An Atypical Incontinentia Pigmenti Female with Persistent Mucocutaneous Hyperinflammation and Immunodeficiency Caused by a Novel Germline IKBKG Missense Mutation.

While most missense mutations of the IKBKG gene typically result in Ectodermal Dysplasia with Immunodeficiency, there have been rare reported instances of missense mutations of the IKBKG gene causing both Incontinentia Pigmenti (IP) and immunodeficiency in female patients. In this study, we described an atypical IP case in a 19-year-old girl, characterized by hyperpigmented and verrucous skin areas over the entire body. Remarkably, she experienced recurrent red papules whenever she had a feverish upper respiratory tract infection. Immunohistochemical staining unveiled a substantial accumulation of CD68+ macrophages alongside the TNF-α positive cells in the dermis tissue of new pustules, with increased apoptotic basal keratinocytes in the epidermis tissue of these lesions. Starting from the age of 8 years old, the patient suffered from severe and sustained chronic respiratory mucous membrane scar hyperplasia and occluded subglottic lumen. In addition to elevated erythrocyte sedimentation rate values, inflammatory cells were observed in the pathologic lesions of endobronchial biopsies and Bronchoalveolar Lavage Fluid (BALF) smear. Further histological analysis revealed a destructive bronchus epithelium integrity with extensive necrosis. Simultaneously, the patient experienced recurrent incomplete intestinal obstructions and lips contracture. The patient's BALF sample displayed an augmented profile of proinflammatory cytokines and chemokines, suggesting a potential link to systemic hyperinflammation, possibly underlying the pathogenic injuries affecting the subglottic, respiratory, and digestive systems. Furthermore, the patient presented with recurrent pneumonias and multiple warts accompanied by a T+BlowNKlow immunophenotype. Next generation sequencing showed that the patient carried a novel de novo germline heterozygous missense mutation in the IKBKG gene (c. 821T>C, p. L274P), located in the highly conserved CC2 domain. TA-cloning sequencing of patient's cDNA yielded 30 mutant transcripts out of 44 clones. In silico analysis indicated that the hydrogen bond present between Ala270 and Leu274 in the wild-type NEMO was disrupted by the Leu274Pro mutation. However, this mutation did not affect NEMO expression in peripheral blood mononuclear cells (PBMCs). Moreover, patient PBMCs exhibited significantly impaired TNF-α production following Lipopolysaccharide (LPS) stimulation. X-chromosome inactivation in T cells and neutrophils were not severely skewed. Reduced levels of IκBα phosphorylation and degradation in patient's PBMCs were observed. The NF-κB luciferase reporter assay conducted using IKBKG-deficient HEK293T cells revealed a significant reduction in NF-kB activity upon LPS stimulation. These findings adds to the ever-growing knowledge on female IP that might contribute to the better understanding of this challenging disorder.

Thrombocytosis and eosinophilia in 32 Chinese neonatal incontinentia pigmenti.

INTRODUCTION: Incontinentia pigmenti (IP) is a rare X-linked dominant genetic disease affecting ectodermal tissue and often misdiagnosed in the neonatal period. The aim of this study was to highlight sequential clinical features and evaluate prognosis of the 32 neonatal IP patients. MATERIAL AND METHODS: A retrospective descriptive analysis was performed, using the clinical, blood analytical, pathological, radiological, genetic, and followed-up data of neonatal patients diagnosed with IP from 2010 to 2021, in Xi'an, China. RESULTS: Of the 32 patients, two (6.25%) were male. Thirty babies (93.75%) had eosinophilia (eosinophilic granulocyte count: 0.31-19.9 × 109 , mean proportion of white blood cells: 20.98 ± 15.21%). Twenty babies (62.5%) had thrombocytosis (thrombocyte count: 139-975 × 109 , mean count: 416.76 ± 176.82). Thirty-one babies (96.88%) exhibited the first three cutaneous lesion stages characterized by erythema and superficial vesicles on inflammatory bases in a linear distribution in the first week of age. Thirteen babies (40%) combined nervous system abnormalities, and nine babies (28.13%) had retinopathy. Two types of genetic mutations were detected in the NEMO gene. Nineteen babies were followed up. According to the follow-up, four babies displayed psychomotor retardation, and five babies developed a decrease in vision with astigmatism and amblyopia. CONCLUSION: It is important that 30 babies (93.75%) had eosinophilia and 20 babies (62.5%) had thrombocytosis. Therefore, we speculate that the mechanism of the injury may be related to the platelet aggregation on the basis of the increase in eosinophil cells and the release of inflammatory factors.

Incontinentia pigmenti inherited from a father with a low level atypical IKBKG deletion mosaicism: a case report.

BACKGROUND: Incontinentia pigmenti (IP) is an X-liked dominant genodermatosis caused by mutations of the IKBKG/NEMO gene. IP is mostly lethal in males in utero, and only very rare male cases with a somatic mosaic mutation or a 47,XXY karyotype have been reported. CASE PRESENTATION: We here report a case of an IKBKG gene deletion in a female infant presenting with a few blisters and erythema in her upper arms at birth. MLPA analysis revealed a rare 94 kb deletion in this patient, encompassing the IKBKG gene and IKBKGP pseudogene. PCR analysis indicated the presence of Alu elements at both ends of the deletion, suggesting non-allelic homologous recombination as an underlying mechanism. Notably, a low-level mosaic deletion was identified in her father's peripheral blood leukocytes by PCR, suggesting a rare father-to-daughter transmission of IP. CONCLUSION: In family studies for an apparently sporadic IP case, parental analysis that includes the father is recommended due to the possibility of male mosaicism.

Incontinentia pigmenti / Bloch-Sulzberger syndrome: a case report.

Incontinentia pigmenti is a rare genodermatosis that almost exclusively affects females. The disease is caused by a mutation of the nuclear factor-κB essential modulator (NEMO) gene in the Xq-28 locus of the X chromosome. The disease can seriously affect various organs, most notably the central nervous system and eyes. Cutaneous manifestation in incontinentia pigmenti is often mild but is an important diagnostic criterion for the disease. Treatment of cutaneous symptoms of incontinentia pigmenti is often not needed because they can spontaneously resolve. However, it should be noted that early diagnosis through parameters such as cutaneous manifestations is important so that prompt diagnosis and intervention for other organs can be made to prevent further fatal complications in the future.

Incontinentia Pigmenti: X-Linked Skin Disorder: A Case Report.

Incontinentia pigmenti (IP) is a rare X-linked neuroectodermal dysplasia affecting the skin, hair, teeth, nails, microvasculature, and central nervous system. Mutations in the IKBKG gene cause this disorder. Incontinentia pigmenti is found in 65-75 percent sporadic mutations and 25-35 percent familial cases. Most patients are female, as the disease is generally lethal in males. The condition often is identified secondary to skin presentations followed by the central nervous system (CNS) manifestations in the eye and brain within the first year of life. In addition to the skin changes, there may be defects in the hair, nails, and teeth. The uniqueness of the disorder and shared findings similar to other skin disorders complicate the diagnosis. Clinical findings point to an array of possibilities. Lack of information on family history complicates the time to diagnosis. With the confirmation of IP, a thorough evaluation with appropriate consultations improves outcomes where possible.

Phenotypic and genetic spectrum of incontinentia pigmenti - a large case series.

BACKGROUND AND OBJECTIVES: Incontinentia pigmenti is a rare X-linked dominantly inherited systemic disease affecting primarily the skin but also other neuroectodermal tissues such as teeth, hair, eyes, and the central nervous system. PATIENTS AND METHODS: This multicenter case series study was conducted at three European departments of Dermatology including 30 patients with incontinentia pigmenti. Twenty patients were evaluated clinically and genetically, another ten only genetically. RESULTS: The study included 28 females and two males with a median age of three years. Cutaneous manifestations were present in all 20 patients with clinical data. Stage I was observed in 90 % of those patients. Stage IV was observed as early as one year of age. Dental (81 %), hair (78 %) and neurological anomalies (53 %) were more frequent than previously reported. Fourteen skin biopsies showed typical features of the corresponding stage. Genetic testing of 24 patients revealed the common exon 4-10 deletion in 14 cases and seven other pathogenic variants, including three unpublished mutations. In another three cases, no genetic alterations were found. CONCLUSIONS: In this study, the phenotype ranged from only subtle cutaneous involvement to severe multisystemic disorders. Extracutaneous involvement should be evaluated at the time of diagnosis and in regular intervals, as some manifestations may develop over time.

[Incontinentia pigmenti in a newborn boy].

Incontinentia pigmenti is an uncommon X-linked dominant neurocutaneous ectodermal dysplasia. The disorder is usually lethal in males in utero, although it may occasionally occur in males with somatic mosaicsism or Klinefelter syndrome. This is a case report of a rare case of incontinentia pigmenti in a newborn male who presented with characteristic skin eruptions following Blaschko's lines. Histopathology and genetic testing confirmed the diagnosis. The management of patients with incontinentia pigmenti may require a multidisciplinary approach, and early diagnosis is of great importance.

Child with a mild phenotype of Incontinentia Pigmenti and inner retinal dysfunction.

PURPOSE: To describe a case of a child with mild phenotype of Incontinentia Pigmenti (IP), with changes in Spectral-Domain Optical Coherence Tomography (SD-OCT) and Optical Coherence Tomography Angiography (OCT-A) and an electronegative dark-adapted (DA) 3.0 electroretinogram (ERG), suggestive of inner retinal dysfunction. CASE REPORT: We described a 7-year-old female child with IP. Her best corrected acuity was 8/10 in the right eye and 6/10 in the left eye. Biomicroscopy, intraocular pressure and fundoscopy were normal. The electroretinography findings showed an electronegative DA 3.0 ERG with a normal a-wave but a b-wave that did not elevate above baseline. SD-OCT identified irregularities in the outer plexiform layer in both eyes, and OCT-A assessment revealed at the superficial capillary plexus, areas of decrease in the flow in parafoveal and perifoveal regions. CONCLUSION: Classically, IP affects the peripheral retina; however, vascular and structural changes in macula can occur as well. To our knowledge, we report the first electronegative electroretinogram in a patient with IP.

Late-onset cerebral arteriopathy in a patient with incontinentia pigmenti.

BACKGROUND: Incontinentia pigmenti (IP) is an X-linked neurocutaneous disorder that can present with cerebral arteriopathy during early infancy. However, no previous reports have demonstrated arteriopathic manifestations during postinfantile childhood in patients with IP. PATIENT DESCRIPTION: We describe a case of IP in a 2-year-old girl who developed encephalopathic manifestations associated with influenza A infection. She presented diffuse magnetic resonance imaging abnormalities involving the cortices, subcortical white matter, corpus callosum, basal ganglia, and thalami, resembling the findings in early infantile cases reported in the previous literatures. Magnetic resonance angiography demonstrated attenuation of the cerebral arteries. Proinflammatory cytokines and chemokines were upregulated in the cerebrospinal fluid. Left hemiplegia remained following the remission of the arteriopathic manifestations. Genetic analyses revealed a novel type of mutation in the IKBKG gene. CONCLUSION: Our findings indicate that patients with IP can develop destructive cerebral arteriopathy even after early infancy. The similarities in magnetic resonance imaging abnormalities between our patient and the previously reported infantile patients may be explained by the underlying immunologic pathophysiology of IP.

Analysis of IKBKG/NEMO gene in five Japanese cases of incontinentia pigmenti with retinopathy: fine genomic assay of a rare male case with mosaicism.

Incontinentia pigmenti (IP) is an X-linked dominant genodermatosis that is usually lethal in utero in males, though exceptionally they survive very rarely either with Klinefelter syndrome or a somatic mosaicism. We performed genomic analysis of five Japanese IP patients including a rare boy case, all of whom were definite cases with retinopathy. Four patients including the boy revealed the recurrent exon 4-10 deletion in the sole known causative gene IKBKG/NEMO, which was confirmed by various specific PCR techniques. The boy's saliva DNA showed a mosaicism consisting of the deletion and intact alleles, but his blood DNA did not. Relative quantification analysis of the real-time PCR data by ∆∆CT method estimated the mosaicism ratio of the boy's saliva as 45:55 (deletion:intact). A genomic analysis for the recurrent deletion at the nucleotide sequence level has been performed directly using patient's DNA and it has been clarified that the breakpoints are within two MER67B repeats in the intron 3 and downstream of exon 10. This is the first report of the assay for the mosaicism ratio of a male IP case with a recurrent exon 4-10 deletion of IKBKG/NEMO and the sequencing analysis of the breakpoints of the recurrent deletion directly using patient's sample.

Molecular analysis of low-level mosaicism of the IKBKG mutation using the X Chromosome Inactivation pattern in Incontinentia Pigmenti.

BACKGROUND: Incontinentia pigmenti (IP) is a rare X-linked disorder affecting the skin and other ectodermal tissues that is caused by mutation of the IKBKG/NEMO gene. Previous studies have reported that the overall mutation detection rate in IP is ~75%. We hypothesized that a low-level mosaicism existed in the remaining cases. METHODS: Genomic variations in the IKBKG gene were examined in 30 IP probands and their family members. Standard mutational analyses were performed to detect common deletions, nucleotide alterations, and copy number variations. To assess skewing of the X chromosome inactivation (XCI) pattern, a HUMARA assay was performed. We compared the results of this analysis with phenotype severity. RESULTS: Pathogenic variants were identified in 20 probands (66.7%), the rate of detection was suboptimal. The remaining 10 probands tended to manifest a mild phenotype with no skewed X chromosome inactivation that is generally observed in IP patients. Quantitative nested PCR and digital droplet PCR were performed for the 10 patients and mosaicism of the common IKBKG deletion were identified in five patients. CONCLUSION: Overall, we detected 25 IKBKG mutations (83.3%). Determination of the XCI value in advance of mutational analyses for IP could improve the mutation detection rate. Our improved detection rate for these mutations, particularly those with a low-level mosaicism, may present opportunities for appropriate genetic counseling.

Multidisciplinary consensus recommendations from a European network for the diagnosis and practical management of patients with incontinentia pigmenti.

BACKGROUND: Incontinentia pigmenti (IP) is a rare multisystemic X-linked dominant genetic disorder characterized by highly diagnostic skin lesions. The disease can be misdiagnosed in infants, and complications affecting the eyes and/or the brain can be severe. Our objective was to highlight the urgency of an appropriate diagnosis and management strategy, as soon as the first symptoms appear, and the need for a well-codified monitoring strategy for each child. METHODS: An in-depth literature review using a large number of databases was conducted. The selection criteria for articles were literature review articles on the disease, case series and retrospective studies based on the disease, clinical studies (randomized or not) on treatment, articles discussing patient care and management (treatment, diagnosis, care pathways), and recommendations. The research period was from 2000 until 2018. A group of multidisciplinary experts in IP management was involved, issued from different healthcare providers of the European Network for Rare Skin Diseases (ERN-Skin). The final recommendations have been submitted to two patient representative associations and to a general practitioner and a neonatal specialist prior to their finalization. RESULTS AND CONCLUSION: The diagnosis of IP must be promptly performed to detect potential extracutaneous manifestations, thus allowing the timely implementation of specific therapeutic and monitoring strategies. Eye involvement can be a therapeutic urgency, and central nervous system (CNS) involvement requires a very rigorous long-term follow-up. Assessments and patient support should take into account the possible co-occurrence of various symptoms (including motor, visual and cognitive symptoms).