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PubMed2002

Role of the autoimmune regulator (AIRE) gene in alopecia areata: strong association of a potentially functional AIRE polymorphism with alopecia universalis.

Alopecia areata is characterized by a reversible form of patchy or complete hair loss associated with T-cell infiltration of hair follicles. The lifetime disease risk of approximately 1.4% in the general population is increased to more than 30% in autoimmune polyendocrinopathy candidiasis ectodermal dysplasia syndrome (APECED), a recessive condition resulting from a mutation of the autoimmune regulator (AIRE) gene on chromosome 21q22.3. Aire protein is thought to have transcriptional regulatory activity but its role is not well defined at present. In this study, we have examined the possible involvement of AIRE in the pathogenesis of alopecia areata. On screening the AIRE coding sequence, we identified 20 variants. Two of these at positions, G961C and T1029C, give rise to amino acid changes, S278R and V301A, located in the DNA-binding segment (SAND) and PHD1 zinc finger motif, respectively. We found no difference in the frequency of the AIRE T1029C polymorphism between the control and patient groups. We genotyped 202 alopecia areata patients and 175 matched Caucasian controls for the AIRE G961C alleles. The frequency of the rare allele (961G) was 0.08 in the controls and there was a significant increase to 0.13 in alopecia areata overall and 0.20 in severe disease (alopecia universalis). We found no association between the AIRE G961G variant and mild (patchy) alopecia areata or alopecia totalis. However, the AIRE 961G allele is a potent risk factor (> 3) for the severest form of alopecia areata, and for disease of early age at onset (at 30 years). The change from serine to arginine in the SAND domain of AIRE protein may have a significant effect on AIRE DNA-binding activity. Moreover, our results could provide a rational explanation of the unusually high frequency of AA in APECED patients, supporting the concept of AA as an autoimmune disease.

Adolescent↗
PubMed2003

Carcinoma and eccrine syringofibroadenoma: a report of five cases.

BACKGROUND: In the literature, there are some reports of cases interpreted as carcinomatous transformation in eccrine syringofibroadenoma (ESFA). RESULTS: We have studied five cases with a histological mixture of ESFA and carcinoma. The carcinoma had a partial squamous cell cytology in all cases. In two of them, there was partial poroma and porocarcinoma picture. However, the squamous cell parts had some features of porocarcinoma such as retiform configuration and funnel-like cavities with luminal carcinoembryonic antigen (CEA) positivity. Also, there was strong epithelial membrane antigen (EMA) positivity. Therefore, we interpret the cases as porocarcinomas with extensive squamous metaplasia. One case had a life-long precursor lesion with a histologic picture interpreted as ESFA, with progressing cytologic atypia. Another case had ectodermal dysplasia, a condition known to predispose to ESFA and a precursor lesion of long-standing, probably benign ESFA. In these two cases, we interpret the carcinoma as a secondary development in a benign ESFA. Three cases were otherwise healthy people with precursor lesions of 10-, 5-, and 2-year duration. We do not know for certain if the ESFA preceded the carcinoma in these cases but we think that it probably did. CONCLUSIONS: We recommend that diagnosed ESFA shall be completely excised or followed, in view of the risk of developing carcinoma.

Adenoma, Sweat Gland↗
PubMedDate not supplied

Presence of Ti (WT31) negative T lymphocytes in normal blood and thymus.

The antigen receptor expressed on most T lymphocytes is a disulphide-linked heterodimer (Ti) that is composed of alpha-chain and beta-chain subunits. On the surface of human T lymphocytes, Ti is non-covalently associated with three invariant proteins, designated CD3-gamma, -delta, and -epsilon. It has been suggested that Ti is obligatory for CD3 expression. But a T leukaemia cell line, IL-2 (interleukin 2) dependent T-cell clones established from fetal blood and IL-2 dependent cell lines established from immunodeficiency patients with bare lymphocyte syndrome and ectodermal dysplasia syndrome have recently been shown to express CD3, but not Ti (detected due to monoclonal antibody WT31). These lymphocytes may express the product of the T-cell antigen receptor gamma (TCR-gamma) gene, rather than the alpha/beta heterodimer, in association with CD3. Preliminary studies suggested that T cells expressing CD3 but lacking Ti are present in low frequency in normal lymphoid tissues. Here we show that in normal blood and thymus CD3+, WT31-T cells express neither CD4 nor CD8. The low frequency (less than 0.2-0.9% of total thymocytes) of CD3+, WT31- cells in the thymus suggests that this population does not represent a major stage of thymic development and may be a distinct lineage of T cells.

Cell Differentiation↗
PubMed2006

Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected].

The transcription factor NF-kappaB is sequestered in the cytoplasm in a complex with IkappaB. Almost all NF-kappaB activation pathways converge on IkappaB kinase (IKK), which phosphorylates IkappaB resulting in Lys 48-linked polyubiquitination of IkappaB and its degradation. This allows migration of NF-kappaB to the nucleus where it regulates gene expression. IKK has two catalytic subunits, IKKalpha and IKKbeta, and a regulatory subunit, IKKgamma or NEMO. NEMO is essential for NF-kappaB activation, and NEMO dysfunction in humans is the cause of incontinentia pigmenti and hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID). The recruitment of IKK to occupied cytokine receptors, and its subsequent activation, are dependent on the attachment of Lys 63-linked polyubiquitin chains to signalling intermediates such as receptor-interacting protein (RIP). Here, we show that NEMO binds to Lys 63- but not Lys 48-linked polyubiquitin, and that single point mutations in NEMO that prevent binding to Lys 63-linked polyubiquitin also abrogates the binding of NEMO to RIP in tumour necrosis factor (TNF)-alpha-stimulated cells, the recruitment of IKK to TNF receptor (TNF-R) 1, and the activation of IKK and NF-kappaB. RIP is also destabilized in the absence of NEMO binding and undergoes proteasomal degradation in TNF-alpha-treated cells. These results provide a mechanism for NEMO's critical role in IKK activation, and a key to understanding the link between cytokine-receptor proximal signalling and IKK and NF-kappaB activation.

Biosensing Techniques↗
PubMed2006

NF-kappaB-related genetic diseases.

The recent identification of genetic diseases (incontinentia pigmenti, anhidrotic ectodermal dysplasia with immunodeficiency and cylindromatosis) resulting from mutations affecting components of the nuclear factor-kappaB (NF-kappaB) signaling pathway provides a unique opportunity to understand the function of NF-kappaB in vivo. Besides confirming the importance of NF-kappaB in innate and acquired immunity or bone mass control, analysis of these diseases has uncovered new critical roles played by this transcription factor in the development and homeostasis of the epidermis and the proper function of lymphatic vessels. In addition, the identified mutations will help understanding at the molecular level how NF-kappaB is activated in response to cell stimulation.

Animals↗
PubMed2006

New p63 targets in keratinocytes identified by a genome-wide approach.

p63 is a developmentally regulated transcription factor related to p53. It is involved in the development of ectodermal tissues, including limb, skin and in general, multilayered epithelia. The DeltaNp63alpha isoform is thought to play a 'master' role in the asymmetric division of epithelial cells. It is also involved in the pathogenesis of several human diseases, phenotypically characterized by ectodermal dysplasia. Our understanding of transcriptional networks controlled by p63 is limited, owing to the low number of bona fide targets. To screen for new targets, we employed chromatin immunoprecipitation from keratinocytes (KCs) coupled to the microarray technology, using both CpG islands and promoter arrays. The former revealed 96 loci, the latter yielded 85 additional genes. We tested 40 of these targets in several functional assays, including: (i) in vivo binding by p63 in primary KCs; (ii) expression analysis in differentiating HaCaT cells and in cells overexpressing DeltaNp63alpha; (iii) promoter transactivation and (iv) immunostaining in normal tissues, confirming their regulation by p63. We discovered several new specific targets whose functional categorization links p63 to cell growth and differentiation.

Animals↗
PubMed2003

Death receptors.

Death receptors [Fas/Apo-1/CD95, TNF-R1 [tumour necrosis factor (TNF) receptor 1], DR3 [death receptor 3], TRAIL-R1 [TNF-related apoptosis-inducing ligand receptor 1], TRAIL-R2, DR6, p75-NGFR [p75-nerve growth factor receptor], EDAR [ectodermal dysplasia receptor]] form a subgroup of the TNF-R superfamily that can induce apoptosis (programmed cell death) via a conserved cytoplasmic signalling module termed the death domain. Although death receptors have been recognized mainly as apoptosis inducers, there is growing evidence that these receptors also fulfil a variety of nonapoptotic functions. This review is focused on the molecular mechanisms of apoptotic and non-apoptotic death receptor signalling in light of the phenotype of mice deficient in the various death receptors.

Animals↗
PubMed1998

Keratin 17 mutations cause either steatocystoma multiplex or pachyonychia congenita type 2.

Pachyonychia congenita type 2 (PC-2; Jackson-Lawler syndrome) is an autosomal dominant disorder characterized by hypertrophic nail dystrophy, mild focal keratoderma, multiple pilosebaceous cysts and other features of ectodermal dysplasia. Keratin 17 (K17) is a differentiation-specific keratin expressed in the nail bed, hair follicle, sebaceous gland and other epidermal appendages. Previously, we have demonstrated that PC-2 is caused by mutations in K17 and that similar mutations in this gene can present as steatocystoma multiplex with little or no nail dystrophy. Here, we describe three unrelated kindreds carrying K17 mutations. Two of these families have identical missense mutations (R94C) in the 1A domain of K17. However, while affected members of one kindred have the classical features of PC-2, affected persons in the other family have the steatocystoma multiplex phenotype. In a third family with PC-2, mutation N92S was detected, bringing the total number of distinct mutations reported in K17 thus far to 11. These results demonstrate that K17 mutations commonly underlie both PC-2 and steatocystoma multiplex and that the alternate phenotypes which arise from these genetic lesions in K17 are independent of the specific mutation involved.

Adolescent↗
PubMed2001

Woolly hair, premature loss of teeth, nail dystrophy, acral hyperkeratosis and facial abnormalities: possible new syndrome in a Dutch kindred.

We describe a Dutch kindred with a possibly novel dominant syndrome of premature loss of curly, brittle hair, premature loss of teeth due to caries, nail dystrophy and acral keratoderma. We discuss the possibility that this ectodermal dysplasia of group 1-2-3-4 is a variant of known disorders such as pachyonychia congenita. We conclude that none of these diagnoses fits the symptoms we observe in our patients and propose the name curly hair-acral keratoderma-caries syndrome in view of the most obvious abnormalities.

Adult↗
PubMed2002

HID and KID syndromes are associated with the same connexin 26 mutation.

BACKGROUND: Keratitis-ichthyosis-deafness (KID) syndrome is a debilitating ectodermal dysplasia that predisposes patients to develop squamous cell carcinomas in addition to leading to profound sensory deafness and erythrokeratoderma. We recently demonstrated that KID can be caused by a specific missense mutation in connexin 26 (GJB2). Another syndrome, called hystrix-like ichthyosis-deafnesss (HID) syndrome, strongly resembles the KID syndrome. These disorders are distinguished mainly on the basis of electron microscopic findings. We hypothesized that KID and HID syndromes may be genetically related. OBJECTIVE: To demonstrate by mutation analysis that HID and KID syndromes are genetically indistinguishable. METHODS: DNA was extracted from paraffin-embedded tissue samples of the first HID syndrome patient described in the literature. Since the KID syndrome mutation abolishes an AspI restriction site, we were able to screen the patient's DNA by polymerase chain reaction and subsequent restriction enzyme analysis. RESULTS: Restriction analysis of the connexin 26 gene in HID syndrome demonstrated the presence of the KID syndrome mutation that we previously described. This result was confirmed by direct DNA sequencing. CONCLUSIONS: We show that KID and HID syndromes are identical at the molecular level and confirm the clinical impression that these syndromes are one and the same. That previous clinical reports made a distinction may be a consequence of sampling artefacts; alternatively, genetic background effects such as the presence of concurrent mutations in other skin-expressed genes may modify the phenotype.

Connexin 26↗
PubMed2002

Congenital hypotrichosis with anodontia in cattle: a genetic, clinical and histological analysis.

Hypotrichosis, an almost complete lack of teeth and the complete absence of eccrine nasolabial glands, was observed among the progeny of a normal cow of the black and white German Holstein breed. Similar congenital anomalies are known in humans and mice as X-linked anhidrotic ectodermal dysplasia (ED1), leading to the impaired formation of hair, teeth and sweat glands. The pedigree of the four affected male calves in the investigated cattle family indicated that the described phenotype is inherited as a monogenic X-linked recessive trait. We used a diagnostic reverse transcription-polymerase chain reaction (RT-PCR) assay to study the heredity of a previously reported causative large genomic deletion in the bovine ED1 gene. This test allowed the unequivocal classification of disease carriers that were phenotypically normal. As the clinical, pathological and genetic findings in human ED1 show striking similarities to the described phenotype in cattle, this bovine disorder may serve as an animal model for human ED1.

Animals↗
PubMed1997

Pulmonary aspiration of gastric contents after a priming dose of vecuronium.

A case is presented of a 16-year-old girl with ectodermal dysplasia for whom dental surgery under general anaesthesia was planned. Following a priming dose of vecuronium, and immediately after injection of sodium thiopentone (5 mg.kg-1) pulmonary aspiration of gastric contents occurred. It is hypothesized that, because of the rapid speed of onset of neuromuscular blocking agents on the laryngeal muscles, that partial laryngeal paralysis was present at the time of induction of anaesthesia and that this was responsible in part for the episode of pulmonary aspiration.

Adolescent↗
PubMed1997

Prenatal diagnosis of ventriculo-coronary communications in a second-trimester fetus using transvaginal and transabdominal color Doppler sonography.

We report on the prenatal diagnosis of ventriculo-coronary communication associated with pulmonary atresia and an intact interventricular septum. The diagnosis was made by transvaginal color Doppler sonography at 17 weeks' gestation and confirmed by transabdominal sonography at 19 weeks. Color Doppler demonstrated the communication between the distal hypoplastic right ventricle and the right coronary artery, with the course of this vessel situated along the outer heart wall. Spectral Doppler assessment showed bidirectional arterial flow in this vessel. Extracardiac skeletal anomalies (cleft hands and feet) were also detected and classified as an ectrodactyly-ectodermal dysplasia clefting (EEC) syndrome. This led the parents to opt for termination of pregnancy. All findings were confirmed on autopsy. Using stereomicroscopy the malformations of the coronary system and main connections to the lumen of the right ventricle were additionally demonstrated. To our knowledge this is the first report on the identification of coronary artery malformations in a midtrimester fetus using transvaginal color Doppler. The early appearance enabled us to investigate the pathophysiological sequence of the combined defect. Further investigation might elucidate whether ventriculo-coronary communications arise secondary to pulmonary atresia and intact inter-ventricular septum, due to increased ventricular pressure, or are the primary defect leading to intrauterine pulmonary atresia or, indeed, whether both defects appear simultaneously.

Adult↗
PubMed2000

A mutation in the V1 domain of K16 is responsible for unilateral palmoplantar verrucous nevus.

Palmoplantar keratodermas are a group of heterogeneous diseases characterized by thickening, and marked hyperkeratosis, of the epidermis of the palms and soles. Palmoplantar keratodermas can be divided into four major classes: diffuse, focal, punctate, and palmoplantar ectodermal dysplasias. All forms are genetic diseases inherited as autosomal dominant disorders. We studied a patient exhibiting a localized thickening of the skin in parts of the right palm and the right sole, following Blaschko's lines, that does not fit into any classes already described. We sequenced the keratin 16 cDNA derived from skin biopsy material from affected and non affected palms. The keratin 16 cDNA sequence from lesional epidermis showed a 12 base pair deletion (309-320del), which deletes codons 104-107. The mutation is predicted to delete four amino acids, GGFA, from the V1 domain of the keratin 16 polypeptide, close to the 1A domain. Full-length keratin 16 cDNA sequence derived from the unaffected palm was completely normal, consistent with a postzygotic mutation as is suggested by the mosaicism observed. We defined this new clinical entity, "unilateral palmoplantar verrucous nevus", rather than localized or focal epidermolytic palmoplantar keratodermas, as the lesions are present only on one side of the body and follow Blaschko's lines. This study is a report of a mosaic mutation in keratin 16 and also the association of a mutation in the V1 domain of a type I keratin associated with a human disease.

Adolescent↗
PubMedDate not supplied

Mutation of the ectodysplasin-A gene results in bone defects in mice.

Anhidrotic ectodermal dysplasia (EDA) is an X-linked, recessive genetic disease characterized by dysfunctional sweat glands, poorly developed teeth, and premature balding in human beings. This disorder results from mutations in the gene for ectodysplasin-A, a type II transmembrane protein with tumour necrosis factor-alpha domains. An animal model of EDA, the Tabby mouse, also has mutations in the ectodysplasin-A gene and defects similar to those of human beings with EDA. In addition to these defects, Tabby mice acquire deformities in the distal portion of their tails at 10-12 weeks of age. Whole-mount staining of the skeleton with Alizarin Red and Alcian Blue revealed that the tail defect resulted from vertebral fractures just distal to the epiphysis. Histological analysis demonstrated that the structure of both the epiphysis and the subepiphyseal zone of the tail vertebrae was dysplastic while the shaft of the diaphysis was relatively normal. The overall structure of the trabecular bone of these animals was examined through 3-dimensional microcomputed tomography of the tibia. This analysis indicated that Tabby mice had a mild increase in the interconnectivity of the intertwined trabecular bone network but that individual trabeculae were relatively normal. Since it has been determined recently that the ectodysplasin-A gene is expressed in the osteoblasts of developing human embryos, it appears likely that this gene plays a role in normal bone development.

Animals↗
PubMed2001

[Zinsser-Engman-Cole syndrome (dyskeratosis congenita) with severe sicca syndrome, panuveitis and corneal perforation--a case report].

BACKGROUND: Zinsser-Engman-Cole syndrome (Z.E.C.) is a very rare type of ectodermal dysplasia, inherited in X-linked recessive manner and characterised by poikiloderma, nail dystrophy, lingual leucoplakia, bone marrow hypoplasia, hyperkeratosis and hyperhidrosis of planta and palms, dental anomalies and caries, premature grey hair. PATIENT AND METHODS: We report on a 46-year-old man who presented with occlusion of lacrimal puncta, trichiasis, severe dry eye, recurrent corneal ulceration and perforation, uveitis. HLA typing, flow cytometry of peripheral lymphocytes, bone marrow biopsy, conjunctival biopsy and extensive laboratory evaluation towards autoimmune and infectious diseases were performed. RESULTS: CD4+ T cells fraction was decreased, CD8+ and CD3+ HLA DR+ elevated. The patient was HLA-B27 positive. Laboratory studies revealed increased erythrocyte sedimentation rate and C-reactive protein level, hypochromic and hypoplastic anaemia, negative serum titers of antibodies to Epstein-Barr virus, HIV, HTLV-I, toxoplasma gondii and treponema pallidum, repeated titers to cytomegalovirus, herpes simplex and herpes zoster viruses--IgM negative, IgG positive. Corneal perforation was treated with amniotic membrane transplantation and corneal transplantation. CONCLUSION: The defect in cell-mediated immune mechanisms in Z.E.C. syndrome explains the corneal perforation, sicca syndrome and uveitis, first reported in this syndrome.

Autoimmune Diseases↗
PubMed2002

Incontinentia pigmenti: a review and update on the molecular basis of pathophysiology.

UNLABELLED: Incontinentia pigmenti is an uncommon X-linked dominant disorder, lethal in the majority of affected males in utero and variably expressed in females. Cutaneous manifestations are classically subdivided into 4 stages: vesicular, verrucous, hyperpigmented, and atrophic. Various hair and nail abnormalities, dental anomalies, and ophthalmologic and neurologic deficits are associated with the disorder. The gene for incontinentia pigmenti has been mapped to Xq28. Recently, mutations in the NEMO/IKKgamma gene located at Xq28 have been found to cause expression of the disease. Knockout mice heterozygous for NEMO/IKKgamma gene deficiency develop a clinical phenotype very similar to that of incontinentia pigmenti. NEMO/IKKgamma is an essential component of the newly discovered nuclear factor kappaB (NF-kappaB) signaling pathway. When activated, NF-kappaB controls the expression of multiple genes, including cytokines and chemokines, and protects cells against apoptosis. The mechanism by which NEMO/IKKgamma deficiency causes, via the NF-kappaB pathway, the phenotypical expression of the disease has recently been elucidated. In addition, the newest research findings on eosinophil recruitment through eotaxin release by activated keratinocytes are described in the review. Finally, anhidrotic ectodermal dysplasia with immunodeficiency, a disorder allelic to incontinentia pigmenti, is discussed together with implications on the current understanding of NF-kappaB function. (J Am Acad Dermatol 2002;47:169-87.) LEARNING OBJECTIVE: At the completion of this learning activity, participants will have a comprehensive and current understanding of incontinentia pigmenti, including its typical and uncommon clinical and histopathologic characteristics, diagnostic assessment, and current management strategies. Additionally, participants will gain the most current knowledge of the genetic and molecular basis of cutaneous pathomechanism.

Animals↗
PubMed2002

Alveolar distraction: analysis of 10 cases.

OBJECTIVE: The purpose of this study was to evaluate intraoperative and postoperative complications of alveolar distraction and outcome. STUDY DESIGN: Ten patients with alveolar ridge deficiencies were treated with alveolar distraction osteogenesis by means of intraosseous distractors (Lead system, Stryker Leibenger, Kalamazoo, Mich). The deficiencies were caused by atrophy after periodontal disease or atrophy after tooth extraction (n = 6), benign tumor resection (n = 2), trauma (n = l), or oligodontia in a case of ectodermal dysplasia (n = l). The location of the defects was the anterior mandible (7), posterior mandible (1), and anterior maxilla (2). The mean follow-up was 1.8 years, with a range of 10 months to 3 years. RESULTS: The mean alveolar distraction achieved in 10 cases was 8.7 mm (5-15 mm). The intraoperative and postoperative problems encountered were lingual (n = 3) and palatal (n = 2) displacement of the distracted segment, fracture of the distracted segment in a very thin alveolar bone (n = 1), and intraoperative bleeding (n = 1). CONCLUSION: Overall complication rate was 70%. However, most of the complications were minor and eliminated easily. Implant success rate was 85%.

Adult↗