Incontinentia pigmenti (Bloch-Sulzberger syndrome).
TL;DR: The name incontinentia pigmenti describes the characteristic, albeit non-specific, histological feature where there is incontinence of melanin from the melanocytes in the basal layer of the epidermis into the superficial dermis.
Abstract: Incontinentia pigmenti (IP) is a rare genodermatosis and was probably first described as early as 1906 by Garrod,' but the credit is given to Bardach,2 Bloch,3 Siemens,4 and Sulzberger5 for defining the condition during the 1920s, although only the names of Bloch and Sulzberger feature in the eponym. It is a multisystem, ectodermal disorder accompanied by dermatological, dental, and ocular features and in a minority of cases may be associated with neurological deficit. The typical phenotype is a result of functional mosaicism, a phenomenon which occurs in X linked dominant disorders because of lyonisation. The name incontinentia pigmenti describes the characteristic, albeit non-specific, histological feature where there is incontinence of melanin from the melanocytes in the basal layer of the epidermis into the superficial dermis.
Citations
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TL;DR: The new Forfar and Arneil is, like its predecessors, a good book, but the absence of the chapter on ear, nose, and throat disorders must surely be an error and there is clearly a marketing problem for British publishers faced with American competition.
Abstract: British authors are the natural heirs to Charles Dickens and Graham Greene.) Nevertheless there are advantages to British readers in a British book especially, for instance, in the chapter on social paediatrics and occasionally as regards therapeutics. The new Forfar and Arneil is, like its predecessors, a good book. There are many new authors and much of it has been completely rewritten. Each chapter has a long list of references, many of them to further reading in books and important 'landmark' papers rather than to very recent original work, and that seems appropriate for a textbook of this nature. It is up to date, including references to topics such as oesophageal pH monitoring in gastrooesophageal reflux, the value of steroids in bacterial meningitis, a full account of the peroxisomal disorders, the significance of dystrophin in muscular dystrophy, the importance of vitamin A in reducing mortality in third world countries, and the use of sumatriptan in migraine and of vigabatrin and lamotrigine in epilepsy. Surprisingly, neither in this nor in Nelson's textbook could I find any reference to Angelman's syndrome. Some topics chosen at random such as Prader-Willi syndrome or haemolytic uraemic syndrome were discussed more fully in the British textbook. There is a surprising omission, however, and that is the chapter on disorders ofear, nose, and throat. Adenoids, glue ear or secretory otitis media, tonsillitis, and tonsillectomy have all been dropped from the index and deafness is dealt with in the chapter on neurology. If you look up 'tonsils' you will be referred to any entry which reads: 'Tonsils: size, presence of infection, exudate, pitting, peritonsillar swelling?'. The index entry 'ear, nose and throat problems' refers to a brief account of such problems in children with cleft palate. It is one of those crazy facts of modern life that the American book costs £60, the British £125. Who will read this new edition? I shall, and I suppose many other consultant paediatricians will also use it as a standard reference book. Undergraduate students will need a more compact text for their basic reading but should use it to look up specific topics, and doctors studying for the MRCP in paediatrics should make a systematic assault on it to provide them with a personal database to be supplemented by journals and monographs. As a textbook of British paediatrics it has no competition and it remains an excellent work of reference which must be available in all paediatric departments in Britain, but the absence of the chapter on ear, nose, and throat disorders must surely be an error and there is clearly a marketing problem for British publishers faced with American competition. If we want British textbooks, and I would not like to think that the time will be forced upon us when we shall have no choice, then it looks as if we must be prepared to pay for the privilege. DOUG ADDY Consultant paediatrician
983 citations
TL;DR: A review of the current knowledge of the physiological and pathophysiological functions of NF-kappaB and its possible role as a target of therapeutic intervention is presented in this article.
Abstract: Nuclear factor-kappaB (NF-kappaB) is a major transcription factor that plays an essential role in several aspects of human health including the development of innate and adaptive immunity. The dysregulation of NF-kappaB is associated with many disease states such as AIDS, atherosclerosis, asthma, arthritis, cancer, diabetes, inflammatory bowel disease, muscular dystrophy, stroke, and viral infections. Recent evidence also suggests that the dysfunction of NF-kappaB is a major mediator of some human genetic disorders. Appropriate regulation and control of NF-kappaB activity, which can be achieved by gene modification or pharmacological strategies, would provide a potential approach for the management of NF-kappaB related human diseases. This review summarizes the current knowledge of the physiological and pathophysiological functions of NF-kappaB and its possible role as a target of therapeutic intervention
882 citations
TL;DR: Most cases of familial incontinentia pigmenti are due to mutations of this locus and that a new genomic rearrangement accounts for 80% of new mutations, which means that NF-κB activation is defective in IP cells.
Abstract: Familial incontinentia pigmenti (IP; MIM 308310) is a genodermatosis that segregates as an X-linked dominant disorder and is usually lethal prenatally in males. In affected females it causes highly variable abnormalities of the skin, hair, nails, teeth, eyes and central nervous system. The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring. Cells expressing the mutated X chromosome are eliminated selectively around the time of birth, so females with IP exhibit extremely skewed X-inactivation. The reasons for cell death in females and in utero lethality in males are unknown. The locus for IP has been linked genetically to the factor VIII gene in Xq28 (ref. 3). The gene for NEMO (NF-kappaB essential modulator)/IKKgamma (IkappaB kinase-gamma) has been mapped to a position 200 kilobases proximal to the factor VIII locus. NEMO is required for the activation of the transcription factor NF-kappaB and is therefore central to many immune, inflammatory and apoptotic pathways. Here we show that most cases of IP are due to mutations of this locus and that a new genomic rearrangement accounts for 80% of new mutations. As a consequence, NF-kappaB activation is defective in IP cells.
623 citations
TL;DR: A new X-linked recessive immunodeficiency syndrome is defined, distinct from other types of HED and immunODeficiency syndromes, and the data provide further evidence that the development of ectodermal appendages is mediated through a tumor necrosis factor/tumor necrosis factors receptor-like signaling pathway, with the IKK signalsome complex playing a significant role.
Abstract: Hypohidrotic ectodermal dysplasia (HED), a congenital disorder of teeth, hair, and eccrine sweat glands, is usually inherited as an X-linked recessive trait, although rarer autosomal dominant and recessive forms exist. We have studied males from four families with HED and immunodeficiency (HED-ID), in which the disorder segregates as an X-linked recessive trait. Affected males manifest dysgammaglobulinemia and, despite therapy, have significant morbidity and mortality from recurrent infections. Recently, mutations in IKK-gamma (NEMO) have been shown to cause familial incontinentia pigmenti (IP). Unlike HED-ID, IP affects females and, with few exceptions, causes male prenatal lethality. IKK-gamma is required for the activation of the transcription factor known as “nuclear factor kappa B” and plays an important role in T and B cell function. We hypothesize that “milder” mutations at this locus may cause HED-ID. In all four families, sequence analysis reveals exon 10 mutations affecting the carboxy-terminal end of the IKK-gamma protein, a domain believed to connect the IKK signalsome complex to upstream activators. The findings define a new X-linked recessive immunodeficiency syndrome, distinct from other types of HED and immunodeficiency syndromes. The data provide further evidence that the development of ectodermal appendages is mediated through a tumor necrosis factor/tumor necrosis factor receptor–like signaling pathway, with the IKK signalsome complex playing a significant role.
464 citations
TL;DR: The results indicate that the mouse model for the human genetic disorder incontinentia pigmenti, together with the recent discovery that mutations in the human NEMO gene cause IP, is created.
413 citations
References
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TL;DR: The new Forfar and Arneil is, like its predecessors, a good book, but the absence of the chapter on ear, nose, and throat disorders must surely be an error and there is clearly a marketing problem for British publishers faced with American competition.
Abstract: British authors are the natural heirs to Charles Dickens and Graham Greene.) Nevertheless there are advantages to British readers in a British book especially, for instance, in the chapter on social paediatrics and occasionally as regards therapeutics. The new Forfar and Arneil is, like its predecessors, a good book. There are many new authors and much of it has been completely rewritten. Each chapter has a long list of references, many of them to further reading in books and important 'landmark' papers rather than to very recent original work, and that seems appropriate for a textbook of this nature. It is up to date, including references to topics such as oesophageal pH monitoring in gastrooesophageal reflux, the value of steroids in bacterial meningitis, a full account of the peroxisomal disorders, the significance of dystrophin in muscular dystrophy, the importance of vitamin A in reducing mortality in third world countries, and the use of sumatriptan in migraine and of vigabatrin and lamotrigine in epilepsy. Surprisingly, neither in this nor in Nelson's textbook could I find any reference to Angelman's syndrome. Some topics chosen at random such as Prader-Willi syndrome or haemolytic uraemic syndrome were discussed more fully in the British textbook. There is a surprising omission, however, and that is the chapter on disorders ofear, nose, and throat. Adenoids, glue ear or secretory otitis media, tonsillitis, and tonsillectomy have all been dropped from the index and deafness is dealt with in the chapter on neurology. If you look up 'tonsils' you will be referred to any entry which reads: 'Tonsils: size, presence of infection, exudate, pitting, peritonsillar swelling?'. The index entry 'ear, nose and throat problems' refers to a brief account of such problems in children with cleft palate. It is one of those crazy facts of modern life that the American book costs £60, the British £125. Who will read this new edition? I shall, and I suppose many other consultant paediatricians will also use it as a standard reference book. Undergraduate students will need a more compact text for their basic reading but should use it to look up specific topics, and doctors studying for the MRCP in paediatrics should make a systematic assault on it to provide them with a personal database to be supplemented by journals and monographs. As a textbook of British paediatrics it has no competition and it remains an excellent work of reference which must be available in all paediatric departments in Britain, but the absence of the chapter on ear, nose, and throat disorders must surely be an error and there is clearly a marketing problem for British publishers faced with American competition. If we want British textbooks, and I would not like to think that the time will be forced upon us when we shall have no choice, then it looks as if we must be prepared to pay for the privilege. DOUG ADDY Consultant paediatrician
983 citations
TL;DR: This work reviewed 464 references from the world literature and found 653 apparently valid reports of patients with incontinentia pigmenti, which is an uncommon genodermatosis that usually affects female infants.
Abstract: • Incontinentia pigmenti (Bloch-Sulzberger syndrome) is an uncommon genodermatosis that usually affects female infants. I reviewed 464 references from the world literature and found 653 apparently valid reports of patients with incontinentia pigmenti. Skin manifestations were found to be somewhat more common than previously reported, and systemic manifestations were found in 79.8% of the patients. (Arch Dermatol112:535-542, 1976)
353 citations
Journal Article•
TL;DR: Patients with anomalous skin pigmentation, particularly when it follows a pattern of Blaschko lines, should be appropriately evaluated for a possible association with chromosomal or genetic mosaicism or chimerism.
Abstract: We have evaluated eight patients with pigmentary anomalies reminiscent of incontinentia pigmenti or hypomelanosis of Ito. All demonstrated abnormal lymphocyte karyotypes with chromosomal mosaicism in lymphocytes and/or skin fibroblasts. In seven the skin was darkly pigmented, and in all of these seven cases the abnormal pigmentation followed Blaschko lines. The literature contains at least 36 similar examples of an association between pigmentary anomalies and chromosomal mosaicism, as well as five examples of an association with chimerism. The pigmentary anomalies are pleomorphic, and the chromosomal anomalies involve autosomes and sex chromosomes. The pigmentation patterns are reminiscent of the archetypal paradigm seen in allophenic mice and demonstrate the clonal origin of melanoblasts from neural crest precursors. Patients with anomalous skin pigmentation, particularly when it follows a pattern of Blaschko lines, should be appropriately evaluated for a possible association with chromosomal or genetic mosaicism or chimerism.
142 citations
TL;DR: Diese Zellen das von ihnen gebildete Melanin abnorm rasch und vollständig in die Cutis strömen lassen, statt es nach oben zu befördern (Incontinentia Pigmenti).
Abstract: Es wird ein Fall einer bisher nicht bekannten kongenitalen Pigmentanomalie beschrieben. Klinisch handelt es sich um bizarr geformte, ganz unregelmasig angeordenete, uber den Stamm (vor allem seitliche und untere Partien) und die unteren Extremitaten verteilte Flecke von eigentumlich schiefrig brauner Farbe, histologisch um massige Chromatophorenanhaufungen der Cutis und Papillarkorper bei geringem oder fehlendem Pigmentgehalt der Epidermis. Die Involution der Flecke geht auserordentlich langsam im Verlauf von Jahren vor sich. Es wird die Hypothese aufgestellt, das primar eine kongenitale pathologische Veranderung der pigmentbildenden Basalzellen, der Melanoblasten, vorleigt, in dem Sinne, das diese Zellen das von ihnen gebildete Melanin abnorm rasch und vollstandig in die Cutis stromen lassen, statt es nach oben zu befordern (Incontinentia Pigmenti). Das in die Cutis abstromende Pigment wird von den Bindegewebezellen aufgenommen und bleibt wie tatowiertes Material jahrelang fast unverandert in ihnen liegen.
114 citations
TL;DR: It is concluded that hypomelanosis of Ito is a manifestation of a heterogeneous group of disorders, the common factor being the presence of two genetically different cell lines.
Abstract: We describe three patients with the cutaneous manifestations of hypomelanosis of Ito. Two, with unusual abnormalities of their toes, had a mixture of diploid and triploid cells in cultured skin fibroblasts. The published clinical descriptions of hypomelanosis of Ito and diploid-triploid mosaicism are reviewed. Chromosome heteromorphisms, HLA types, and DNA fingerprints were studied in an attempt to elucidate the origin of the disease in our patients. We conclude that hypomelanosis of Ito is a manifestation of a heterogeneous group of disorders, the common factor being the presence of two genetically different cell lines. It can result from chromosomal mosaicism or chimerism, from a postzygotic mutation, or from X inactivation. The risk of recurrence is negligible if the proband is a male; if the proband is female the risk is also low but an X linked mutation must be considered.
108 citations