Xeroderma pigmentosum: clues to understanding cancer initiation

AbstractXeroderma pigmentosum (XP) type C is a rare autosomal recessive disorder that occurs because of inactivation of the xeroderma pigmentosum group C (XPC) protein, which is an important DNA damage recognition protein involved in DNA nucleotide excision repair (NER). This defect, which prevents removal of a wide array of direct and indirect DNA lesions, is associated with a decrease in catalase activity. As a novel photoprotective approach, lentivirus-mediated catalase overexpression in XPC human keratinocytes results in a marked decrease in sunburn cell formation, caspase-3 activation, and p53 accumulation following UVB irradiation. While not correcting the gene defect, indirect gene therapy using antioxidant enzymes may be helpful in limiting photosensitivity in XP type C, as well as in other monogenic/polygenic photosensitive disorders characterized by reactive oxygen species (ROS) accumulation. Hypoxia-inducible factor-1 (HIF-1), a major transcription factor sensitive to oxygen levels, responds to various stress factors. As a common stressor of skin, UVB induces a biphasic HIF-1a variation through ROS generation in keratinocytes. HIF-1a has an important regulator effect on the expression of XPC protein and other NER genes, indicating indirect regulation of NER by ROS. The intrinsic genomic instability arising in XP type C provides a good opportunity to investigate the complex molecular mechanisms underlying the Warburg effect (the shift of mito-chondrial metabolism towards glycolysis). Overall, the monogenic disorder XP type C is a powerful tool for studying photoprotection and cancer

Surgical Correction of Hallermann-Streiff Syndrome: A Case Report of Esotropia, Entropion, and Blepharoptosis

We report a case of surgical treatment for Hallermann-Streiff syndrome in a patient with ocular manifestations of esotropia, entropion, and blepharoptosis. A 54-year-old man visited Yeouido St. Mary's Hospital complaining of ocular discomfort due to cilia touching the corneas of both eyes for several years. He had a bird-like face, pinched nose, hypotrichosis of the scalp, mandibular hypoplasia with forward displacement of the temporomandibular joints, a small mouth, and proportional short stature. His ophthalmic features included sparse eyelashes and eyebrows, microphthalmia, nystagmus, lower lid entropion in the right eye, and upper lid entropion with blepharoptosis in both eyes. There was esodeviation of the eyeball of more than 100 prism diopters at near and distance, and there were limitations in ocular movement on lateral gaze. The capsulopalpebral fascia was repaired to treat the right lower lid entropion, but an additional Quickert suture was required to prevent recurrence. Blepharoplasty and levator palpebrae repair were performed for blepharoptosis and dermatochalasis. Three months after lid surgery, the right medial rectus muscle was recessed 7.5 mm, the left medial rectus was recessed 7.25 mm, and the left lateral rectus muscle was resected 8.0 mm

Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis

Twenty-six families with keratinopathic ichthyoses (epidermolytic ichthyosis, superficial epidermolytic ichthyosis or congenital reticular ichthyosiform erythroderma) were studied. Epidermolytic ichthyosis is caused by mutations in the genes KRT1 or KRT10, mutations in the gene KRT2 lead to superficial epidermolytic ichthyosis, and congenital reticular ichthyosiform erythroderma is caused by frameshift mutations in the genes KRT10 or KRT1, which lead to the phenomenon of revertant mosaicism. In this study mutations were found in KRT1, KRT2 and KRT10, including 7 mutations that are novel pathogenic variants. Novel clinical features found in patients with congenital reticular ichthyosiform erythroderma are described, such as mental retardation, spasticity, facial dysmorphisms, symblepharon and malposition of the 4th toe

Severity of Retrognathia and Glossoptosis Does Not Predict Respiratory and Feeding Disorders in Pierre Robin Sequence

Pierre Robin sequence (PRS) may lead to life-threatening respiratory and feeding disorders. With the aim to analyse the association of the severities of retrognathia and glossoptosis with those of respiratory and feeding disorders, we retrospectively studied a series of 50 infants with retrognathia, glossoptosis, cleft palate, and airway obstruction. The patients were managed from birth to at least 6 years of age by a single pediatric team at the Armand Trousseau Hospital in Paris within a 12 years period (2000–2012). Retrognathia and glossoptosis were graded in the neonatal period according to a specific clinical examination. Ventilation assistance was required for 32/50 (64%) patients, and enteral feeding for 41/50 (82%). The grades of retrognathia and glossoptosis and the severity of respiratory disorders did not differ between patients with isolated PRS and syndromic PRS. Severe respiratory disorders were more common and long-lasting feeding (>12 months) was more frequently required in patients with syndromic PRS compared with isolated PRS (42 vs. 13%, p = 0.04 and 42 vs. 4%, p < 0.01 respectively). Using univariate analysis, neurological impairments and laryngomalacia were associated with severe respiratory disorders [Odds ratio (OR) 5.0, 95% CI 1.3–19.6; and OR 14.6, 95% CI 1.3–161.4; p < 0.05] as well as with long-lasting feeding (>12 months) disorders (OR 18.6, 95% CI 3.9–89.2 and OR 20.4, 95% CI 3,4–122.8; p < 10−2). Syndromic SPR status was also associated with severe respiratory disorders (OR 4.9, 95% CI 1–32.5; p < 0.05). Using multivariate analysis, only syndromic PRS status was predictive for severe respiratory disorders (adjusted OR 8, 95% CI 1.47–44.57; p < 0.05); and only neurological impairments remained a significant risk for long lasting feeding disorders (>12 months) (adjusted OR 21.72, 95% CI 3.4–138.63; p < 10−2). The grades of retrognathia and glossoptosis were not predictive factors for the severity of respiratory and feeding disorders.Conclusion: In children with PRS, the severity of clinical conditions may not correlate with anatomic variables but rather with laryngeal abnormalities, neurological impairement and syndromic PRS status

FATP4 missense and nonsense mutations cause similar features in Ichthyosis Prematurity Syndrome

<p>Abstract</p> <p>Background</p> <p>Ichthyosis Prematurity Syndrome (IPS) is an autosomal recessive disorder characterized by premature birth, non-scaly ichthyosis and atopic manifestations. The disease was recently shown to be caused by mutations in the gene encoding the fatty acid transport protein 4 (FATP4) and a specific reduction in the incorporation of very long chain fatty acids (VLCFA) into cellular lipids.</p> <p>Findings</p> <p>We screened probands from five families segregating IPS for mutations in the <it>FATP4 </it>gene. Four probands were compound heterozygous for four different mutations of which three are novel. Four patients were heterozygous and one patient homozygous for the previously reported non-sense mutation p.C168X (c.504c > a). All patients had clinical characteristics of IPS and a similar clinical course.</p> <p>Conclusions</p> <p>Missense mutations and non-sense mutations in <it>FATP4 </it>are associated with similar clinical features suggesting that missense mutations have a severe impact on FATP4 function. The results broaden the mutational spectrum in <it>FATP4 </it>associated with IPS for molecular diagnosis of and further functional analysis of FATP4.</p

Epidermolysis bullosa simplex generalized severe induces a T helper 17 response and is improved by apremilast treatment

International audienceBACKGROUND: Epidermolysis bullosa simplex generalized severe is a genetic disorder caused by mutation in KRT5 or KRT14 genes. Usually considered as a mechanical disease, recent data argue for additional inflammatory mechanisms. OBJECTIVES: The aim of this study was to assess the inflammation in the skin of patients with EBS. METHODS: A first immunohistochemical retrospective study was performed on frozen skin samples from 17 EBS-gen sev patients. A second multicenter prospective study was conducted on 10 patients with severe EBS-gen sev. Blister fluid and epidermis were processed for immunochemistry analysis and quantitative real time PCR. Cytokine expression was analyzed in blister fluid and compared with controls. RESULTS: Histological analysis showed a constant dermal perivascular CD4+ lymphocytes infiltrate in skin biopsies of blister (n=17) as well as in rubbed skin (n=5), an epidermal infiltration of neutrophils and eosinophils in 70% of cases and an increased immunostaining for CXCL9 and CXCL10 in blistering skin. High levels of Th17 cytokines were detected in lesional skin. Three adult patients with EBS-gen sev were treated with apremilast with a dramatic improvement of skin blistering and good tolerance. CONCLUSION: Our study demonstrates the importance of inflammation in EBS-gen sev patients and underlines the key role for Th17 cells in its pathogenesis. In addition, this study provides promising new therapeutic approaches for this disabling disorder. This article is protected by copyright. All rights reserved

International Teaching Programme

Nicolaides-Baraitser syndrome (NBS) is an infrequently described condition, thus far reported in five cases. In order to delineate the phenotype and its natural history in more detail, we gathered data on 18 hitherto unreported patients through a multi-center collaborative study, and follow-up data of the earlier reported patients. A detailed comparison of the 23 patients is provided. NBS is a distinct and recognizable entity, and probably has been underdiagnosed until now. Main clinical features are severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges. Some of the features are progressive with time. The main differential diagnosis is Coffin-Siris syndrome. There is no important gender difference in occurrence and frequency of the syndrome, and all cases have been sporadic thus far. Microarray analysis performed in 14 of the patients gave normal results. Except for the progressive nature there are no clues to the cause. (C) 2009 Wiley-Liss, Inc

Invest Ophthalmol Vis Sci

PURPOSE. Albinism is a group of genetic disorders that includes several conditions related to a defect in melanin production. There is a broad phenotypic and genotypic variability between the different forms. The aim of this study was to assess the ophthalmologic characteristics according to patients' genotypes in a cohort followed in the Reference Center for oculocutaneous albinism (OCA) of Bordeaux University Hospital, France.METHODS. A retrospective observational study was conducted in a cohort of patients with OCA seen in consultation in the ophthalmology department between 2017 and 2021 in whom a genetic analysis was performed.RESULTS. In total, 127 patients with OCA were included in this study and matched with the results of the genetic analysis. In the population aged over 6 years, there was no statistical difference in binocular visual acuity between the OCA1, OCA2, and OCA4 forms (P = 0.27). There was difference in ametropia between the three forms (P = 0.003). A twoby-two comparison using the Bonferroni correction showed a significant difference in ametropia between the OCA2 and OCA4 forms (P = 0.007) and between the OCA1 and OCA2 forms (P = 0.0075). Regardless of the form, most patients (75.4%) had grade 4 foveal hypoplasia. There was no association between the grade of foveal hypoplasia and the gene involved (P = 0.87).CONCLUSIONS. We described a genotype-phenotype correlation for the three most represented forms of albinism in our cohort. This study allowed assessing the degree of visual deficiency in young children with OCA

A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling

Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. De novo dominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategie