Introduction Les répercussions buccales du diabète sont nombreuses et sont principalement représentées par une hyposialie, des hyperplasie(s) gingivale(s), une susceptibilité à la carie et à diverses ...infections, notamment la maladie parodontale. Selon l'ADA, la parodontite est ainsi la 6e complication du diabète. De Pinho AM. et al (2012) ont montré que 60 % des diabétiques sont insatisfaits de leur qualité de vie. Peu d'études relatent la qualité de la vie orale des diabétiques. Matériels et Méthodes L'objectif de cette étude était d'évaluer les répercussions du diabète de type 1 sur la qualité de vie liée à la santé orale, à l'aide d'un autoquestionnaire, le General Oral Health Assessment Index (GOHAI, 12 items scorés, reflétant une bonne satisfaction de 57 à 60, une satisfaction moyenne de 51 à 56 et une satisfaction faible de 50 et moins). Les malades inclus avaient entre 18 et 50 ans, sans perte d'autonomie et comprenaient le français. Les femmes enceintes ont été exclues (troubles gravidiques de la sphère orale). Les données médicales ont été recueillies. L'analyse statistique a été réalisée grâce au logiciel Graph Pad Prism v5. Résultats 104 dossiers complets ont été retenus. La moyenne du GOHAI était de 53.46 ± 6,78, donnant une qualité de vie orale moyenne et indiquant la présence de troubles bucco-dentaires. Aucune corrélation n'a été trouvée entre ancienneté du diabète et GOHAI ; Il a été trouvé une corrélation inverse entre taux d'HbA1c et GOHAI (r = − 0,3351, p < 0,001), ainsi qu'une diminution significative du GOHAI en présence de complications liées au diabète (50,86 ± 1,45 vs 54.47 ± 0,69, p < 0,05). Discussions On retrouve des similarités avec les études de Glavind et al, (1969) ou celle d'Abikshyeet P et al, (2012) qui ont noté une association entre la survenue de problèmes dentaires et les complications liées au diabète. De même, le diabète n'est pas un facteur déclenchant de la maladie parodontale ; il est par contre un facteur aggravant. L'utilisation du questionnaire GOHAI pour le non spécialiste pourrait être utile dans la détection de problèmes bucco-dentaires.
The current standard of care for diagnosis of severe intellectual disability (ID) and epileptic encephalopathy (EE) results in a diagnostic yield of ∼50%. Affected individuals nonetheless undergo ...multiple clinical evaluations and low‐yield laboratory tests often referred to as a ‘diagnostic odyssey’. This study was aimed at assessing the utility of clinical whole‐exome sequencing (WES) in individuals with undiagnosed and severe forms of ID and EE, and the feasibility of its implementation in routine practice by a small regional genetic center. We performed WES in a cohort of 43 unrelated individuals with undiagnosed ID and/or EE. All individuals had undergone multiple clinical evaluations and diagnostic tests over the years, with no definitive diagnosis. Sequencing data analysis and interpretation were carried out at the local molecular genetics laboratory. The diagnostic rate of WES reached 32.5% (14 out of 43 individuals). Genetic diagnosis had a direct impact on clinical management in four families, including a prenatal diagnostic test in one family. Our data emphasize the clinical utility and feasibility of WES in individuals with undiagnosed forms of ID and EE and highlight the necessity of close collaborations between ordering physicians, molecular geneticists, bioinformaticians and researchers for accurate data interpretation.
Several genes have been implicated in Rett syndrome (RTT) in its typical and variant forms. We applied next‐generation sequencing (NGS) to evaluate for mutations in known or new candidate genes in ...patients with variant forms of Rett or Rett‐like phenotypes of unknown molecular aetiology. In the first step, we used NGS with a custom panel including MECP2, CDKL5, FOXG1, MEF2C and IQSEC2. In addition to a FOXG1 mutation in a patient with all core features of the congenital variant of RTT, we identified a missense (p.Ser240Thr) in CDKL5 in a patient who appeared to be seizure free. This missense was maternally inherited with opposite allele expression ratios in the proband and her mother. In the asymptomatic mother, the mutated copy of the CDKL5 gene was inactivated in 90% of blood cells. We also identified a premature stop codon (p.Arg926*) in IQSEC2 in a patient with a Rett‐like phenotype. Finally, exome sequencing enabled us to characterize a heterozygous de novo missense (p.Val408Ala) in KCNA2 encoding the potassium channel Kv 1.2 in a girl with infantile‐onset seizures variant of RTT. Our study expands the genetic heterogeneity of RTT and RTT‐like phenotypes. Moreover, we report the first familial case of CDKL5‐related disease.
Proximal 16p11.2 microdeletions are recurrent microdeletions with an overall prevalence of 0.03%. In patients with segmentation defects of the vertebra (SDV), a burden of this microdeletion was ...observed with TBX6 as a candidate gene for SDV. In a published cohort of patients with congenital scoliosis (CS), TBX6 haploinsufficiency was compound heterozygous with a common haplotype. Besides, a single three‐generation family with spondylocostal dysostosis (SCD) was reported with a heterozygous stop‐loss of TBX6. These observations questioned both on the inheritance mode and on the variable expressivity associated with TBX6‐associated SDV. Based on a national recruitment of 56 patients with SDV, we describe four patients with variable SDV ranging from CS to SCD associated with biallelic variations of TBX6. Two patients with CS were carrying a proximal 16p11.2 microdeletion associated with the previously reported haplotype. One patient with extensive SDV was carrying a proximal 16p11.2 microdeletion associated with a TBX6 rare missense change. One patient with a clinical diagnosis of SCD was compound heterozygous for two TBX6 rare missense changes. The three rare variants were affecting the chromatin‐binding domain. Our data illustrate the variable expressivity of recessive TBX6 ranging from CS to SCD.
Background
Alterations in GFER gene have been associated with progressive mitochondrial myopathy, congenital cataracts, hearing loss, developmental delay, lactic acidosis and respiratory chain ...deficiency in 3 siblings born to consanguineous Moroccan parents by homozygosity mapping and candidate gene approach (OMIM#613076). Next generation sequencing recently confirmed this association by the finding of compound heterozygous variants in 19‐year‐old girl with a strikingly similar phenotype, but this ultra‐rare entity remains however unknown from most of the scientific community.
Materials and Methods
Whole exome sequencing was performed as part of a “diagnostic odyssey” for suspected mitochondrial condition in 2 patients, presenting congenital cataracts, progressive encephalomyopathy and hypotrophy and detected unreported compound heterozygous variants in GFER.
Results
Thanks to an international data sharing, we found 2 additional patients carrying compound heterozygous variants in GFER. Reverse phenotyping confirmed the phenotypical similarities between the 4 patients. Together with the first literature reports, the review of these 8 cases from 4 unrelated families enables us to better describe this apparently homogeneous disorder, with the clinical and biological stigmata of mitochondrial disease.
Conclusion
This report highlights the clinical utility of whole exome sequencing and reverse phenotyping for the diagnosis of ultra‐rare diseases and underlines the importance of a broad data sharing for accurate clinical delineation of previously unrecognized entities.
BackgroundMEN1, which is secondary to the mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence ...of direct genotype-phenotype correlations. The existence of a higher risk of death in the Groupe d'étude des Tumeurs Endocrines-cohort associated with a mutation in the JunD interacting domain suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intrafamilial correlations and heritability of the six main tumor types in MEN1.MethodsThe study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software.ResultsIntrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; P<0.001) for pituitary tumor, 65% (s.e.m.=0.21; P<0.001) for adrenal tumors, and 97% (s.e.m.=0.41; P=0.006) for thNETs.ConclusionThe present study shows the existence of modifying genetic factors for thymus, adrenal, and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.
SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething ...delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had four or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included intrauterine growth restriction (IUGR) <10th percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended.
Abstract During post-meiotic maturation, male germ cells undergo a formidable reorganization and condensation of their genome. During this phase most histones are globally acetylated and then ...replaced by sperm-specific basic proteins, named protamines, which compact the genome into a very specific structure within the sperm nucleus. Several studies suggest that this sperm-specific genome packaging structure conveys an important epigenetic message to the embryo. This paper reviews what is known about this fundamental, yet poorly understood, process, which involves not only global changes of the structure of the haploid genome, but also localized specific modifications of particular genomic regions, including pericentric heterochromatin and sex chromosomes. After fertilization, the male genome undergoes a drastic decondensation, and rapidly incorporates new histones. However, it remains different from the maternal genome, bearing specific epigenetic marks, especially in the pericentric heterochromatin region. The functional implications of male post-meiotic and post-fertilization genome reprogramming are not well known, but there is experimental evidence to show that it affects early embryonic development.
Summary
Focal dermal hypoplasia (FDH, Goltz syndrome, MIM #305600) constitutes a rare multisystem genetic disorder of the skin, skeleton, teeth and eyes with considerable variation in the clinical ...features. FDH is transmitted as an X‐linked dominant trait and is caused by mutations in PORCN. In male children, hemizygous PORCN mutations are lethal in utero. Around 300 cases have been reported in the literature to date. About 10% of them are male patients presenting with either Klinefelter syndrome (karyotype 47, XXY) or mosaicism of a postzygotic mutation. Here we describe four cases of women with typical features of FDH, in whom a PORCN mutation was found in DNA from affected cutaneous tissue but not in DNA from peripheral blood. This study suggests that mosaicism caused by a postzygotic mutation occurs more often than assumed to date in female patients with FDH. A negative analysis performed on peripheral blood DNA does not exclude the diagnosis of FDH and it is therefore of practical importance to analyse DNA from the affected skin in order to identify low‐level mosaicism and thus to improve diagnostic precision. In total, we found two missense variants, one novel indel and one novel splice‐site variant. Individuals harbouring postzygotic mosaicism run a risk of transmitting the disorder to their daughters, because the maternal mosaic could also affect the gonads.
What's already known about this topic?
Mutations in PORCN cause focal dermal hypoplasia (FDH).
In male children, hemizygous PORCN mutations are lethal in utero.
To date, only around 300 patients with mutations in PORCN have been reported.
What does this study add?
In four women affected by FDH, PORCN mutations were found to be present in affected cutaneous tissue but not in peripheral blood.
Negative mutation analysis of blood samples does not exclude the diagnosis of FDH, as a mosaic constellation due to postzygotic mutations has been repeatedly observed in female patients with FDH as shown in this study.
Linked Comment: Traupe. Br J Dermatol 2019; 180:461–462.
Plain language summary available online
Summary
Papillomatous pedunculated sebaceous naevus (PPSN) has been described as a subtype of sebaceous naevus (SN), typically affecting the scalp and face. In contrast with Schimmelpenning syndrome, ...no cerebral, ocular or skeletal anomalies have hitherto been reported. We report two unrelated fetuses with PPSN, one with large pink exophytic tumours, the other with minor features but similar microscopic findings. We performed whole‐exome sequencing in affected skin tissue from fetus 1, which identified a postzygotic de novo FGFR2 c.1144T>C (p.Cys382Arg) mutation in 34·6% of reads which was absent in the parents’ blood. Targeted deep sequencing of FGFR2 confirmed its mosaic status in additional affected skin from fetus 1, and identified the same substitution in 26% of reads in affected skin from fetus 2. FGFR2 p.Cys382Arg is a known somatic driver mutation in human cancer, previously reported to result in activation of RAS signalling. A similar paralogous missense mutation in the transmembrane domain of FGFR3 (p.Gly380Arg) has been reported in keratinocytic epidermal naevi. Our findings define a distinct clinical and molecular subgroup of SN, beside HRAS or KRAS‐related SN, and expand the spectrum of mosaic skin conditions associated with receptor tyrosine kinase mutations.
What's already known about this topic?
A rare subtype of papillomatous pedunculated sebaceous naevus (PPSN) has been reported in neonates and a fetus.
Most epidermal naevi have been associated with postzygotic mutations in genes encoding cell growth and proliferation signalling molecules: HRAS and KRAS in sebaceous naevi (SN), FGFR2 in acne or comedo naevi, and HRAS, KRAS, NRAS, FGFR3 and PIK3CA in keratinocytic epidermal naevi.
What does this study add?
Here we report a novel postzygotic activating FGFR2 mutation in two unrelated fetuses with PPSN.
Mosaic receptor tyrosine kinase gene mutations, particularly in FGFR2, have not previously been reported in SN.
Linked Comment: Has. Br J Dermatol 2017; 176:15–16.
PDF
