnormalities, 2 had severe ophthalmologic abnormalities, and 1 had dental abnormalities. Extensive skin involvement is a systemic risk factor, unlike cutaneous scarring. Conclusion IP in boys is often due to a mosaic mutation that should be sought in blood and skin. Long-term neurological and ophthalmological monitoring is essential, especially in cases of extensive skin involvement.

Santrauka. Pigmento nelaikymo liga – tai genodermatozė, kuriai budingas odos ir kitų ektoderminių organų pažeidimas. Tai reta liga, paveldima su X chromosoma susijusiu dominantiniu būdu. Liga pasireiškia dėl X chromosomoje įvykusio IKBKG/NEMO patogeninio pokyčio. Manoma, kad dėl to audiniuose sutrinka imuninė tolerancija, sukelianti autoimuninę reakciją. Šia liga serga beveik išimtinai mergaitės, nes liga dažniausiai yra letali vyriškosios lyties embrionams. Straipsnyje pristatomas labai retas pigmento nelaikymo klinikinis atvejis, nuo prenatalinės diagnostikos galimybių iki tolesnių paciento priežiūros gairių, apžvelgiami mokslinės literatūros duomenys.

Incontinentia Pigmenti (IP) is an X-linked rare genodermatosis caused by mutations in the IKBKG gene, which is essential to NF-κB pathway activation and thus fundamental for cell survival. Our objective was to study the intrafamilial clinical variability in IP by investigating how the signs of IP, and especially dental anomalies, vary within affected families. Four families, encompassing a total of 15 IP familial cases, were included in the study. The patients were subjected to clinical examination and collection of family histories for assessment of intrafamilial clinical variability. All familial cases carried the IKBKGdel recurrent deletion. A noticeable intrafamilial clinical variability was observed in all studied families, with mild and severe cases co-occurring within a same family. Additionally, to best of our knowledge, our study was the first to address the variability of dental defects within IP families, and here too, our results reveal remarkable differences among affected relatives. A number of as yet unidentified genes might act as modifiers, influencing disease expressivity. Our study found important clinical variability within four IP families and contributes to the understanding of the genetic background involved in IP expressivity.

Incontinentia pigmenti is a rare neuroectodermal dysplasia caused by a defect in the IKBKG gene (formerly known as NEMO). There are 27.6 new cases per year worldwide; 65% to 75% are sporadic mutations, and 25% to 35% are familial. It is usually lethal in males, but females survive because of X-inactivation mosaicism. The disorder is typically identified by unique skin findings, a series of four stages that emerge throughout the first year of life. The central nervous system manifestations in the eye and in the brain cause the most disability. Defects of hair, nails, and teeth occur, and there can be other systemic involvement. Surveillance protocols for medical management have been established by the Incontinentia Pigmenti International Foundation. This article will summarize the existing knowledge of this condition and detail the protocols to help manage the care of the infant or child who presents with incontinentia pigmenti.

Incontinentia pigmenti is a rare neurocutaneous disorder with a frequency of 1 in 40,000 newborn; it is associated with mutations in IKBKG gene in Xq28, inherited as an X-linked dominant trait. Clinical manifestations detected since the newborn period are highly variable, with skin, teeth, eyes, and nervous system manifestations, and each with a characteristic differential diagnosis. We present a pediatric patient diagnosed with incontinentia pigmenti at the first week of life. In the initial ophthalmologic evaluation, retinal vascular lesions were observed. The outcomes of laser treatment of the ischemic peripheral retina were good and resulted in stability of vision.

Most patients with ectodermal dysplasia-immunodeficiency (ED-ID) or incontinentia pigmenti (IP) harbor hemizygous/hypomorphic mutations in the IKBKG gene which encodes the protein NEMO

In this issue of Blood, Miot et al report encouraging results in a retrospective analysis of hematopoietic stem cell transplantation (HSCT) in 29 patients with hypomorphic mutations in the IKBKG gene encoding nuclear factor κB essential modulator (NEMO).

International audience; BACKGROUND:Noonan syndrome (NS) is an autosomal dominant multisystem disorder caused by the dysregulation of several genes belonging to the RAS Mitogen Activated Protein Kinase (MAPK) signaling pathway. Incontinentia Pigmenti (IP) is an X-linked, dominantly inherited multisystem disorder.CASE PRESENTATION:This study is the first report of the coexistence of Noonan (NS) and Incontinentia Pigmenti (IP) syndromes in the same patient. We report on the clinical phenotype and molecular characterization of this patient. The patient was examined by a pluridisciplinary staff of clinicians and geneticist. The clinical diagnosis of NS and IP was confirmed by molecular investigations. The newborn girl came to our clinics due to flagrant dysmorphia and dermatological manifestations. The clinical observations led to characterize the Incontinentia Pigmenti traits and a suspicion of a Noonan syndrome association. Molecular diagnosis was performed by Haloplex resequencing of 29 genes associated with RASopathies and confirmed the NS diagnosis. The common recurrent intragenic deletion mutation in IKBKG gene causing the IP was detected with an improved PCR protocol.CONCLUSION:This is the first report in the literature of comorbidity of NS and IP, two rare multisystem syndromes.

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]

SUMMARY 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 pathohisto- logical 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. Keywords: Incontinentia pigmenti; IKBKG gene; IKBKG exon 4-10 deletion; X-chromosome; X-chromo- some inactivation; phenotype

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.

Ectodermal dysplasias (ED) are uncommon genetic disorders resulting in abnormalities in ectodermally derived structures. Many ED-associated genes have been described, of which ectodysplasin-A (EDA) is one of the more common. The NF-κB essential modulator (NEMO encoded by the IKBKG gene) is unique in that mutations result in severe humoral and cellular immunologic defects in addition to ED. We describe three unrelated kindreds with defects in both EDA and IKBKG resulting from X-chromosome crossover. This demonstrates the importance of thorough immunologic consideration of patients with ED even when an EDA etiology is confirmed, and raises the possibility of a specific phenotype arising from coincident mutations in EDA and IKBKG.

Incontinentia 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. We analyzed the literature data from 1,286 IP cases from the period 1993–2010. Dental 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. According 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. Because 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.

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.