Incontinentia Pigmenti Research Articles

Congenital Localized Hypopigmentation Disorders as a Clue of Severe Neurologic Involvement: An Update Review.

In clinical practice, cutaneous disorders associated with neurologic involvement are relatively common, as both cutaneous and systems often originate from similar or synchronous embryonic mechanisms. Cutaneous hypopigmentation includes a wide range of disorders that can be categorized congenital and acquired based on the onset, and as localized and generalized types, depending on their skin distribution. Although cutaneous hypopigmentation may appear as a benign clinical manifestation, its association with neurologic or others systemic involvement can indicate more severe underlying disorders. This literature review focuses on congenital localized types of cutaneous hypopigmentation that are classically linked to neurologic impairment. Four congenital disorders were highlighted for their characteristic presentation of localized cutaneous hypopigmentation and neurologic involvement: Waardenburg syndrome, incontinentia pigmenti, hypomelanosis of Ito, and tuberous sclerosis complex.Clinical and genetic findings for these conditions were reviewed and updated, with an emphasis on the cutaneous manifestations, associated systemic anomalies, and neurologic involvement. Established diagnostic criteria and emerging trends in therapeutic approaches were also explored. Promising results, particularly the use of mammalian target of rapamycin (mTOR) in the treatment of tuberous sclerosis complex, highlight the potential for improved outcomes. Early diagnosis, rapid treatment, and innovative therapies may play a crucial role in positively altering the clinical course of these disorders.

Single-Cell RNA Sequencing in Incontinentia Pigmenti With Neonatal Encephalopathy Reveals Broad Immune Activation Moderated by Steroids.

DNA variations in the NF-kappa-B essential modulator (NEMO) gene are linked to incontinentia pigmenti (IP) and also immunodeficiency and autoinflammatory conditions. Some patients with IP present with neonatal vasculitis-like brain changes, although pathogenesis is unclear. We investigated cell-specific gene expression in a neonate with IP, who had encephalopathy, seizures, and vasculitis-like brain changes, and responded to steroid treatment. Single-cell RNA (ribonucleic acid) sequencing (scRNAseq), using the HIVE single-cell system, was performed on a neonate with IP, before and after steroid treatment, compared with a sex-matched healthy control toddler. A total of 20,411 cells were sequenced and clustered into 10 cell types. In IP compared with control, upregulated significant gene set enrichment analysis gene ontology pathways (FDR <0.05) included defense response, complement activation, humoral immune response, and phagocytosis across all cell types. After steroid treatment, these pathways were predominantly downregulated in monocytes and neutrophils. The upregulated genes in IP that became downregulated after steroid treatment were interferon-related genes, oligoadenylate synthases, and immunoglobulin genes. IP-associated loss of NEMO function is associated with a proinflammatory phenotype, that is moderated by steroids. scRNAseq provides a rationale for immune modulation in an n = 1 setting and valuable insights into the pathogenesis and therapeutics of this rare disease.

A Series of Patients with Genodermatoses in a Reference Service for Rare Diseases: Results from the Brazilian Rare Genomes Project

Background/Objectives: Genodermatoses are genetic conditions with clinical symptoms manifesting in the skin and adjoining tissues, individually rare but comprising a large and heterogeneous group of disorders that represents 15% of genetic diseases. This article discusses the results of individuals with genodermatoses from a reference center for rare diseases studied through whole genome sequencing conducted by the Brazilian Rare Genomes Project between 2021 and 2023. Methods: A retrospective case series with data comprising sex, age at first assessment in the hospital, family history, clinical findings, and molecular results. Results: Excluding neurofibromatosis type 1, Ehlers–Danlos syndrome and RASopathies are discussed elsewhere. Diagnoses in this work comprised ectodermal dysplasias (n = 6), ichthyosis (n = 4), albinism (n = 4), tuberous sclerosis complex (n = 4), and incontinentia pigmenti (n = 3), in addition to 11 others with individual rare conditions. The sex ratio was 17:16 (M:F), consanguinity was present in 6/33 (18%), and the age at the first evaluation ranged from neonatal to 26 years (median 13.65 years). Negative results were 3/33 (9%), novel variants were 17/41 (41.4%), and 7/30 (23%) presented initially with a double molecular diagnosis, three confirming composed phenotypes. Conclusions: Besides reporting 17 novel variants in 14 genes (BLM, CACNA1B, EDA, ELN, ENG, ERC6, EVC2, PNPLA1, PITCH1, PORCN, SIN3A, TP63, TYR, and WNT10B), the study also identified three atypical clinical presentations due to dual diagnoses, and the c.454C&gt;T variant in the SDR9C7 gene, previously reported only in dogs, was, for the first time, confirmed as causative for ichthyosis in humans.

A Case of NEMO Deficiency Syndrome in a 2-Month-Old Male from Belarus

Introduction Nuclear factor kappa B essential modulator (NEMO) deficiency syndrome is a rare X-linked recessive genetic disorder characterized by a wide range of clinical features, including increased susceptibility to bacterial and mycobacterial infections, as well as skin manifestations such as ectodermal dysplasia, dental abnormalities, hypospadias, and alopecia. The syndrome is caused by mutations in the IKBKG gene. Hypomorphic mutations in the IKBKG are associated with two clinically distinct conditions: hypohidrotic or anhidrotic ectodermal dysplasia with immunodeficiency and incontinentia pigmenti. These differences may result from the specific types and locations of the mutations, as well as the mosaic expression of IKBKG due to random X-chromosome inactivation in heterozygous females. Materials and Methods This case report describes a 2-month-old male who presented with a history of Enterobacter aerogenes and Klebsiella pneumonia infections, osteogenesis imperfecta, and erythematous skin lesions. The patient’s mother and sister exhibited symptoms consistent with incontinentia pigmenti. Genetic analysis was carried out by whole-exome sequencing (WES) using Exome Capture V5 Probe Set (MGI). WES was performed using a DNBSEQ-G50 genetic analyzer (MGI). Clinically significant observations were confirmed by Sanger sequencing. Results Genetic analysis of the gDNA sample identified a heterozygous pathogenic variant in exon 10 of the IKBKG gene (NM_003639.4: c.1167dupC, p.Glu390ArgfsTer5). The presence of heterozygous variants in IKBKG gene, located on the X-chromosome in males, may be due to the presence of pseudogenes IKBKGP1. Long-range PCR (LR-PCR) was performed to confirm the presence of pathogenic mutation in the IKBKG gene. As expected, Sanger sequencing of the LR-PCR amplicon confirmed the pathogenic variant c.1167dupC in a hemizygous state. Conclusion We report the first genetically confirmed case of NEMO deficiency syndrome in Belarus. Our results demonstrate that heterozygous genetic variations in the IKBKG gene observed in boys may be caused by the presence of the IKBKGP1 pseudogene, and the approach to genetic diagnosis employed enables us to detect potential pathogenic variants and differentiate between them derived from IKBKG or its pseudogene.

Quando la pelle racconta: dalle vescicole al gene NEMO

The paper presents the case of a 7-day-old newborn, born at term, with widespread cutaneous lesions on their limbs and trunk, sparing their face, palms and soles. The lesions, initially vesicular, evolved into crusts and hyperkeratosis, following Blaschko’s lines. Given the maternal history of similar neonatal lesions, incontinentia pigmenti (IP) was suspected, confirmed by the typical lesion distribution and absence of infections. IP is an X-linked dominant genetic disorder primarily affecting females, potentially involving other ectodermal tissues with ocular, dental and neurological abnormalities. Early recognition of cutaneous manifestations is crucial for timely multidisciplinary follow-up and definitive genetic diagnosis.

Long-Read Sequencing is Required for Precision Diagnosis of Incontinentia Pigmenti.

Incontinentia pigmenti (IP) is caused by loss-of-function variants in IKBKG, with molecular genetic diagnosis complicated by a pseudogene. We describe seven individuals from three families with IP but negative clinical testing in whom long-read sequencing identified causal variants. Concurrent methylation analysis explained disease severity in one individual who died from neurologic complications, identified a mosaic variant in an individual with an atypical presentation, and confirmed skewed X-chromosome inactivation in an XXY individual.

Partial Loss of NEMO Function in a Female Carrier with No Incontinentia Pigmenti.

Background/Objectives: The nuclear factor (NF)-kB essential modulator (NEMO) has a crucial role in the NFκB pathway. Hypomorphic IKBKG pathogenic variants cause ectodermal dysplasia with immunodeficiency (EDA-ID) in affected males. However, heterozygous amorphic IKBKG variants could be responsible for Incontinentia Pigmenti (IP) in female carriers. Typically, IP patients do not exhibit immunodeficiency, although hypomorphic variants might lead to immunodeficiency in female IP patients. Here, we report the case of an IKBKG female carrier, with no IP but an unexpected picture of immunodeficiency. She had a positive family history for the same genetic condition. Methods: We performed immunological, molecular, and functional analysis to evaluate NEMO contribution. Results: The patient was healthy until the age of 25 when severe asthma and Hashimoto thyroiditis occurred. She had HLAB27-positive ankylosing spondylitis, non-tubercular mycobacteriosis, and pulmonary aspergillosis infections. We found CD19+ B cell lymphopenia and T cell subset alterations. Sanger sequencing revealed a heterozygous IKBKG variant at position +1 of the 5' UTR of the gene which disrupted the normal pre-mRNA splicing. We observed a decreased NEMO protein expression, a reduced level of mRNA, and a defective NF-κB pathway. Conclusions: These findings suggest a possible correlation between the partial loss of NEMO function and the immunodeficiency observed in this patient. This case could expand our understanding of NEMO deficiency in female carriers.

Incorporating Nanopore Sequencing Into a Diverse Diagnostic Toolkit for Incontinentia Pigmenti

Incontinentia pigmenti (IP) is a rare hereditary disorder affecting 1.2 in 100,000 live births, predominantly females. Genetic analysis of IP is complicated by a homologous pseudogene, making conventional short‐read sequencing challenging. While long‐range PCR is typically used to overcome this, skewed X‐inactivation detection can also aid in assigning variants to IKBKG. We employed a comprehensive approach, incorporating whole‐exome sequencing (WES), long‐range PCR, RT‐PCR, X‐inactivation analysis, and nanopore sequencing, to identify and accurately phase a small heterozygous deletion, NM_001099857.5: c.363_367del, p.(Leu122Glyfs ∗14), in the IKBKG gene in an IP‐affected family. The deletion was initially detected via WES, with skewed X‐inactivation observed in both the proband and her mother. Long‐range PCR specific to IKBKG confirmed the variant’s location in the IKBKG gene, not in the pseudogene. On the RNA level, the variant was undetectable, suggesting nonsense‐mediated decay of the transcript. Nanopore sequencing precisely mapped the variant to IKBKG and analyzed the methylation status of both alleles, confirming the skewed X‐inactivation, with the variant‐carrying allele predominantly inactivated. This demonstrates the nanopore sequencing’s value in genetic diagnosis, enabling precise variant localization and analysis of X chromosome activation status in females with skewed X‐inactivation, aiding in accurate diagnosis and understanding of IP.

Asymmetric imaging features in incontinentia pigmenti

Asymmetric imaging features in incontinentia pigmenti

Prevalence and clinical characteristics of incontinentia pigmenti: a nationwide population-based study

BackgroundIncontinentia pigmenti (IP) is an X-linked dominant multisystemic disorder caused by pathogenic variants in the IKBKG gene. Population-based research into the epidemiology of IP is lacking.MethodsThis nationwide cross-sectional study from Jan 1st, 1995 to August 25th, 2021, searched the Danish National Patient Registry (DNPR), the Danish National Database of Rare Genetic Diseases (RareDis) and the Danish Genodermatosis Database to identify patients recorded with a diagnosis of IP. This search was followed by diagnosis validation and collection of clinical data from patient medical records. We investigated the clinical characteristics and genetics of the final cohort of validated IP cases. We estimated the point prevalence in the Danish population, based on non-deceased IP patients currently living in Denmark. Furthermore, we estimated the birth prevalence from 1995 to 2020, assuming a diagnostic delay of up to six months.ResultsWe identified a validated cohort of 75 IP patients, including 71 (94.7%) females and 4 (5.3%) males. We estimated a birth prevalence of 2.37 (95% CI: 1.74–3.25) per 100,000 or 1 in 42,194. A total of 54 (72%) patients had a genetic diagnosis, including 39 (72.2%) with the recurrent exon 4–10 deletion and 10 (18.5%) with point mutations in IKBKG. A positive family history was reported in 53.3%. Besides the recognizable blaschkolinear skin lesions reported in 70 (93.3%) of the patients, commonly reported manifestations included the involvement of the teeth (58.7%), the central nervous system (30.7%), hair (26.7%), and eyes (22.6%), as well as nail dystrophy (16.0%).ConclusionsWe identified and characterized a nationwide population-based cohort of IP patients and report a birth prevalence of 2.37 per 100,000 live births, which is twice as high as previous estimates.

Genome sequencing reveals novel IKBKG structural variants associated with incontinentia pigmenti.

Using genome sequencing, we identified novel structural variants in the IKBKG gene in two patients affected by incontinentia pigmenti (IP). As a large proportion of patients with IP do not have a molecular diagnosis, and new variants remain to be identified. Emerging technologies, such as long-read sequencing, hold promise for further advancing the molecular diagnosis of IP.

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.

Orthopedic Manifestations of Degenerative Melanosis (Clinical Case Report)

Bloch-Sulzberger syndrome is a rare hereditary disease caused by a mutation in the IKBKG/NEMO gene linked to the X chromosome. The disease manifests itself in the form of mottled skin pigmentation and can be accompanied by congenital deformities, including clubfoot. This hereditary disease is transmitted by the dominant type of inheritance and is usually observed in girls. In men, it is less common due to the lethality of the mutation for the male fetus. In some cases, the syndrome may be accompanied by congenital deformities such as clubfoot. Although Bloch-Sulzberger syndrome is a rare disease, research into its molecular mechanisms and the development of new treatments may help improve the prognosis for patients. The aim of the study was to review a clinical case of Bloch-Sulzberger syndrome in a child and to evaluate the results of surgical intervention. The diagnosis of a child with this syndrome confirmed the presence of characteristic signs: variegated skin pigmentation, congenital deformities of the foot and other anomalies. Surgical correction of the deformities using the Zatsepin method was applied, which helped to restore the correct position of the foot and improve the patient’s quality of life. Research into the molecular mechanisms of the syndrome may contribute to a better understanding of the pathogenesis and the development of new treatments and prevention methods. Clinical trials of new medications and surgical techniques are important to improve patient care and assess their efficacy and safety in the long term. Long-term follow-up of patients with this syndrome will help identify risks and complications arising from the pathology and develop strategies for their prevention and management. The development of additional diagnostic and treatment methods, as well as further research into this rare pathology, has great potential to improve the prognosis of patients and reduce the impact of the disease on their lives.

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.