Incontinentia Pigmenti Research Articles

Finding NEMO in the thymus.

Rosain et al. (https://doi.org/10.1084/jem.20231152) describe the association between anti-type I interferon autoantibodies and severe viral infections in patients with incontinentia pigmenti and heterozygous loss-of-function NEMO variants, suggesting a role for canonical NF-κB signaling in immune tolerance. The mechanisms behind this selective autoimmunity remain unclear.

Incontinentia pigmenti underlies thymic dysplasia, autoantibodies to type I IFNs, and viral diseases.

Human inborn errors of thymic T cell tolerance underlie the production of autoantibodies (auto-Abs) neutralizing type I IFNs, which predispose to severe viral diseases. We analyze 131 female patients with X-linked dominant incontinentia pigmenti (IP), heterozygous for loss-of-function (LOF) NEMO variants, from 99 kindreds in 10 countries. Forty-seven of these patients (36%) have auto-Abs neutralizing IFN-α and/or IFN-ω, a proportion 23 times higher than that for age-matched female controls. This proportion remains stable from the age of 6 years onward. On imaging, female patients with IP have a small, abnormally structured thymus. Auto-Abs against type I IFNs confer a predisposition to life-threatening viral diseases. By contrast, patients with IP lacking auto-Abs against type I IFNs are at no particular risk of viral disease. These results suggest that IP accelerates thymic involution, thereby underlying the production of auto-Abs neutralizing type I IFNs in at least a third of female patients with IP, predisposing them to life-threatening viral diseases.

Ocular genetics in the Japanese population.

In today's globalized society, ophthalmologists can examine people of different ethnicities regardless of where they live. The frequency of disease-causing genes varies according to a patient's ethnic background. We explain genetic findings for Japanese patients with inherited eye diseases. Ocular genetics has made great advances over the past 30 years. For example, detecting mutations at nucleotide position 11778 in mitochondrial DNA was useful in the genetic diagnosis of Leber's hereditary optic neuropathy (LHON). I evaluated the genotype-phenotype relationship in cases of corneal dystrophy and inherited retinal dystrophy (IRD). I identified the entire exon sequence of the eyes shut homolog (EYS) gene in patients with autosomal recessive retinitis pigmentosa (RP). EYS gene mutations are the most frequent cause of autosomal recessive RP. RPGRIP1 may be a common causative gene with early-onset severe retinal dystrophy, including Leber congenital amaurosis. However, some genes have complex structures that are difficult to analyze, including the OPN1LW/OPN1MW gene cluster in blue cone monochromacy and the IKBKG/NEMO genes in incontinentia pigmenti. This review will also present two cases with uniparental disomy, a case of IRD with double mutations, and a case with RP complicated with LHON-like neuropathy. Precise understanding of the effects of genetic variants may reveal differences in the clinical characteristics of patients with the same variant. When starting genome medicine, accurately diagnosing the patient, making accurate prediction, determining the genetic pattern, and providing genetic counseling are important. Above all, that both the doctors and patients understand genetic diseases correctly is important.

Non-Skewed X-inactivation Results in NF-κB Essential Modulator (NEMO) Δ-exon 5-autoinflammatory Syndrome (NEMO-NDAS) in a Female with Incontinentia Pigmenti

PurposeGenetic hypomorphic defects in X chromosomal IKBKG coding for the NF-κB essential modulator (NEMO) lead to ectodermal dysplasia and immunodeficiency in males and the skin disorder incontinentia pigmenti (IP) in females, respectively. NF-κB essential modulator (NEMO) Δ-exon 5-autoinflammatory syndrome (NEMO-NDAS) is a systemic autoinflammatory disease caused by alternative splicing and increased proportion of NEMO-Δex5. We investigated a female carrier presenting with IP and NEMO-NDAS due to non-skewed X-inactivation.MethodsIKBKG transcripts were quantified in peripheral blood mononuclear cells isolated from the patient, her mother, and healthy controls using RT-PCR and nanopore sequencing. Corresponding proteins were analyzed by western blotting and flow cytometry. Besides toll-like receptor (TLR) and tumor necrosis factor (TNF) signaling, the interferon signature, cytokine production and X-inactivation status were investigated.ResultsIP and autoinflammation with recurrent fever, oral ulcers, hepatitis, and neutropenia, but no immunodeficiency was observed in a female patient. Besides moderately reduced NEMO signaling function, type I interferonopathy, and elevated IL-18 and CXCL10 were found. She and her mother both carried the heterozygous variant c.613 C > T p.(Gln205*) in exon 5 of IKBKG previously reported in NEMO-deficient patients. However, X-inactivation was skewed in the mother, but not in the patient. Alternative splicing led to increased ratios of NEMO-Dex5 over full-length protein in peripheral blood cell subsets causing autoinflammation. Clinical symptoms partially resolved under treatment with TNF inhibitors.ConclusionNon-skewed X-inactivation can lead to NEMO-NDAS in females with IP carrying hypomorphic IKBKG variants due to alternative splicing and increased proportions of NEMO-∆ex5.

Pott's puffy tumor with intracranial extension in a child with incontinentia pigmenti: case based review of the eponymous disease.

Pott's puffy tumor (PPT) is an uncommon infection involving the frontal bone, first described by Sir Percival Pott more than 250years ago. It can present with intracranial extension and serious neurological morbidity. Incontinentia pigmenti (IP) is a rare inherited genodermatosis that is lethal prenatally in males and manifests clinically in females. IP is associated with recurrent infections and immune dysfunction/suppression. We report a case of Pott's puffy tumor presenting in a child with IP. We also performed a literature review of reported cases of PPT associated with immune dysfunction. We discuss the clinical presentation, diagnosis, and management of these lesions. We identified 12 cases of PPT associated with immune dysfunction/suppression. Diabetes was the most commonly identified cause followed by iatrogenic immunosuppression. Surgery is the standard treatment for managing PPT and the management of PPT with and without intracranial involvement, particularly in the context of underlying immune dysfunction/suppression, is discussed. PPT remains a rare but not infrequent diagnosis, often requiring neurosurgical intervention. Immune dysfunction/suppression is an additional risk factor that may predispose to PPT. Early and aggressive management should be instituted for optimal outcome.

Bilateral hypomelanosis of Ito: Report of two cases

Hypomelanosis of Ito, also known as incontinentia pigmenti achromians of Ito, is a rare neuroectodermal disorder often associated with mental retardation and epilepsy. Here we report two patients with bilateral hypopigmented streaks and patches.

Ashy Dermatosis: Suatu Laporan Kasus Jarang

Background: Ashy dermatosis is a rare, acquired, benign, and idiopathic hypermelanotic disease. It is manifested asashy-colored lesion with no signs of inflammation. Commonly affected sites of the body include the trunk, neck, face, also proximal and distal extremities. Case: A 33-year-old woman came to Dr. Moewardi Hospital, Surakarta, with chief complaints asymptomatic, ashy colored macule that appear on her right arm. Physical examination in general region shows ashy-colored macule and multiple discrete patches of hyperpigmentation with irregular border. Dermoscopy examinationmacules showed bluish-gray skin markings over bluish background. Histopathological examination showed thin epidermis layer, hyperkeratosis, incontinentia pigmenti, dropping melanin resembles the basal layer civatte bodies. At dermis focal fibrosis was found with infiltrates, incontinentia pigmenti, and dropping melanin. Discussion: Ashy dermatosis or known as erythema dyschromicum perstans is a rare hyperpigmentation disorder that started with reddish, active-bordered lesions, then disappear, leaving a round or oval shape, polycyclic, and ashy macule on the proximal region of the trunk andneck. Onset of symptoms usually at young adult, between first and second decade of life. Etiology of ashy dermatosis is still unclear, and many factors were thought to be involved. Dermoscopy examination showed bluish-gray macules overbluish background. Histopathological examination showed lichenoid reactions and an increase melanin on the dermis. This report aims to describe the diagnosis a rare condition based on anamnesis, physical examination, dermoscopy, and histopathological examination. Clinical findings in this patient were in accordance with the result of previous studies.

An efficient molecular genetic testing strategy for incontinentia pigmenti based on single-tube long fragment read sequencing

Incontinentia pigmenti (IP) is a rare X-linked dominant neuroectodermal dysplasia that primarily affects females. The only known causative gene is IKBKG, and the most common genetic cause is the recurrent IKBKG△4–10 deletion resulting from recombination between two MER67B repeats. Detection of variants in IKBKG is challenging due to the presence of a highly homologous non-pathogenic pseudogene IKBKGP1. In this study, we successfully identified four pathogenic variants in four IP patients using a strategy based on single-tube long fragment read (stLFR) sequencing with a specialized analysis pipeline. Three frameshift variants (c.519-3_519dupCAGG, c.1167dupC, and c.700dupT) were identified and subsequently validated by Sanger sequencing. Notably, c.519-3_519dupCAGG was found in both IKBKG and IKBKGP1, whereas the other two variants were only detected in the functional gene. The IKBKG△4–10 deletion was identified and confirmed in one patient. These results demonstrate that the proposed strategy can identify potential pathogenic variants and distinguish whether they are derived from IKBKG or its pseudogene. Thus, this strategy can be an efficient genetic testing method for IKBKG. By providing a comprehensive understanding of the whole genome, it may also enable the exploration of other genes potentially associated with IP. Furthermore, the strategy may also provide insights into other diseases with detection challenges due to pseudogenes.

Incontinentia Pigmenti In a Female Infant: A Case Report

Incontinentia pigmenti (IP) is an X-linked disorder characterized by a variety of findings that affect different systems, including cutaneous, ophthalmologic, neurologic, and dental. The cutaneous findings occur in 4 consecutive stages, generally referred to as vesicular, verrucous, hyperpigmented, and atrophic. The first stage is often observed in infancy, and this may be the first indication of IP in an infant. Early diagnosis is critical so that interventions can be implemented as soon as possible to monitor for complications and mitigate the effects of IP given the potential for multisystem involvement. Here, we describe a case of IP that was diagnosed in a female infant with no prior family history of IP. Prompt diagnosis and family counseling is critical, as early interventions can help optimize patients’ quality of life and genetic testing may help families make informed future family planning decisions.

Chorioretinal Anastomosis and Retinal Detachment with Laser Photocoagulation Treated Incontinentia Pigmenti.

To describe a case of incontinentia pigmenti in which chorioretinal anastomosis occurred after laser photocoagulation, which was ultimately complicated by tractional and rhegmatogenous detachment. Observational case report. A 2-month-old was referred to ophthalmology for a rash characteristic of incontinentia pigmenti due to concern for ocular involvement and was found to have peripheral avascular retina with early neovascularization. Following several rounds of panretinal photocoagulation, a chorioretinal anastomosis was noted on follow up fluorescein angiography in the left eye. Subsequently, a tractional retinal detachment formed and was treated initially with a lens sparing pars plana vitrectomy, endolaser, and scleral buckle. Despite treatment, it progressed to a combined tractional/rhegmatogenous detachment and was deemed inoperable. Chorioretinal anastomosis is a rare complication of laser photocoagulation.

Incontinentia Pigmenti - One case, two diagnoses

Incontinentia Pigmenti is a rare X-linked genodermatosis caused by mutations in the IKBKG gene. It is a systemic disease mainly involving tissues of ectodermic origin, manifesting itself primarily as skin lesions but also as changes in the hair, nails, teeth, breasts, eyes and nervous system. We present a case of a newborn who presented with a vesicular rash in the first week of life.

The role of fluorescein angiography in incontinentia pigmenti: A case report

Aims/Purpose: To present the angiographic findings in a case of a 6‐year‐old girl with incontinentia pigmenti.Methods: We describe the case of a 6‐year‐old girl with a known diagnosis of incontinentia pigmenti that presented with retinal vascular changes in a routine ophthalmologic evaluation. Fundoscopic examination revealed a peripheral avascular area with adjacent vascular proliferation. In order to better evaluate these findings, a fluorescein angiography was performed.Results: Angiography findings included abnormal vascular loops, capillary nonperfusion areas and vascular anastomoses. There were also leakage areas (corresponding to active neovascularization) and areas of staining (due to fibrosis). Laser photocoagulation of the peripheral avascular area was done.Conclusions: Incontinentia pigmenti often presents with neovascularization and other vascular changes that are more pronounced in the retinal periphery. Therefore, fluorescein angiography is very valuable in the documentation and study of vascular lesions associated with this condition.

Incontinentia pigmenti Stage 1 is not simply vesiculo-bullous but vesiculo-pustular.

Incontinentia pigmenti (IP) is a rare X-linked dominant, male-lethal disorder characterized by pathognomic skin lesions. As described in the literature the typical cutaneous changes follow the pattern of Blaschko's lines and develop in four stages that usually start at birth. Stage 1 is called vesicular, bullous or inflammatory. The vesicles are rapidly filled with eosinophils and thus turn into pustules. Thus, the term "pustular" is relevant to the first phase of IP, and the stage can be considered as "vesiculopustular/inflammatory" to be more precise than "vesicular" or "bullous."

Bloch–Sulzberger syndrome (Incontinentia pigmenti)

Bloch–Sulzberger syndrome or Incontinentia pigmenti is a genetic disease that causes skin pathology in the first days of a child's life and is suspected of identifying the disease.
 The article presents the characteristic signs of this syndrome and the pronounced manifestations of the disease. A presumptive case of a girl born in a family without a burdened anamnesis: the first manifestations of the disease appeared on the fifth day of life, were represented by linearly arranged vesicular-bullous rashes on an erythematous background and were regarded as a skin infection. Due to the ineffectiveness of the therapy, the patient was consulted by a dermatovenerologist, geneticist, neurologist. The child was consulted again at 5.5 years old: the article presents the data of a medical and genetic study and distant clinical signs of this syndrome in the form of hyperpigmented spots in combination with foci of atrophy, alopecia and dental anomalies in the sixth year of life.
 Thus, the clinical signs of Bloch–Sulzberger syndrome made it possible to diagnose the disease at the newborn stage, which, in turn, helped to avoid unjustified prescribing of various systemic medications, to develop an individual treatment plan for the child and, as a result, contributed to the prevention of the development of complications of the disease and to improve the patient's quality of life.

Variable clinical consequences of mosaicism for c.1167dupC in IKBKG in male and female patients with incontinentia pigmenti and related phenotypes.

In the present study, we report a duplication variant found in two families with incontinentia pigmenti, which exhibited a variety of phenotypes in both male and female carriers. Although natural mosaicism through Lyonization, with variably skewed X-inactivation, accounts for the phenotype in females, our study also demonstrates that mosaicism, albeit through a different mechanism, should also be remembered in understanding the phenotypic expression of IKBKG-related disorders in some males.

Dental Management in Children with Incontinencia Pigmenti (Bloch-Sulzberger Syndrome): Case Reports and Literature Review

Introduction: Incontinentia Pigmenti (IP) is a multisystem genodermatosis characterized by cutaneous, neurologic, ophthalmologic, and dental abnormalities. Skin alterations are the main characterestic of IP. They can change and even disappear over time, in contrast, dental ones are permanent and considered as the most frequent extra cutaneous signs. The aim of this work is to present two rare clinical reports of Incontinentia Pigmenti and to adress its frequent orofacial manifestations in the dental litterature. Case Reports: In this paper, we report two clinical cases of incontinencia pigmenti in two female patients, five and nine years old, who were first examined by a dermatologist due to skin changes and then referred to our pediatric dentistry department in la Rabta hospital for oral examination. We managed these cases in collaboration with the pediatric department. We also conducted a research in the following electronic databases: PubMed and google scholar using the following keywords: ("Incontinentia Pigmenti" AND "Child" AND "Tooth Abnormalities”), from 2011 to 2021, to compare dental findings in our patients with literature. Discussion: The most representative dental features of IP are: delayed tooth eruption, agenesis, high arched palate, peg like and malformed teeth, affecting both primary and permanent teeth. Therapeutic management of our patients consisted in the replacement of absent teeth with an aesthetic and functional space maintainer. The assessment of orofacial manifestations in Children with Bloch Sulzberger syndrome indicates that it appears almost exclusively in females and is usually lethal in males. The clinical expression of this disease found in our patients reflects the Data reported in the literature. The latter showed that the presence of symptoms other than skin changes is important if dermatological signs are subtle, which is in accordance with both our patients’ clinical expression. The most relevant finding of this review is the observation that most IP patients with odontological findings had the congenital absence of six or more teeth opposed to our second patient who had only one absent tooth. Conclusions: Incontinencia pigmenti is of a good prognosis but it may affect patients' quality of life hence the importance of knowing this syndrom and its oro-facial characteristics in order to obtain a correct diagnosis and apply an appropriate approach treatment.

A Rare Case of Incontinentia Pigmenti in a Male Child with Dermoscopic and Histopathological Correlation

Abstract Incontinentia pigmenti (IP) is a rare X-linked genodermatosis mostly occurring in females with the condition being fatal in males but certain mechanisms may allow survival of male subjects. We report a rare case of IP in a 19-day-old male patient with no history of similar lesions in the family adding to its rarity. The histopathological correlation of the lesions with dermatoscopy showed yellow oil drop-like globular structures correlating with spongiosis in the vesicular stage and verrucous lesions showed brown blotches in a circular pattern with overlying gray-brown dots correlating with hyperkeratosis and dyskeratosis.

Magnetic resonance imaging for diagnosing a rare disease: incontinentia pigmenti (Bloch–Sulzberger syndrome) on the example of a clinical case

Incontinentia pigmenti, also known as BlochSulzberger syndrome, is a rare hereditary disease characterized by typical skin rashes and involvement of other organs and systems. Magnetic resonance imaging stands as the primary method for visualizing the structural pathology of the brain and predicting neurological manifestations in an affected child.
 Diagnosing incontinentia pigmenti predominantly falls within the domain of dermatologists; verification is performed by molecular genetic analysis of the IKBKG gene. This study involved magnetic resonance imaging of the brain in a patient with skin rashes, characteristic of BlochSulzberger syndrome, and deletion in the IKBKG gene, where numerous foci of ischemia, hemorrhages, and lesions of the tracts were detected.
 Magnetic resonance imaging of the brain in patients with BlochSulzberger syndrome is used to evaluate the severity of damage to the brain substance, which makes it possible to explain the cause of neurological symptoms and correct habilitation, as well as predict the development of the child.

Incontinentia Pigmenti in a 3-Year-Old Female: A Case Report

Incontinentia Pigmenti (IP), also known as Bloch-Sulzberger syndrome, is a rare X-linked genetic disorder characterized by a distinctive cutaneous manifestation along with variable systemic involvement. We present a case of a 3-month-old female infant diagnosed with IP, highlighting the clinical features, diagnostic approach, and management strategies. Early recognition and multidisciplinary care are crucial for optimizing outcomes in affected infants.

Dermatologic care of patients with differences of sex development.

Differences of sex development (DSD or disorders of sex development) are uncommon congenital conditions, characterized by atypical development of chromosomal, gonadal, or anatomic sex. Dermatologic care is an important component of the multidisciplinary care needed for individuals with DSD. This article discusses the most common primary dermatologic manifestations of DSD in addition to the cutaneous manifestations of hormonal and surgical therapies in individuals with DSD. Published articles including case series and case reports on PubMed. Selection was conducted by examining existing literature with a team of multidisciplinary specialists. Narrative review. This article was not conducted as a systematic review. In Klinefelter syndrome, refractory leg ulcers and incontinentia pigmenti have been described. Turner syndrome is associated with lymphatic malformations, halo nevi, dermatitis, and psoriasis. Virilization can be seen in some forms of congenital adrenal hyperplasia, where acne and hirsutism are common. Dermatologists should consider teratogenic risk for treatments of skin conditions in DSD depending on pregnancy potential. Testosterone replacement, commonly used for Klinefelter syndrome, androgen insensitivity syndrome, 5-alpha reductase deficiency, gonadal dysgenesis, or ovotesticular DSD, may cause acne.