Incontinentia Pigmenti Patients Research Articles

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.

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.

Thrombocytosis and eosinophilia in 32 Chinese neonatal incontinentia pigmenti.

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. 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. 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. 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.

Immunodeficiency in a female patient with Incontinentia Pigmenti

Incontinentia pigmenti (IP) is a rare X-linked dominant neuroectodermal disorder characterized by ocular, dermatologic, and neurological abnormalities. It is caused by heterozygous mutations in IKBKG (NEMO), which encodes a regulatory factor involved in NF-kB activation. Random and skewed X-inactivation allows for female survival and determines extent of disease. Although immune function is typically normal in IP patients, hypomorphic IKBKG mutations are known to cause immunodeficiency, as occurs in X-linked NEMO deficiency. A female newborn presented with bullous vesicles, peeling skin, alopecia, hearing loss, and tonic-clonic seizures with MRI demonstrating evidence of in utero stroke. She developed intermittent fevers and cellulitis and was diagnosed with IP based on clinical findings. Following discharge, she was readmitted at 1 month of age due to bronchiolitis complicated by pulmonary abscess. Labs demonstrated hyperleukocytosis with hypereosinophilia, normal T, B, and NK lymphocyte enumeration, abnormal lymphocyte proliferation to phytohemagglutinin (PHA) and anti-CD3, and abnormal toll-like receptor (TLR) function. Genetic analysis revealed a heterozygous deletion of exons 4–10 in IKBKG. Labs at 1 year follow up showed normal lymphocyte (T, B, and NK) enumeration and mitogen responses, normal immunoglobulin levels, and normal responses to pneumococcal and tetanus vaccines. While about 70% of IP patients harbor a deletion of exons 4–10 in IKBKG. unlike other hypomorphic NEMO mutations, this mutation is not typically associated with altered immune function. This case highlights that immunodeficiency may be an early clinical manifestation in female patients with IP.

The Impact of the IKBKG Gene on the Appearance of the Corpus Callosum Abnormalities in Incontinentia Pigmenti

Incontinentia pigmenti (IP) is a rare skin disease combined with anomalies of the teeth, eyes, and central nervous system (CNS). Mutations of the IKBKG gene are responsible for IP. Among the most frequent CNS abnormalities found in IP using magnetic resonance imaging (MRI) are corpus callosum (CC) abnormalities. The aim of the study was to determine the presence of CC abnormalities, their relationship with the IKBKG mutations, and the possible presence of mutations of other genes. A group of seven IP patients was examined. Analyses of the IKBKG gene and the X-chromosome inactivation pattern were performed, as well as MRI and whole exome sequencing (WES) with the focus on the genes relevant for neurodegeneration. WES analysis showed IKBKG mutation in all examined patients. A patient who had a mutation of a gene other than IKBKG was excluded from further study. Four of the seven patients had clinically diagnosed CNS anomalies; two out of four had MRI-diagnosed CC anomalies. The simultaneous presence of IKBKG mutation and CC abnormalities and the absence of other mutations indicate that IKBKG may be the cause of CC abnormalities and should be included in the list of genes responsible for CC abnormalities.

Uncovering incontinentia pigmenti: From DNA sequence to pathophysiology.

Incontinentia pigmenti (IP) is an X-linked dominant genodermatosis. The disease is known to be caused by recurrent deletion of exons 4–10 of the Inhibitor Of Nuclear Factor Kappa B Kinase Regulatory Subunit Gamma (IKBKG) gene located at the Xq28 chromosomal region, which encodes for NEMO/IKKgamma, a regulatory protein involved in the nuclear factor kappa B (NF-κB) signaling pathway. NF-κB plays a prominent role in the modulation of cellular proliferation, apoptosis, and inflammation. IKBKG mutation that results in a loss-of-function or dysregulated NF-κB pathway contributes to the pathophysiology of IP. Aside from typical skin characteristics such as blistering rash and wart-like skin growth presented in IP patients, other clinical manifestations like central nervous system (CNS) and ocular anomalies have also been detected. To date, the clinical genotype-phenotype correlation remains unclear due to its highly variable phenotypic expressivity. Thus, genetic findings remain an essential tool in diagnosing IP, and understanding its genetic profile allows a greater possibility for personalized treatment. IP is slowly and gradually gaining attention in research, but there is much that remains to be understood. This review highlights the progress that has been made in IP including the different types of mutations detected in various populations, current diagnostic strategies, IKBKG pathophysiology, genotype-phenotype correlation, and treatment strategies, which provide insights into understanding this rare mendelian disorder.

Incontinentia pigmenti and the eye.

Incontinentia pigmenti (IP) is a rare X-linked dominant phakomatosis that predominately presents with dermatologic manifestations but can also cause central nervous system and ocular abnormalities. Awareness of the ocular complications of IP is crucial to identify ocular abnormalities early and prevent permanent vision loss. There have been significant recent advances in ocular diagnostic imaging in IP. Optical coherence tomography (OCT) has helped characterize outer plexiform layer abnormalities in the macula, which can help explain central vision loss in IP patients. OCT angiography (OCT-A) also identifies macular vascular changes that induce these foveal structural abnormalities and may supplement fluorescein angiography, the current standard of care to identify peripheral retinal ischemia and neovascularization for infants with IP. Additionally, recent studies have presented excellent anatomic outcomes years after laser photocoagulation to ischemic retina. Early data indicates that antivascular endothelial growth factor therapy can induce retinal revascularization, but runs the risk of late recurrent neovascularization and requires long-term monitoring. Ophthalmic imaging is evolving in the evaluation of IP and is increasingly guiding treatment modalities. A particular focus on the ocular manifestations of IP has been the ideal treatment for retinopathy in this disorder.

Speckled brain lesions in Incontinentia Pigmenti patients with acquired brain syndromes.

Incontinentia Pigmenti (IP) is a neurocutaneous syndrome, with malformations of cortical development and neurodevelopmental delay in some patients. Neonates with IP may develop acute encephalopathy with multifocal ischemic brain lesions with a speckled pattern on diffusion-weighted magnetic resonance imaging (MRI). We observed a similar MRI pattern in 4 female patients with IP who presented with childhood acute encephalopathy syndromes. These patients, aged 9 days to 13 years old, had acute neonatal encephalitis, Influenza A virus related acute necrotizing encephalopathy (ANE) of childhood, Influenza B virus related acute encephalopathy with biphasic seizures and late restricted diffusion (AESD) and acute disseminated encephalitis (ADEM) with transverse myelitis (TM). These lesions could possibly reflect the white matter changes in IP patients with encephalopathy.

Importance of extracutaneous organ involvement in determining the clinical severity and prognosis of incontinentia pigmenti caused by mutations in the IKBKG gene.

Incontinentia pigmenti (IP) is a rare X-linked skin disease caused by mutations in the IKBKG gene, which is required for activation of the nuclear factor-kappa B signalling pathway. Multiple systems can be affected with highly variable phenotypic expressivity. We aimed to clarify the clinical characteristics observed in molecularly confirmed Korean IP patients. The medical records of 25 females confirmed as IP by molecular genetic analysis were retrospectively reviewed. The phenotypic score of extracutaneous manifestations was calculated to assess the disease severity. The IKBKG gene partial deletion or intragenic mutations were investigated using long-range PCR, multiplex ligation-dependent probe amplification and direct sequencing methods. Among the 25 individuals, 18 (72%) were sporadic cases. All patients showed typical skin manifestations at birth or during the neonatal period. Extracutaneous findings were noted in 17 (68%) patients; ocular manifestations (28%), neurological abnormalities (28%), hair abnormalities (20%), dental anomalies (12%), nail dystrophy (8%). The common exon 4-10 IKBKG deletion was observed in 20 (80%) patients. In addition, five intragenic sequence variants were identified, including three novel variants. The phenotype scores were highly variable, ranging from abnormal skin pigmentation only to one or more extracutaneous features, although no significant difference was observed for each clinical characteristic between the group with sequence variants and that with common large deletion. Our cohort with IP showed heterogeneity of extracutaneous manifestations and high incidence of sporadic cases. Long-term monitoring with multidisciplinary management is essential for evaluating the clinical status, providing adequate genetic counselling and understanding the genotype-phenotype correlation in IP.

The Anesthetic Challenges of Caring for a Pediatric Patient With Incontinentia Pigmenti: A Case Report

Incontinentia pigmenti (IP) is a rare X-linked dominant disorder. We present a case of an infant with IP who was brought to the operating room for panretinal diode photocoagulation under general anesthesia. The anesthesia team was unable to obtain intravenous access even with instruments such as a vein finder and ultrasound. Anesthesia for IP patients also poses challenges such as prevention of the oculocardiac reflex, obesity and airway management, and preemptive measures for intravenous access due to skin manifestations. Patients with IP may present with many challenges for the anesthesiologist during all phases of anesthetic management.

Incontinentia Pigmenti Associated with Aplasia Cutis Congenita in a Newborn Male with Klinefelter Syndrome: Is the Severity of Neurological Involvement Linked to Skin Manifestations?

We report a rare case of a newborn male affected by incontinentia pigmenti, Klinefelter syndrome, and aplasia cutis congenita, who developed severe cutaneous, neurological, and ophthalmological manifestations. Genetic analysis showed the presence of the common mutation of NEMO (exon 4–10 deletion), Klinefelter syndrome karyotype (47 XXY), and random X inactivation. This is in accordance with the severity of involvement of the affected tissues (skin, central nervous system, and retina). Indeed, the patient developed typical skin lesions all over the body, except the head. Equally, multiple lesions diffusely involving both the cortical grey matter and subcortical white matter of the cerebellum and cerebral hemispheres were observed. Discussing current knowledge about the etiopathogenesis of skin and brain lesions in incontinentia pigmenti, our case seems to support the proapoptotic origin of central nervous system involvement. Possibly, incontinentia pigmenti patients suffer an impaired protection against apoptosis at the level of cerebral endothelial cells of small vessels, leading to vascular damage and subsequent ischemic brain lesions.

Unraveling incontinentia pigmenti: A comparison of phenotype and genotype variants

Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis that affects multiple systems with highly variable phenotypic expressivity. Although most affected individuals carry a common pathogenic variant on the IKBKG gene, approximately 20% have no identifiable mutation. To describe clinical characteristics and genotype of IP patients and compare clinical differences between IKBKG pathogenic variant positive and negative cohorts. Retrospective cohort study conducted at a large tertiary pediatric center from 1990 to 2017, for children with a clinical diagnosis of IP. Forty-two children with IP were identified, including 33 of 42 (79%) females. Most presented with cutaneous stage I findings (31 of 42; 74%). Extracutaneous involvements were common: dental (50%), ocular (31%), hair (31%), nail (15%), and neurodevelopmental (26%). An IKBKG pathogenic variant was detected in 20 of 34 (59%) patients. Compared with these, 14 of 34 (41%) patients who tested negative were significantly more likely (P<.05) to be male, have no family history of IP, and have lower incidences of dental and hair anomalies. Retrospective methodology limits clear determination of the temporality of symptoms. Clinical differences between IKBKG pathogenic variant positive and negative IP cohorts support the prognostic utility of molecular genetic evaluation.

Intravitreal injection of ranibizumab in severe retinopathy of incontinentia pigmenti

Incontinentia pigmenti (IP) is a rare X-linked multisystem disorder that mainly affects females and is usually lethal to males in utero. Mutations in the NEMO gene on chromosome Xq28 (IKBKG, inhibitor of kB kinase gamma) have been shown to cause IP. Approximately 35% of patients have ophthalmic manifestations, and 20% develop vision-threatening diseases. Retinal vascular abnormalities, from peripheral retinal avascularity to neovascular proliferation, have been described in IP patients. Laser photocoagulation and cryotherapy are traditionally effective therapy for retinopathy of IP. However, some cases still progress to retinal detachment. We report 2 cases of IP infants treated with intravitreal ranibizumab with subsequent resolution of the vasculopathy.

NEMO regulates a cell death switch in TNF signaling by inhibiting recruitment of RIPK3 to the cell death-inducing complex II.

Incontinentia Pigmenti (IP) is a rare X-linked disease characterized by early male lethality and multiple abnormalities in heterozygous females. IP is caused by NF-κB essential modulator (NEMO) mutations. The current mechanistic model suggests that NEMO functions as a crucial component mediating the recruitment of the IκB-kinase (IKK) complex to tumor necrosis factor receptor 1 (TNF-R1), thus allowing activation of the pro-survival NF-κB response. However, recent studies have suggested that gene activation and cell death inhibition are two independent activities of NEMO. Here we describe that cells expressing the IP-associated NEMO-A323P mutant had completely abrogated TNF-induced NF-κB activation, but retained partial antiapoptotic activity and exhibited high sensitivity to death by necroptosis. We found that robust caspase activation in NEMO-deficient cells is concomitant with RIPK3 recruitment to the apoptosis-mediating complex. In contrast, cells expressing the ubiquitin-binding mutant NEMO-A323P did not recruit RIPK3 to complex II, an event that prevented caspase activation. Hence NEMO, independently from NF-κB activation, represents per se a key component in the structural and functional dynamics of the different TNF-R1-induced complexes. Alteration of this process may result in differing cellular outcomes and, consequently, also pathological effects in IP patients with different NEMO mutations.

Clinical study of 20 patients with incontinentia pigmenti.

Incontinentia pigmenti (IP) is a rare genodermatosis with early prenatal lethality in affected males. Clinical manifestations are usually more exuberant in sporadic than in familial cases. Cutaneous manifestations occur in all sporadic cases and about 96% of familial cases. As well as the skin, other tissues arising from the neuroectoderm may be affected. This study was designed to evaluate dermatologic, dental, neurologic, and ophthalmologic manifestations in patients with IP. Findings in IP patients and family members also diagnosed with IP in Porto Alegre, Brazil, during 2003-2012, were analyzed. Thirteen children and seven relatives were diagnosed with IP; 38.4% of cases were familial, and 61.5% were sporadic. Mean ± standard deviation follow-up was 46.08 ± 39.47 months. Frequencies of 100% and 85.7% for dermatologic manifestations, 23.0% and 0% for neurologic manifestations, 62.5% and 71.4% for dental manifestations, and 11.1% and 42.8% for ophthalmologic manifestations were found in affected children and relatives, respectively. Associated diseases include Wilms' tumor, myasthenia gravis, Still's syndrome, and congenital hypothyroidism. These findings reinforce the heterogeneity of dermatologic findings and the numerous extracutaneous manifestations requiring a multidisciplinary approach. The follow-up of patients with IP is important in the detection of serious associated diseases. The relationships between these disorders and IP raise the need for additional longitudinal studies with longterm monitoring of these patients. The management of IP in clinical practice may benefit from early efforts to detect associated diseases.

Blaschko line analogies in the central nervous system: A hypothesis

In X-chromosome-linked skin disorders the pattern of involvement follows Blaschko lines. Patterns of changes analogous to cutaneous Blaschko lines in different X-linked diseases existed in other organs. There is no commonly accepted analogy to Blaschko lines in the central nervous system (CNS). The objective of this study was to consider a hypothesis of the existence of Blaschko lines in the CNS in the example of incontinentia pigmenti (IP). Articles were analyzed in which brain imaging methods were used in IP patients with CNS anomalies. In IP patients with neurological signs brain lesions usually were localized and extended radially. Affected areas did not correspond to territories vascularized by any determined artery. Radially distributed brain lesions morphologically match the radial unit model of cortical development. It can be proposed that in IP in CNS Blaschko line analogies, similar to those in the skin, represent the trace of development of the clone of neurons arising from the cell marked with IKBKG mutation. The hypothesis of the existence of Blaschko line analogies in CNS is supported by radially distributed CNS image findings in IP, the radial unit model of CNS development, and the common embryonic origin of skin, CNS, and eyes.

Systematic review of central nervous system anomalies in incontinentia pigmenti

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.

NEMO gene rearrangement (exon 4–10 deletion) and genotype–phenotype relationship in Japanese patients with incontinentia pigmenti and review of published work in Japanese patients

Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis caused by mutations of the NEMO gene, which is required for activation of the nuclear factor-κB signaling pathway. NEMO gene rearrangement, exon 4-10 deletion, is the most common mutation with a frequency of 60-80%. Only four case reports about NEMO rearrangement in Japanese IP cases have been published. In our study, NEMO gene rearrangement was examined in 10 Japanese IP patients and their mothers and was revealed in five of 10 patients and three of their mothers. Interestingly, NEMO gene rearrangement was confirmed in the mothers of two patients without clinical symptoms; thus, NEMO mutation analysis is helpful to detect subclinical IP patients. The clinical symptoms of recently diagnosed Japanese IP patients were summarized for examination of the phenotype-genotype relationship and for comparison between those with and without NEMO gene rearrangement. Results revealed no definite difference in extracutaneous manifestations between the patients with NEMO rearrangement in our study and in other Japanese IP patients previously reported in both Japanese and English-language published work. However, there is higher frequency of ocular manifestation in our study than in other reports. Furthermore, evaluation of dental and nail abnormalities was difficult because most of our patients were observed for 1 year only. Long-term observation is needed for proper evaluation of the clinical status and phenotype-genotype relationship in IP patients.

First IKBKG gene mutation study in Serbian incontinentia pigmenti patients

Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis. Mutations of the IKBKG gene are the only known cause of IP. The presence or other than skin changes is important in the diagnosis of atypical IP cases when skin changes are discrete. 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. 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 pathohistological and ultrastructural analyses of skin biopsies were done. 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. 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.

The Men behind Incontinentia Pigmenti

Incontinentia pigmenti (IP), listed in the Online Inheritance of Man (OMIM), under the number (#308300), is an x-linked dominant condition that affects skin, teeth, eyes and may also have neurological problems. The IP name describes the histological characteristics, the incontinence of melanin into the melanocytes cells in the epidermal basal layer and its presence in superficial dermis [1,2]. Garrod reported the first probable case of incontinentia pigmenti in 1906 and described it as a peculiar pigmentation of the skin in an infant with mental deficiency and tetraplegia. Subsequently, Bloch and Sulzberger further defined the condition in 1926 and 1928, respectively, as a clinical syndrome. Hermann Werner Siemens (1891-1969), is a German dermatologist, who also, contributed to the description of this disease and his name is also linked to the eponyms of this disease. IP is caused by mutations in the NEMO (NF-κB essential modulator) gene, the protein product of which protects against tumor necrosis factor-α-induced apoptosis. Between 900 and 1,200 affected individuals have been reported in the scientific literature. Most of these individuals are female. Cutaneous findings are the most common manifestation of IP and usually represent the presenting signs. They are divided into four overlapping stages: (1) vesiculobullous, which favors the extremities during the first few months of life (but occasionally recurs during childhood in association with a febrile illness); (2) verrucous, which favors the distal extremities in patients one to six months of age (and sometimes adolescents); (3) hyperpigmented, which favors the trunk and intertriginous sites from three months of age through adolescence; and (4) hypopigmented/atrophic, which affects the calves in adolescents and adults [1,2]. The extracutaneous manifestations of IP, which are less frequent than are the skin findings, are more likely to cause morbidity. These include dental abnormalities (such as small teeth or few teeth), eye abnormalities that can lead to vision loss, and central nervous system (CNS) abnormalities also occur in one-third of IP patients and can include seizures, developmental delay, and spastic paresis. However, most people with incontinentia pigmenti have normal intelligence. Infants with IP should be referred to a pediatric ophthalmologist for evaluation and close follow-up. In addition, neurodevelopmental status should be monitored, and a pediatric neurologist consulted if problems arise [1,2]. Early dental intervention is also recommended. Incontinentia Pigmenti International foundation (IPIF) is a voluntary nonprofit organization founded in 1995. Its mission is to encourage and support research on IP, and to provide family support and education. Further details about this organization can be seen at its official website, http:// www.ipif.org/ There are several synonyms for IP. These includes Bloch– Siemens syndrome, Bloch–Sulzberger disease, Bloch– Sulzberger syndrome, Bloch-Siemens-Sulzberger Syndrome, melanoblastosis cutis, melanoblastosis cutis linearis, nevus pigmentosus systematicus, and pigmented dermatosis, Siemens-Bloch type. However, Bloch–Sulzberger syndrome, is the most common eponym for this disorder, I am going to highlight on the dermatologists behind this eponym.