X-linked Dominant Genodermatosis Research Articles

Germline intergenic duplications at Xq26.1 underlie Bazex-Dupré-Christol basal cell carcinoma susceptibility syndrome.

Bazex-Dupré-Christol syndrome (BDCS; MIM301845) is a rare X-linked dominant genodermatosis characterized by follicular atrophoderma, congenital hypotrichosis and multiple basal cell carcinomas (BCCs). Previous studies have linked BDCS to an 11·4-Mb interval on chromosome Xq25-q27.1. However, the genetic mechanism of BDCS remains an open question. To investigate the genetic aetiology and molecular mechanisms underlying BDCS. We ascertained multiple individuals from eight unrelated families affected with BDCS (F1-F8). Whole-exome (F1 and F2) and genome sequencing (F3) were performed to identify putative disease-causing variants within the linkage region. Array comparative genomic hybridization and quantitative polymerase chain reaction (PCR) were used to explore copy number variations, followed by long-range gap PCR and Sanger sequencing to amplify the duplication junctions and to define the head-tail junctions. Hi-C was performed on dermal fibroblasts from two affected individuals with BDCS and one control. Public datasets and tools were used to identify regulatory elements and transcription factor binding sites within the minimal duplicated region. Immunofluorescence was performed in hair follicles, BCCs and trichoepitheliomas from patients with BDCS and sporadic BCCs. The ACTRT1 variant c.547dup (p.Met183Asnfs*17), previously proposed to cause BDCS, was evaluated with t allele frequency calculator. In eight families with BDCS, we identified overlapping 18-135-kb duplications (six inherited and two de novo) at Xq26.1, flanked by ARHGAP36 and IGSF1. Hi-C showed that the duplications did not affect the topologically associated domain, but may alter the interactions between flanking genes and putative enhancers located in the minimal duplicated region. We detected ARHGAP36 expression near the control hair follicular stem cell compartment, and found increased ARHGAP36 levels in hair follicles in telogen, in BCCs and in trichoepitheliomas from patients with BDCS. ARHGAP36 was also detected in sporadic BCCs from individuals without BDCS. Our modelling showed the predicted maximum tolerated minor allele frequency of ACTRT1 variants in control populations to be orders of magnitude higher than expected for a high-penetrant ultra-rare disorder, suggesting loss of function of ACTRT1 variants to be an unlikely cause for BDCS. Noncoding Xq26.1 duplications cause BDCS. The BDCS duplications most likely lead to dysregulation of ARHGAP36. ARHGAP36 is a potential therapeutic target for both inherited and sporadic BCCs. What is already known about this topic? Bazex-Dupré-Christol syndrome (BDCS) is a rare X-linked basal cell carcinoma susceptibility syndrome linked to an 11·4-Mb interval on chromosome Xq25-q27.1. Loss-of-function variants in ACTRT1 and its regulatory elements were suggested to cause BDCS. What does this study add? BDCS is caused by small tandem noncoding intergenic duplications at chromosome Xq26.1. The Xq26.1 BDCS duplications likely dysregulate ARHGAP36, the flanking centromeric gene. ACTRT1 loss-of-function variants are unlikely to cause BDCS. What is the translational message? This study provides the basis for accurate genetic testing for BDCS, which will aid precise diagnosis and appropriate surveillance and clinical management. ARHGAP36 may be a novel therapeutic target for all forms of sporadic basal cell carcinomas.

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 with ocular, cutaneous and CNS manifestation

Incontinentia Pigmenti (IP) is an uncommon X-linked genodermatosis, with an estimated prevalence at birth of 0.7/100,000, caused by mutations in the NEMO gene. Ectodermic and mesodermic origin of tissue is seen in this systemic disease including cutaneous tissue, teeth, eyes, and the central nervous system. Herein, we present a case of a female newborn with inflammatory vesiculopustular lesions all over the body. This baby also had ocular, and CNS manifestations as well. The importance of a detailed diagnostic workup for the newborns with pustular skin disease has been highlighted in this case. IP is a rare, x-linked dominant genodermatosis with the involvement of multiple organs. Dermatological abnormalities are the most prominent manifestation. The diagnosis is based on the clinical findings of skin lesion brain imaging and biopsy. The skin lesions do not require specific treatment and prognosis depend on other organ involvement.

Retos ligos klinikinis pasireiškimas ir diagnostika: nuo prenatalinio laikotarpio iki ankstyvosios vaikystės. Klinikinis pigmento nelaikymo ligos atvejis

Santrauka. Pigmento nelaikymo liga – tai genodermatozė, kuriai budingas odos ir kitų ektoderminių organų pažeidimas. Tai reta liga, paveldima su X chromosoma susijusiu dominantiniu būdu. Liga pasireiškia dėl X chromosomoje įvykusio IKBKG/NEMO patogeninio pokyčio. Manoma, kad dėl to audiniuose sutrinka imuninė tolerancija, sukelianti autoimuninę reakciją. Šia liga serga beveik išimtinai mergaitės, nes liga dažniausiai yra letali vyriškosios lyties embrionams. Straipsnyje pristatomas labai retas pigmento nelaikymo klinikinis atvejis, nuo prenatalinės diagnostikos galimybių iki tolesnių paciento priežiūros gairių, apžvelgiami mokslinės literatūros duomenys.

Incontinentia pigmenti in adults.

Incontinentia Pigmenti (IP; MIM 308300) is an X-linked dominant genodermatosis caused by pathogenic variant in IKBKG. The phenotype in adults is poorly described compared to that in children. Questionnaire survey of 99 affected women showed an age at diagnosis from newborn to 41 years, with 53 diagnosed by 6 months of age and 30 as adults. Stage I, II, and III lesions persisted in 16%, 17%, and 71%, respectively, of those who had ever had them. IP is allelic to two forms of ectodermal dysplasia. Many survey respondents reported hypohidrosis and/or heat intolerance and most had Stage IV findings. This suggests that "Stage IV" may be congenitally dysplastic skin that becomes more noticeable with maturity. Fifty-one had dentures or implants with 26 having more invasive jaw or dental surgery. Half had wiry or uncombable hair. Seventy-three reported abnormal nails with 27 having long-term problems. Cataracts and retinal detachment were the reported causes of vision loss. Four had microphthalmia. Respondents without genetic confirmation of IP volunteered information suggesting more involved phenotype or possibly misassigned diagnosis. Ascertainment bias likely accounts for the low prevalence of neurocognitive problems in the respondents.

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.

UNRAVELING INCONTINENTIA PIGMENTI: A COMPARISON OF PHENOTYPE AND GENOTYPE VARIANTS

Abstract BACKGROUND Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis that predominantly affects the skin, beginning with a characteristic linear vesicular rash shortly after birth. Multisystem abnormalities can further be seen in hair, nail, ocular, dental, and central nervous system. Although most affected individuals carry a common pathological deletion of the IKBKG gene, approximately 20% have no molecular confirmation. There remains a lack of understanding of phenotypic variations between mutation positive and negative patients with IP. OBJECTIVES We aim to 1) Describe clinical characteristics, phenotype, and genotype of patients with IP, and 2) Compare clinical differences between mutation positive and negative cohorts. DESIGN/METHODS A retrospective chart review was conducted at a large tertiary paediatric centre from January 1990 to June 2017, for children under 19 with a clinical diagnosis of IP by a paediatric dermatologist or geneticist. Baseline characteristics, diagnostic history, family history, cutaneous and extracutaneous symptoms were extracted. Further subspecialty reports such as dental and ophthalmology, and available laboratory results including bloodwork, histopathology, and genetic reports were reviewed. Patients who had undergone molecular genetic testing were further divided into either positive (IKBKG mutation) or negative (no identifiable mutation) genetics cohorts for analyses. RESULTS A total of 44 children with IP were identified, including 79% female, 64% white (non-hispanic), 24% with IP family history, and 85% were confirmed on biopsy. Median age at first dermatology or genetics consult was 6 weeks and 26% had undergone a full septic workup (cultures negative) prior for the IP rash. Extracutaneous involvements were common: dental (49%), ocular (32%), hair (31%), nail (15%), and neurodevelopmental (24%). Compared to the mutation positive (59%) cohort, those with negative mutations (41%) were significantly more likely to be male, have a negative family history of IP, and lower incidences of dental and hair anomalies (P &lt;0.05). CONCLUSION Clinical approach to IP should involve not only dermatology and genetics evaluation, but may benefit from multidisciplinary monitoring for extracutaneous manifestations. Findings of unique clinical variations between positive and negative mutation cohorts suggests the need for further in-depth evaluation into key differences as they may affect disease counselling and future prognosis.

A Case Report of Incontinentia Pigmenti in a Newborn with Positive Family History Extending Over Three Generations

Background: Incontinentia pigmenti (IP), also known as Bloch-Sulzberger syndrome, is a rare X-linked dominant genodermatosis that presents at the time of birth or soon after birth with cutaneous manifestation. This disorder may also affect the ectodermal tissues, such as the central nervous system, skeletal system, eyes, hair, nails, and teeth. The dermatological findings occur in four successive phases.Case report: Herein, we presented the case of a two day-old female newborn with inflammatory vesiculopustular lesions on the right forearm and lower limbs, who was in a good general condition. The patient had a history of similar disease in three other members of her family, who had dental abnormalities as the most common non-cutaneous manifestation. This case report highlighted the importance of a detailed diagnostic workup for the newborns with pustular skin disease.Conclusion: IP is a rare, x-linked dominant genodermatosis with multiple organs involvement. Dermatological abnormalities are the most prominent manifestation. The diagnosis is based on the clinical findings, the presence of positive family history of skin vesiculopustular lesions support the diagnosis. The skin lesions do not require specific treatment and prognosis depend to other organs involvement.

Incontinentia Pigmenti in a newborn: Case report and review of the literature

Incontinentia Pigmenti (IP) is a rare X-linked dominant genodermatosis resulting from mutations in IKBKG gene, affecting primary females. Most cases present with early dermatologic changes, but clinical features can be found in hair, teeth, nails, eyes, and central nervous system (CNS). A typical 4 stages skin chronologic evolution occurs from the first weeks of life and may persist into adulthood: vesicobullous, verrucous/inflammatory, hyperpigmentar and atrophic (some stages may overlap). A distribution pattern along Blaschko's Lines (BL) is typical. We describe a newborn report focusing on the aesthetic relevance and we enhance an early and correct diagnosis based on reviewed literature. A 6-day-old female neonate presented with a progressive vesicobullous eruption in the trunk, limbs and scalp, as well as infected skin lesions. No systemic involvement was found and she underwent intravenous antibiotherapy. Inflammatory markers, blood culture and polymerase chain reaction (PCR) studies to herpes simplex virus (HSV) and varicella-zoster virus (VZV) were negative. Skin biopsy was compatible with IP and IKBKG mutation was confirmed. There was spontaneous regression of most skin lesions. She had no extra-cutaneous complications and growth and psychomotor development were satisfactory until 18-months-old. This report alerts to a rare disease with potential morbidity and great aesthetic relevance, often misdiagnosed and mistaken for more common neonatal skin infections.

Long-term follow-up of neurological manifestations in a boy with incontinentia pigmenti

Incontinentia pigmenti (IP) is an X-linked dominant genodermatosis confined to females. It is usually lethal in males. However, the survival of some males has been reported in literature. We describe a long follow-up case of a 12-year-old male with IP and a normal karyotype but a genomic deletion of the NEMO gene in the Xq28 position in the form of somatic mosaicism. The patient showed severe ophthalmic abnormalities and neurological manifestations characterised by very mild cerebellar ataxia and a history of epilepsy that was severe at the beginning with West syndrome, become moderate overtime and is now resolved. Despite these neurological manifestations, probably related to the presence of at least some mutated cells in his brain, the long-term follow-up in this patient demonstrated good neurological and cognitive outcome.

Incontinentia pigmenti (Bloch–Siemens syndrome)

Incontinentia pigmenti (IP) is an uncommon X-linked dominant genodermatosis. It affects predominantly females and is lethal in utero in male fetuses. We herein report a baby girl born with blisters on trunk and limbs. The diagnosis of IP was based on clinical findings and on histopathological analysis of biopsy specimen.

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.

Incontinencia pigmentaria asociada a fisura palatina. Reporte de un caso

Incontinentia pigmenti (IP2, Block-Sulzberger Syndrome) is a rare x-linked dominant genodermatosis mainly affecting females. It consists of characteristic skin manifestations and dental, ocular, neurological, and other disorders. We present a case report with classical cutaneous features diagnosed with incontinentia pigmenti associated with a cleft palate.

Incontinentia pigmenti (Bloch-Sulzberger-Syndrom)

A female infant, aged two weeks, presented with linear erythematous crusted papules, plaques and blisters on the right leg which had occurred two days after birth. Histological examination revealed typical features of incontinentia pigmenti in the inflammatory stage. Incontinentia pigmenti is a rare X-linked dominant genodermatosis caused by mutations in the NEMO gene located at Xq28 affecting the skin, different organ systems, the central nervous system, eyes, teeth and skeleton with variable expression. We summarize important clinical and diagnostic aspects of incontinentia pigmenti as well as its genetic and molecular basis.

Varied presentations of incontinentia pigmenti

Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis with cutaneous, neurological, ophthalmological and dental manifestations. 80% of cases have a deletion mutation in the nuclear factor-κB (NF-κB) essential modulator (NEMO) gene located on chromosome Xq28. This gene is required for activation of the transcription factor NF-κB which is central to many immune, inflammatory and apoptotic pathways. The authors present two cases of IP to demonstrate the varied presenting features of this condition. The first case is a 9-month-old girl who presented mildly unwell, with erythematous lines on her abdomen in a “Chinese-writing” distribution. Further examination showed hyperkeratotic lesions on her calves, and a hyperkeratotic papule and blister which had been present on her hand since birth. Her mother had a history of two spontaneous abortions. She had linear hypopigmentation on the legs and only 16 teeth. A diagnosis was made of a viral exanthem arising on a background of IP. She is now 5 years old and has linear hyperpigmentation on her legs, teeth abnormalities and patchy alopecia. Her mother has a confirmed mutation in the NEMO gene. The second case is a 3-month-old baby girl who had developed seizures on the second day of life. An MRI showed two unusual areas on the lateral ventricle which had been interpreted as small areas of ischaemia. She developed linear erythematous papules, blistering and crusting on her groin and trunk on day 4 and a clinical diagnosis of IP was made. Genetic analysis confirmed a mutation in the NEMO gene. Her mother has no mutation in the NEMO gene. There are four cutaneous stages classically seen in IP from birth: vesicular, verrucous, hyperpigmented and, in adulthood, an atrophic hypopigmented stage. In both of our cases, the presenting features were not the classical cutaneous features of IP: case 1 presented with a viral exanthem within the lines of Blaschko; case 2 presented with neurological involvement. The authors present these two cases of IP as examples of the varied presentations of this condition to increase awareness of possible presenting features of this unusual genodermatosis.

Incontinentia pigmenti

Incontinentia pigmenti (IP) or Bloch-Sulzberger syndrome is a rare X-linked dominant genodermatosis related to the NF kappa B essential modulator (NEMO) gene with approximately 800 cases reported worldwide. It usually occurs in females characterized by cutaneous, skeletal, neurological, ocular and dental abnormalities as well as an increased risk of childhood malignancies. Herein, we report a case of IP in a 14-year-old girl emphasizing early diagnosis and adding to the current literature on the subject.

A Case of Incontinentia Pigmenti in Japan and Its Genetic Examination

Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis with approximately one-third of cases with associated ocular complications. Deletion of exons 4 to 10 of the nuclear factor kappaB essential modulator (NEMO) gene accounts for the majority of new mutations. The disease is more commonly found among Caucasians. We studied a case of an IP patient in Japan, and the genomic rearrangements. An 11-month-old female infant exhibited the skin lesions of IP. Ocular findings were total retinal detachment with a retrolental fibrovascular mass in the right eye, and patchy retinal avascular zones and neovascularization in the left eye. The genomic rearrangement of NEMO was investigated by a polymerase chain reaction (PCR)-based diagnostic test. A skewed X-inactivation assay was also performed using the human androgen receptor gene as a genetic marker. Deletion of exons 4 to 10 in NEMO was detected in the proband and in other female members of her family. A complete skewing of the X-inactivation pattern causing IP was observed, indicating cells having no protection against apoptosis in response to tumor necrosis factor as the pathogenicity of the disease. This is the first case report of a Japanese female phenotype demonstrating the common genomic rearrangement in the NEMO gene.

Incontinentia pigmenti in male patients

Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis that is typified by distinctive cutaneous findings and often by abnormalities of teeth, hair, nails, eyes, musculoskeletal system, and central nervous system. The gene that is mutated in patients with IP has been mapped to Xq28 and encodes the NF-kappaB essential modulator, NEMO. Female patients with IP show functional mosaicism and cutaneous manifestations follow Blaschko's lines of ectodermal embryologic development. The condition is generally considered to be lethal in utero in male fetuses, suggesting that having some normal gene expression is critical for survival. We observed 9 boys with IP. All had normal karotypes and no apparent family history of IP. In 8 of these 9 patients, lesions were localized to one extremity at presentation. The diagnosis was confirmed by histopathologic examination that showed eosinophils within intraepidermal, multiloculated vesicles. One of the boys later developed dental and neurologic abnormalities. The case series was small and the workup for these patients from different sites was not uniform. Male individuals may show cutaneous and noncutaneous features of IP in a limited distribution that allows survival. Postzygotic mutation/somatic mosaicism is the likely mechanism. Given the potential sequelae associated with this condition, continuing follow-up of these patients is recommended.

Pulmonary Tuberculosis and Cutaneous Mycobacterial Infection in a Patient with Incontinentia Pigmenti

Lupus vulgaris is reinfection tuberculosis of the skin and may result from direct extension, or hematogenous or lymphatic spread from a tuberculosis focus. Lupus vulgaris following bacille Calmette-Guerin (BCG) vaccination is a rare entity. Incontinentia pigmenti is an X-linked dominant genodermatosis in which vesicular, verrucous, and pigmented lesions are associated with various developmental defects. There is evidence of altered immunologic reactivity in some patients with incontinentia pigmenti. A 12-year-old girl hospitalized for pulmonary tuberculosis presented with bizarre-shaped brown macules following Blaschko lines on the left deltoid area, compatible with incontinentia pigmenti, which had appeared following BCG vaccination at the age of 7 years. Histopathologic examination found noncaseated granulomas in the dermis. Antituberculous treatment for pulmonary and cutaneous tuberculosis was initiated along with genetic counseling. Immunologic abnormalities have been reported in conjunction with incontinentia pigmenti. Simultaneous occurrence of pulmonary and cutaneous tuberculosis in our patient might be either coincidental or indicate derangements in the cellular immune system.

Incontinentia pigmenti: a window to the role of NF-kappaB function.

Incontinentia pigmenti is an uncommon X-linked dominant genodermatosis primarily affecting females. Its hallmark is a unique skin eruption that presents in infancy along the lines of Blaschko and evolves through four stages: inflammatory, verrucous, hyperpigmented, and atrophic. Other persistent findings of the disease include alopecia and dental anomalies. In a minority of cases, serious ophthalmologic and neurological alterations may occur. Mutations in the NF-kappaB essential modulator (NEMO) that lead to an inability to activate the NF-kappaB pathway produce IP. Less deleterious mutations in NF-kappaB essential modulator give rise to hypohidrotic ectodermal dysplasia with immune deficiency in affected males, a related but distinct phenotype. These recent discoveries provide insight into the crucial role of NF-kappaB function in regulating the developmental, inflammatory, immune, and anti-apoptotic responses of the skin and other organs.