Human Genetic Diseases Linked to the Absence of NEMO: An Obligatory Somatic Mosaic Disorder in Male.

De novo somatic mutations are well documented in diseases such as neoplasia but are rarely reported in rare diseases. Hovewer, severe genetic diseases that are not compatible with embryonic development are caused exclusively by deleterious mutations that could only be found as mosaic and not as inherited mutations. We will review here the paradigmatic case of Incontinentia Pigmenti, a rare X-linked dominant disease caused by deficiency of the NEMO (also called IKKgamma) protein, which plays a pivotal role in tissue homeostasis. The loss-of-function mutations of NEMO are embryonically lethal in males while females survive because of unbalanced X-inactivation due to NEMO wild type (WT) expressing cells survival despite of NEMO mutant expressing cells. The few surviving IP males are obligatory mosaic mutants with the typical clinical presentation of IP in female. Indeed, the IP pathogenesis in the female and most likely also in the male somatic mosaics is based on the cellular effects of an impaired NEMO activity, but in the context of the interaction of genetically different cells in the affected tissue, which might underline the inflammatory status.

EDA-ID and IP, two faces of the same coin: how the same IKBKG/NEMO mutation affecting the NF-κB pathway can cause immunodeficiency and/or inflammation.

Anhidrotic Ectodermal Dysplasia with ImmunoDeficiency (EDA-ID, OMIM 300291) and Incontinentia Pigmenti (IP, OMIM 308300) are two rare diseases, caused by mutations of the IKBKG/NEMO gene. The protein NEMO/IKKγ is essential for the NF-κB activation pathway, involved in a variety of physiological and cellular processes, such as immunity, inflammation, cell proliferation, and survival. A wide spectrum of IKBKG/NEMO mutations have been identified so far, and, on the basis of their effect on NF-κB activation, they are considered hypomorphic or amorphic (loss of function) mutations. IKBKG/NEMO hypomorphic mutations, reducing but not abolishing NF-κB activation, have been identified in EDA-ID and IP patients. Instead, the amorphic mutations, abolishing NF-κB activation by complete IKBKG/NEMO gene silencing, cause only IP. Here, we present an overview of IKBKG/NEMO mutations in EDA-ID and IP patients and describe similarities and differences between the clinical/immunophenotypic and genetic aspects, highlighting any T and B lymphocyte defect, and paying particular attention to the cellular and molecular defects that underlie the pathogenesis of both diseases.

Incontinencia pigmenti: a propósito de dos casos / Incontinentia pigmenti: report of two cases

La Incontinencia Pigmenti (IP) o síndrome de Bloch Sulzberger es un trastorno multisistémico neuroectodérmico, que afecta predominantemente al género femenino, cuya manifestación inicial incluye lesiones cutáneas que evolucionan por brotes. En ocasiones, se asocia a compromiso oftalmológico, neurológico y dentales parte del diagnóstico diferencial de lesiones ampollares en un neonato. Se presentan dos casos de IP diagnosticados en etapas cutáneas distintas, uno de ellos con compromiso neurológico.

Incontinentia Pigmenti (IP) or Bloch Sulzberger syndrome is a neuroectodermal multisystemic disorder, that predominantly affects women, whose initial manifestation includes skin lesions that evolve by outbreaks. Sometimes, is associated with ophthalmological, neurological and dental commitment. It is part of the differential diagnosis of bullous lesions in a newborn. We present 2 cases of IP diagnosed in different skin stages and one of them with neurological involvement.

IKK regulation and human genetics.

The IKK kinase complex is the core element of the NF-κB cascade. It is essentially made of two kinases (IKKα and IKKß) and a regulatory subunit, NEMO/IKKγ. Additional components may exist, transiently or permanently, but their characterization is still uncertain. In this review, we will focus on the NEMO molecule, and describe the results which have been obtained, and the hypotheses which have been proposed, to explain how NEMO controls the activation of the IKK complex. NEMO is one of the very few non-redundant components of the NF-κB cascade, and the localization of the gene that encodes it on the X chromosome suggests it is likely to be the target of mutations leading to pathologies: this is indeed the case, and we will also present the current status of our knowledge regarding NEMO-associated pathologies.

Incontinentia pigmenti in a male infant with Klinefelter syndrome: a case report and review of the literature.

Incontinentia pigmenti, also known as Bloch-Sulzberger syndrome, is a hereditary, X-linked dominant disorder characterized by abnormalities of skin, hair, teeth, eyes, and the central nervous system. It is classically considered a male-lethal disorder leading to recurrent miscarriages of male fetuses. We report a rare case of a surviving baby boy with the classic clinical features of incontinentia pigmenti that can be explained by Klinefelter syndrome.

NF-kappaB and inflammation in genetic disease.

By responding to pro-inflammatory cytokines, such as IL-1beta and TNF-alpha, and controlling itself the expression of numerous mediators of inflammation, NF-kappaB plays a pivotal role in controlling the proper sequence of events characterizing the inflammation process. Although excessive NF-kappaB activation is often associated with inflammatory signs in many different tissues, impaired NF-kappaB activation can also generate inflammation. This is the case in humans suffering from the genetic disease incontinentia pigmenti that exhibit severe skin inflammation. Identifying the molecular basis of this pathology, mutations affecting the gene coding for NEMO, has allowed production of mouse models for investigating the disease. Their characterization supports the view that a very tight positive and negative regulation of the NF-kappaB signaling pathway is required in vivo to ensure not only a fine-tuned response to injury or infection but also to maintain tissue homeostasis.

Incontinencia Pigmentaria. Consideraciones odontoestomatológicas: profilaxis y terapéutica / Incontinentia pigmenti. Odontostomtomatologics considerations: prevention and therapeutic

La incontinencia pigmentaria es una rara enfermedad, familiar, transmisión genética ligada al cromosoma X, de aparición casi exclusiva en mujeres, afectación cutánea muy típica y anomalías que afectan al pelo, dientes, ojos, sistema nervioso central, con una importante incidencia en las estructuras estomatognáticas tanto cuantitativa como cualitativamente. Los dientes se ven afectados en el 50-80% de los pacientes. Existe un retraso en la erupción dental, ausencia parcial o total de dientes, formas anormales de los mismos, dientes impactados, mal oclusiones. Por tanto, se considera importante la prevención en estos pacientes insistiendo en la higiene oral, control de caries, revisiones orales periódicas, etc.. Se hace una exposición de las distintas opciones de tratamiento para obtener una armonía, una funcionalidad y estética dental aceptables (AU)

Incontinentia pigmenti is a rare, family disorder of genetic transmisión linked to the X chromosome which appears almost exclusively in females; it causes skin disorders and anomalies that affect hair, teeth, eyes and the central nervous system. Teeth are affected in 50-80% of patients. Patients are late in teething, some or all teeth maybe lacking, those that exist may have malformations, maloclusions. Therefore prevention is of ut most importance in these patients, with special attention given to dental hygiene, control of tooth decay, regular check-ups, etc..The different options for treatment will be examined in order to obtain acceptable dental harmony, functioning and aesthetics (AU)

Incontinência pigmentar: revisão da literatura / Incontinentia pigmenti: literature review

A incontinência pigmentar é uma doença genética dominante ligada ao X, com comprometimento neurológico, oftalmológico, dental e cutânea. Este trabalho apresenta aspectos etiológicos e clínicos, tratamento e prognóstico

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.

Manifestaciones y secuelas cutáneas de la drogadicción / Cutaneous manifestations and sequelae in drug addicts

Las lesiones dermatológicas producidas por la administración de drogas ilícitas y sus eventuales secuelas, tienen implicancias médico-legales y sumo valor para el diagnóstico retrospectivo de adicción. Estas lesiones son de origen multifactorial: combinan la reacción del huésped ante agentes químicos sensibilizantes e irritantes, traumatismos reiterados por técnicas de aplicación incorrectas e infección sobreagregada. Clínicamente, se observan como hiperpigmentaciones sobre trayectos vasculares indurados, cicatrices atróficas en áreas de inyección subcutánea, abscesos sépticos y granulomas por cuerpo extraño, en su mayoría provocados por excipientes y adulterantes, como lesiones más características. Se presentan casos clínicos y se hace revisión de estos procesos, enfatizando la situación particular en Argentina en relación a la bibliografía consultada, proveniente de países del Primer Mundo. Asimismo, se ilustra brevemente el léxico tan particular de los adictos, cuyos rudimentos se vuelven imposibles de obviar cuando se avanza en el estudio de estos pacientes (AU)

Role of the NF-kappaB pathway in the pathogenesis of human disease states.

The NF-kappaB family consists of a group of inducible transcription factors which regulate immune and inflammatory responses and protect cells from undergoing apoptosis in response to cellular stress. A number of signal transduction cascades can activate the NF-kappaB pathway to result in the translocation of the NF-kappaB proteins from the cytoplasm to the nucleus where they activate the expression of specific cellular genes. In this review, we discuss cellular genes which are regulated by NF-kappaB and disease states which are associated with constitutive activation of the NF-kappaB pathway. Strategies to prevent prolonged activation of the NF-kappaB pathway are also discussed.

Incontinentia pigmenti: A propósito de un caso / Incontinentia pigmenti

Incontinentia Pigmenti is a rare X-linked multisystem neuroectodermic disorder with signs and symptonms related mainly to the dermatologic, dental, ocular and central nervous systems, and characterized by death in the majority of male embryos. Affected children do not appear sick, in spite of the skin eruption, the peripheral leucocytosis and marked eosinophilia. Most of the cases are reported in caucasians, although there are description in black children, orientals, north, central and south american indians, and in our mestizos. The name of Incontinentia Pigmeti describes the incontinence of the melain pigment from the basal layer of the epidemermis into the superficial dermis