Mechanisms of transcriptional repression of cell-cycle G2/M promoters by p63.
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p63 is a developmentally regulated transcription factor related to p53, which activates and represses specific genes. The human AEC (Ankyloblepharon-Ectodermal dysplasia-Clefting) and EEC (Ectrodactyly-Ectodermal dysplasia-Cleft lip/palate) syndromes are caused by missense mutations of p63, within the DNA-binding domain (EEC) or in the C-terminal sterile alpha motif domain (AEC). We show here that p63 represses transcription of cell-cycle G(2)/M genes by binding to multiple CCAAT core promoters in immortalized and primary keratinocytes. The CCAAT-activator NF-Y and DeltaNp63alpha are associated in vivo and a conserved alpha-helix of the NF-YC histone fold is required. p63 AEC mutants, but not an EEC mutant, are incapable to bind NF-Y. DeltaNp63alpha, but not the AEC mutants repress CCAAT-dependent transcription of G(2)/M genes. Chromatin immunoprecipitation recruitment assays establish that the AEC mutants are not recruited to G(2)/M promoters, while normally present on 14-3-3sigma, which contains a sequence-specific binding site. Surprisingly, the EEC C306R mutant activates transcription. Upon keratinocytes differentiation, NF-Y and p63 remain bound to G(2)/M promoters, while HDACs are recruited, histones deacetylated, Pol II displaced and transcription repressed. Our data indicate that NF-Y is a molecular target of p63 and that inhibition of growth activating genes upon differentiation is compromised by AEC missense mutations. (+info)
Oromaxillofacial osseous abnormality in Sturge-Weber syndrome: case report and review of the literature.
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We report a case of a 17-month-old child affected by Sturge-Weber syndrome who had unusually rapid overgrowth of the left frontal, temporal, orbital, and maxillary regions. CT angiography illustrated osteohypertrophy with periostitis and associated soft tissue hypertrophy directly corresponding to the distribution of the cutaneous port-wine stain. Extended maxillectomy was performed because of rapid growth and clinical debilitation, with surgical pathology revealing juvenile ossifying fibroma. (+info)
Cockayne's syndrome: a case report. Literature review.
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Cockayne s syndrome is a genetic disorder with a recessive autosomal inheritance, described first by Cockayne in 1936. Patients with this syndrome present failure to thrive, short stature, premature aging, neurological alterations, photosensitivity, delayed eruption of the primary teeth, congenitally absent of some permanent teeth, partial macrodontia, atrophy of the alveolar process and caries. It could be caused by two gene mutations, CNK1 (ERCC8) and ERCC6, located on the 5 and 10 chromosomes respectively, causing two variations of Cockayne s syndrome, CS-A, secondary to a ERCC8 mutation and CS-B with ERCC6 mutation, the last one causes hypersensitivity to the ultraviolet light secondary to a DNA repair defect. The syndrome is also associated with mutations of the XPB, XPD and XPG genes. In this report we present a 9 year and 4 month old patient. He had a height of 94 cm, weight of 8.6 Kg, head circumference of 42 cm. and blood pressure of 120/80. Cachectic habitus, kyphosis, microcephaly, oval face, sunken eyes, a thin and beaklike nose, lack of subcutaneous facial fat (especially in the middle of the face), and large ears give the patient a birdlike appearance. It is notorious the photosensitivity in all the sun-exposed skin. The patient also displays delayed psychomotor skills and mental retardation. In the oral cavity we found deficient hygiene, gingivitis, cervical caries, enamel hipoplasia, abnormal position of the upper and inferior lateral incisors, macrodontia of the upper central teeth, the left one presented a caries. In the x-ray we observed congenital absence of 14, 23 and 24 teeth and mandibular hipoplasia. The aim of this review is to show the dentistry community the characteristics of the Cockayne s syndrome by means of a clinical case. (+info)
Peters Plus syndrome is caused by mutations in B3GALTL, a putative glycosyltransferase.
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Peters Plus syndrome is an autosomal recessive disorder characterized by anterior eye-chamber abnormalities, disproportionate short stature, and developmental delay. After detection of a microdeletion by array-based comparative genomic hybridization, we identified biallelic truncating mutations in the beta 1,3-galactosyltransferase-like gene (B3GALTL) in all 20 tested patients, showing that Peters Plus is a monogenic, primarily single-mutation syndrome. This finding is expected to put Peters Plus syndrome on the growing list of congenital malformation syndromes caused by glycosylation defects. (+info)
Cholesterol precursors and facial clefting.
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Inborn errors of cholesterol synthesis cause human malformation syndromes, including Smith-Lemli-Opitz syndrome, lathosterolosis, desmosterolosis, X-linked dominant chondrodysplasia punctata type 2, and congenital hemidysplasia with ichthyosiform erythroderma and limb defects. Because adequate cholesterol is not transported across the placenta, low cholesterol and elevated sterol precursor levels are present during embryogenesis. It has been debated whether the malformations result from low cholesterol or the buildup of sterol precursors. In this issue of the JCI, Engelking et al. provide evidence that sterol precursor accumulation plays a pivotal role in the genesis of facial malformations (see the related article beginning on page 2356). (+info)
Severe facial clefting in Insig-deficient mouse embryos caused by sterol accumulation and reversed by lovastatin.
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Insig-1 and Insig-2 are regulatory proteins that restrict the cholesterol biosynthetic pathway by preventing proteolytic activation of SREBPs and by enhancing degradation of HMG-CoA reductase. Here, we created Insig-double-knockout (Insig-DKO) mice that are homozygous for null mutations in Insig-1 and Insig-2. After 18.5 days of development, 96% of Insig-DKO embryos had defects in midline facial development, ranging from cleft palate (52%) to complete cleft face (44%). Middle and inner ear structures were abnormal, but teeth and skeletons were normal. The animals were lethargic and runted; they died within 1 day of birth. The livers and heads of Insig-DKO embryos overproduced sterols, causing a marked buildup of sterol intermediates. Treatment of pregnant mice with the HMG-CoA reductase inhibitor lovastatin reduced sterol synthesis in Insig-DKO embryos and reduced the pre-cholesterol intermediates. This treatment ameliorated the clefting syndrome so that 54% of Insig-DKO mice had normal faces, and only 7% had cleft faces. We conclude that buildup of pre-cholesterol sterol intermediates interferes with midline fusion of facial structures in mice. These findings have implications for the pathogenesis of the cleft palate component of Smith-Lemli-Opitz syndrome and other human malformation syndromes in which mutations in enzymes catalyzing steps in cholesterol biosynthesis produce a buildup of sterol intermediates. (+info)
Prosthetic assessment in cleft lip and palate patients: a case report with oronasal communication.
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The cleft lip and palate patient is mainly characterized by the presence of an oronasal communication, malformation or agenesis of the teeth close to the cleft, and deficient sagittal and transverse growth of the maxilla. These patients require various treatments involving a multidisciplinary team, which may include a maxillofacial surgeon, an orthodontist, a speech therapist, a paediatrician, a general dentist, a prosthodontist, an ENT specialist, a psychologist and all those professionals who can help provide functional, aesthetic and psychological improvement. This report describes a case of prosthetic rehabilitation in a patient with cleft lip and palate and an oronasal fistula (communication) following surgery. Different prosthetic treatments are described, with emphasis being placed on the approach chosen after to discuss the various limitations which arose. (+info)
Feeding problems of infants and toddlers.
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OBJECTIVE: To propose a diagnostic and therapeutic approach to feeding problems in early childhood. QUALITY OF EVIDENCE: Articles were retrieved through a MEDLINE search from January 1990 to December 2005 using the MeSH terms eating disorders, infant, and child. Recommended practice is based mainly on levels II and III evidence. MAIN MESSAGE: Feeding problems are classified under structural abnormalities, neurodevelopmental disabilities, and behavioural disorders, with overlap between categories. A medical approach also needs an evaluation of diet and an assessment of the interaction between parent and child. Treating medical or surgical conditions, increasing caloric intake, and counseling about general nutrition can alleviate mild to moderate problems. More complicated cases should be referred to multidisciplinary teams. Behavioural therapy aims to foster appropriate behaviour and discourage maladaptive behaviour. CONCLUSION: Feeding problems in early childhood often have multifactorial causes and a substantial behavioural component. Family physicians have a key role in detecting problems, offering advice, managing mildly to moderately severe cases, and referring more complicated cases to multidisciplinary teams. (+info)