Incontinentia Pigmenti Patients Research Articles

Dental and oral anomalies in incontinentia pigmenti: a systematic review

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.

Ocular anomalies in incontinentia pigmenti: Literature review and meta-analysis

Incontinentia pigmenti (IP) is an X-linked genodermatosis in which skin changes are combined with dental, eye and central nervous system anomalies. The goal of the study was to analyze ocular findings, IP minor criteria in available literature concerning IP cases published until now. We have done meta-analysis of 1931 IP patients found in 302 references published until 2010. Comparison of data published for the 1906-1976 and 1976-2010 periods was made. The collected data were mainly frequencies of ocular anomalies. Chi-square test was used to compare observed frequencies with their expectations. Of total number of IP patients, 1227 were ophthalmologically investigated. In 449 such patients 972 eye anomalies were registered, 2.16 anomalies per patient. Proportion of ophthalmologically investigated IP patients in the period 1906-1975 (70%) was higher than corresponding proportion (60%) for the period 1976-2010. For 1906-2010 period 36.5% IP patients with eye anomalies were diagnosed. The number of amaurotic eyes per patient did not significantly differ for the two periods (p = 0.50; > 0.05). The total number of eye anomalies per patient significantly differed for the same periods (p = 0.00005; < 0.05). Retinal anomalies were most frequent in both periods. This study suggests that IP is far more frequent than anyone could estimate. We believe that this study, covering 1906-2010 period, gives more reliable information about ophthalmological findings in IP; considering them as severe anomalies. Early detection and treatment of ophthalmological, neurological etc. findings may prevent severe consequences that IP may cause.

Ophthalmological findings in series of incontinentia pigmenti patients from Serbia

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. The aim of our study was to investigate type and frequency of ocular features in Serbian population. 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. 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. 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 Common NF-κB Essential Modulator (NEMO) Gene Rearrangement in Korean Patients with Incontinentia Pigmenti

Incontinentia pigmenti (IP) is a rare X-linked dominant disorder characterized by highly variable abnormalities of the skin, eyes and central nervous system. A mutation of the nuclear factor-κB essential modulator (NEMO) located at Xq28 is believed to play a role in pathogenesis and the mutation occurs mostly in female patients due to fatal consequence of the mutation in males in utero. This study was designed to identify the common NEMO rearrangement in four Korean patients with IP. Deletion of exons 4 to 10 in the NEMO, the most common mutation in IP patients, was detected in all of the patients by the use of long-range PCR analysis. This method enabled us to discriminate between NEMO and pseudogene rearrangements. Furthermore, all of the patients showed skewed XCI patterns, indicating pathogenicity of IP was due to cells carrying the mutant X chromosome. This is the first report of genetically confirmed cases of IP in Korea.

Acute disseminated encephalomyelitis in an infant with incontinentia pigmenti

We report the case of a female Japanese infant who was diagnosed with incontinentia pigmenti (IP) on the basis of the clinical and pathological findings of characteristic skin lesions and the detection of deletion in the nuclear factor-kappa B essential modulator gene at Xq28. The patient developed repetitive seizures at the age of 7 months when she was diagnosed with acute disseminated encephalomyelitis (ADEM), an inflammatory demyelinating disease of the central nervous system that often occurs after vaccination or infection. The causative infectious agent in this patient seemed to be Mycoplasma pneumoniae because of the increased titer of its serum antibody and the detection of its DNA in the initial cerebrospinal fluid sample. This patient showed significant improvement on receiving immunosuppressive therapy with corticosteroids. This is the second case report presenting an IP patient susceptible to ADEM, and therefore, ADEM should be considered early in the differential diagnosis of acute neurological illness for IP patients.

Clinical and molecular analysis of NF‐κB essential modulator in Chinese incontinentia pigmenti patients

To analyze clinical manifestation and gene of NF-kappaB essential modulator (NEMO) in 12 pediatric incontinentia pigmenti (IP) patients. Twelve pediatric probands with three of their mothers were enrolled in this study. Physical examinations were undertaken for all patients and questionnaires requesting additional medical and developmental data were sent to the patients' families. The deletion of exon 4-10 and all 10 exons of NEMO gene were analyzed in these cases. Skin biopsy was performed in one case. All 15 patients had skin pigmentation abnormality and were diagnosed according to classic skin lesions. The prevalence of the dental, neurologic system, hair abnormality, and definite family history were 80.0%, 41.67%, 58.33%, and 25.0%, respectively. Histopathological examination was consistent with the diagnosis of IP with ectodermal dysplasia. In NEMO gene, deletion of exons 4-10 were noted in three cases and two of their mothers. A deletion of 19545 T in exon 6 was noted in one case and her mother. A 21690 T to C mutation in intron 8 of NEMO were found in another one case and her mother. The results suggest that skin lesion are the most prominent findings in clinics and the traditional diagnosis of IP is based on classic melanin pigmentation. Nucleotide deletion of exons 4-10 and single nucleotide mutation/polymorphism were found in these patients, which might account for etiopathogenesis of IP.

Skin lesion development in a mouse model of incontinentia pigmenti is triggered by NEMO deficiency in epidermal keratinocytes and requires TNF signaling

NF-kappaB essential modulator (NEMO), the regulatory subunit of the IkappaB kinase, is essential for NF-kappaB activation. Mutations disrupting the X-linked NEMO gene cause incontinentia pigmenti (IP), a human genetic disease characterized by male embryonic lethality and by a complex pathology affecting primarily the skin in heterozygous females. The cellular and molecular mechanisms leading to skin lesion pathogenesis in IP patients remain elusive. Here we used epidermis-specific deletion of NEMO in mice to investigate the mechanisms causing the skin pathology in IP. NEMO deletion completely inhibited NF-kappaB activation and sensitized keratinocytes to tumor necrosis factor (TNF)-induced death but did not affect epidermal development. Keratinocyte-restricted NEMO deletion, either constitutive or induced in adult skin, caused inflammatory skin lesions, identifying the NEMO-deficient keratinocyte as the initiating cell type that triggers the skin pathology in IP. Furthermore, genetic ablation of tumor necrosis factor receptor 1 (TNFRI) rescued the skin phenotype demonstrating that TNF signaling is essential for skin lesion pathogenesis in IP. These results identify the NEMO-deficient keratinocyte as a potent initiator of skin inflammation and provide novel insights into the mechanism leading to the pathogenesis of IP.

The NF-kappaB signalling pathway in human diseases: from incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes

The transcription factor NF-kappaB regulates the expression of numerous genes controlling the immune and stress responses, inflammatory reaction, cell adhesion, and protection against apoptosis. Incontinentia pigmenti (IP) is the first genetic disorder to be ascribed to NF-kappaB dysfunction. IP is an X-linked dominant genodermatosis antenatally lethal in males. A complex rearrangement of the NEMO (NF-kappaB essential modulator) gene accounts for 85% of IP patients, and results in undetectable NEMO protein and absent NF-kappaB activation. On the other hand, hypohidrotic/anhidrotic ectodermal dysplasia (HED/EDA) has been ascribed to at least three genes also involved in NF-kappaB activation: ectodysplasin (EDA1), EDA-receptor (EDAR) and EDAR-associated death domain (EDARADD). During hair follicle morphogenesis, EDAR is activated by ectodysplasin, and uses EDARADD as an adapter to build a signal transducing complex that leads to NF-kappaB activation. Hence, several forms of HED/EDA also result from impaired activation of the NF-kappaB cascade. Finally, hypomorphic NEMO mutations have been found to cause anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), whilst stop codon mutations cause a more severe phenotype associating EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). The immunological and infectious features observed in patients result from impaired NF-kappaB signalling, including cellular response to LPS, IL-1beta, IL-18, TNF-alpha, Tlr2 and CD40 ligand. Consistently, mouse knockout models have shown the essential role of NF-kappaB in the immune, inflammatory and apoptotic responses. Unravelling the molecular bases of other forms of EDA not associated with mutations in NEMO will possibly implicate other components of the NF-kappaB signalling pathway.

Multiple pathogenic and benign genomic rearrangements occur at a 35 kb duplication involving the NEMO and LAGE2 genes.

The X-linked dominant and male-lethal disorder incontinentia pigmenti (IP) is caused by mutations in a gene called NEMO (IKK-gamma). We recently reported the structure of NEMO and demonstrated that most IP patients carry an identical deletion that arises due to misalignment between repeats. Affected male abortuses with the IP deletion had provided clues that a second, incomplete copy of NEMO was present in the genome. We have now identified clones containing this truncated copy (Delta NEMO) and incorporated them into a previously constructed physical contig in distal Xq28. Delta NEMO maps 22 kb distal to NEMO and only contains exons 3-10, confirming our proposed model. A sequence of 26 kb 3' of the NEMO coding sequence is also present in the same position relative to the Delta NEMO locus, bringing the total length of the duplication to 35.5 kb. The LAGE2 gene is also located within this duplicated region, and a similar but unique LAGE1 gene is located just distal to the duplicated loci. Mapping and sequence information indicated that the duplicated regions are in opposite orientation. Analysis of the great apes suggested that the NEMO/LAGE2 duplication occurred after divergence of the lineage leading to present day humans, chimpanzees and gorillas, approximately 10-15 million years ago. Intriguingly, despite this substantial evolutionary history, only 22 single nucleotide differences exist between the two copies over the entire 35.5 kb, making the duplications >99% identical. This high sequence identity and the inverted orientations of the two copies, along with duplications of smaller internal sections within each copy, predispose this region to various genomic alterations. We detected four rearrangements that involved NEMO, Delta NEMO or LAGE1 and LAGE2. The high sequence similarity between the two NEMO/LAGE2 copies may be due to frequent gene conversion, as we have detected evidence of sequence transfer between them. Together, these data describe an unusual and complex genomic region that is susceptible to various types of pathogenic and polymorphic rearrangements, including the recurrent lethal deletion associated with IP.

A recurrent deletion in the ubiquitously expressed NEMO (IKK-gamma) gene accounts for the vast majority of incontinentia pigmenti mutations.

Incontinentia pigmenti (IP) is an X-linked dominant disorder characterized by abnormal skin pigmentation, retinal detachment, anodontia, alopecia, nail dystrophy and central nervous system defects. This disorder segregates as a male lethal disorder and causes skewed X-inactivation in female patients. IP is caused by mutations in a gene called NEMO, which encodes a regulatory component of the IkappaB kinase complex required to activate the NF-kappaB pathway. Here we report the identification of 277 mutations in 357 unrelated IP patients. An identical genomic deletion within NEMO accounted for 90% of the identified mutations. The remaining mutations were small duplications, substitutions and deletions. Nearly all NEMO mutations caused frameshift and premature protein truncation, which are predicted to eliminate NEMO function and cause cell lethality. Examination of families transmitting the recurrent deletion revealed that the rearrangement occurred in the paternal germline in most cases, indicating that it arises predominantly by intrachromosomal misalignment during meiosis. Expression analysis of human and mouse NEMO/Nemo showed that the gene becomes active early during embryogenesis and is expressed ubiquitously. These data confirm the involvement of NEMO in IP and will help elucidate the mechanism underlying the manifestation of this disorder and the in vivo function of NEMO. Based on these and other recent findings, we propose a model to explain the pathogenesis of this complex disorder.

Female Mice Heterozygous for IKKγ/NEMO Deficiencies Develop a Dermatopathy Similar to the Human X-Linked Disorder Incontinentia Pigmenti

IKKγ/NEMO is the essential regulatory subunit of the IκB kinase (IKK), encoded by an X-linked gene in mice and humans. It is required for NF-κB activation and resistance to TNF-induced apoptosis. Female mice heterozygous for Ikkγ/Nemo deficiency develop a unique dermatopathy characterized by keratinocyte hyperproliferation, skin inflammation, hyperkeratosis, and increased apoptosis. Although Ikkγ +/− females eventually recover, Ikkγ − males die in utero. These symptoms and inheritance pattern are very similar to those of incontinentia pigmenti (IP), a human genodermatosis, synthenic with the IKKγ/NEMO locus. Indeed, biopsies and cells from IP patients exhibit defective IKKγ/NEMO expression but normal expression of IKK catalytic subunits. This unique self-limiting disease, the first to be genetically linked to the IKK signaling pathway, is dependent on X-chromosome inactivation. We propose that the IKKγ/NEMO-deficient cells trigger an inflammatory reaction that eventually leads to their death.