Pathophysiology and management of sensitive skin: position paper from the special interest group on sensitive skin of the International Forum for the Study of Itch (IFSI).

The special interest group on sensitive skin of the International Forum for the Study of Itch previously defined sensitive skin as a syndrome defined by the occurrence of unpleasant sensations (stinging, burning, pain, pruritus and tingling sensations) in response to stimuli that normally should not provoke such sensations. This additional paper focuses on the pathophysiology and the management of sensitive skin. Sensitive skin is not an immunological disorder but is related to alterations of the skin nervous system. Skin barrier abnormalities are frequently associated, but there is no cause and direct relationship. Further studies are needed to better understand the pathophysiology of sensitive skin - as well as the inducing factors. Avoidance of possible triggering factors and the use of well-tolerated cosmetics, especially those containing inhibitors of unpleasant sensations, might be suggested for patients with sensitive skin. The role of psychosocial factors, such as stress or negative expectations, might be relevant for subgroups of patients. To date, there is no clinical trial supporting the use of topical or systemic drugs in sensitive skin. The published data are not sufficient to reach a consensus on sensitive skin management. In general, patients with sensitive skin require a personalized approach, taking into account various biomedical, neural and psychosocial factors affecting sensitive skin.

The impact of atopic dermatitis on sexual health.

BACKGROUND: Sexual health is frequently affected by chronic diseases but has been poorly investigated in patients with atopic dermatitis (AD). OBJECTIVE: To evaluate the risk factors for impaired sexual desire and its relationship with the burden and quality of life of patients with AD. METHODS: A multicentre prospective transversal study in patients with AD. Socio-demographic and clinical data were obtained from all patients using a specifically developed questionnaire. In addition, patients were asked to answer validated scales, that is ABS-A, DLQI, SF-12 and EQ-5D. RESULTS: A total of 1024 patients participated in the study. Severity of AD, sites involved and treatment type was found to negatively impact the sexual desire of patients and their partners. In addition, the involvement of the genital and visible areas was associated with a higher burden and more significant alterations in quality of life. CONCLUSIONS: The results of this study are substantial and clearly demonstrate the deep impact of AD on sexual health, its relationship with disease-related burden and alterations to quality of life. Psychosociological as well as neurosensory phenomena could help to understand these data.

Sensitive skin can be small fibre neuropathy: results from a case-control quantitative sensory testing study.

BACKGROUND: Sensitive skin syndrome (SSS) is defined as the occurrence of unpleasant sensations (itch, pain, burning, prickling) in response to stimuli that should not normally cause such sensations. Previous studies show that SSS could be a small fibre neuropathy, but quantitative sensory testing (QST) is lacking. OBJECTIVES: Using QST, to determine the presence or absence of tactile sensitivity disorder, mainly heat pain threshold (HPT), in patients with SSS. METHODS: This monocentric case-control study included 21 patients with SSS and 21 controls. The patients underwent QST. Neuropathic pain was assessed by two questionnaires: the Douleur Neuropathique 4 (DN4) and the Neuropathic Pain Symptom Inventory (NPSI). RESULTS: Forty-two patients were included in the study. The HPT was significantly lower in the cases (14·5 ± 2·8) than in the controls (17·8 ± 2·5) (P < 0·001). Intermediate pain (HPT 5·0) was also significantly decreased in patients with SSS. The DN4 and NPSI scores were significantly higher in the cases than in the controls. CONCLUSIONS: The decrease in HPT in patients with SSS compared with controls suggests the presence of hyperalgesia, probably due to the damage of C-fibres. These findings, as well as the increased DN4 and NPSI scores, strengthen the neuronal hypothesis of SSS and are new arguments for consideration of SSS as small fibre neuropathy.

Development and validation of a new tool to assess the Burden of Sensitive Skin (BoSS).

BACKGROUND: Sensitive skin usually manifests itself as unpleasant sensations and sometimes erythema. There are various triggering factors for this condition. Although sensitive skin may alter quality of life, its burden has not yet been explored. OBJECTIVE: The aim of this study was to develop and validate a specific sensitive skin burden questionnaire called the BoSS (Burden of Sensitive Skin). METHODS: A conceptual phase was developed, followed by a development phase, external validation, psychometric analysis, test-retest analysis and, finally, a translation, cross-cultural adaptation and cognitive debriefing. RESULTS: A total of 6471 individuals participated in the study (4614 people in the validation study). The dimensionality of items was evaluated using factor analyses, suggesting three dimensions (self-care, daily life and appearance). Unidimensionality was confirmed by higher order factor analysis. The overall Cronbach's α coefficient was high, and intradimensional coherences all demonstrated good reliability. The final instrument consisted of 14 items. The test-retest reliability demonstrated very good reproducibility. The intraclass correlation of each dimension was high. External validity was confirmed by the correlation coefficients of the BoSS vs. those of the SF-12 and the DLQI assessment tools. CONCLUSION: BoSS is the first reliable tool to assess the burden of sensitive skin.

Sensitive skin in France: a study on prevalence, relationship with age and skin type and impact on quality of life.

BACKGROUND: Many epidemiological studies have been performed, but a potential increase in the prevalence of sensitive skin, its relationship with age and skin type and the impact of sensitive skin on quality of life are still debated. OBJECTIVE: To answer these unresolved questions. METHODS: An opinion poll was conducted on a representative French 5000 person sample. RESULTS: Fifty-nine per cent of the people declared very sensitive or fairly sensitive skin (together: sensitive skin), and women (66%) declared sensitive skin more frequently than men (51.9%). The results also showed that sensitive skin is more common (more than 60%) in younger people (<35 years old), and there was a decrease in the following age groups. The univariate analysis demonstrated that sensitive skin was more likely to be reported by people with fair skin (OR = 1.83) and by people with an atopic predisposition (OR = 2.51). The risk of sensitive skin is higher for people with dry skin (OR = 6.18 compared with normal skin), but sensitive skin can occur in other skin types (OR = 2.45 for mixed skin and OR = 2.16 for greasy skin). Quality of life was clearly altered in patients with sensitive skin, as assessed by SF-12 and DLQI. CONCLUSION: This large study demonstrates that sensitive skin can alter quality of life and is more common in young people and in women as well as patients with dry skin or fair skin or an atopic predisposition. It also suggests that there is an increase in the prevalence of sensitive skin.

Autosomal recessive truncating MAB21L1 mutation associated with a syndromic scrotal agenesis.

We report on a boy with a rare malformative association of scrotum agenesis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global development delay. The reported patient was carrying a homozygous frameshift in MAB21L1 detected by whole-exome sequencing, considered as the most likely disease-causing variant. Mab21l1 knockout mice present a strikingly similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia. We hypothesize that MAB21L1 haploinsufficiency cause a previously undescribed syndrome with scrotal agenesis, ophthalmological anomalies, facial dysmorphism and gross psychomotor delay as remarkable hallmarks. Four cases from the literature were reported with features suggestive of a similar and recognizable clinical entity. We hypothesize that MAB21L1 should be the culprit gene in these patients.

Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test.

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.

Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management.

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.

Clinical spectrum of eye malformations in four patients with Mowat-Wilson syndrome.

Mowat-Wilson syndrome (MWS) is a rare genetic syndrome characterized by a specific facial gestalt, intellectual deficiency, Hirschsprung disease and multiple congenital anomalies. Heterozygous mutations or deletions in the zinc finger E-box-binding homeobox2 gene (ZEB2) cause MWS. ZEB2 encodes for Smad-interacting protein 1, a transcriptional co-repressor involved in TGF-beta and BMP pathways and is strongly expressed in early stages of development in mice. Eye abnormalities have rarely been described in patients with this syndrome. Herein, we describe four patients (two males and two females; mean age 7 years) with MWS and eye malformations. Ocular anomalies included, iris/retinal colobomas, atrophy or absence of the optic nerve, hyphema, and deep refraction troubles, sometimes with severe visual consequences. All eye malformations were asymmetric and often unilateral and all eye segments were affected, similarly to the nine MWS cases with ophthalmological malformations previously reported (iris/chorioretinal/optic disc coloboma, optic nerve atrophy, retinal epithelium atrophy, cataract, and korectopia). In human embryo, ZEB2 is expressed in lens and neural retina. Using the present report and data from the literature, we set out to determine whether or not the presence of eye manifestations could be due to specific type or location of mutations. We concluded that the presence of eye malformations, although a rare feature in MWS, should be considered as a part of the clinical spectrum of the condition.

Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.

Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.

Take a Swipe at Actinide Bioavailability: Application of a New In Vitro Method.

ABSTRACT: Filter swipe tests are used for routine analyses of actinides in nuclear industrial, research, and weapon facilities as well as following accidental release. Actinide physicochemical properties will determine in part bioavailability and internal contamination levels. The aim of this work was to develop and validate a new approach to predict actinide bioavailability recovered by filter swipe tests. As proof of concept and to simulate a routine or an accidental situation, filter swipes were obtained from a nuclear research facility glove box. A recently-developed biomimetic assay for prediction of actinide bioavailability was adapted for bioavailability measurements using material obtained from these filter swipes. In addition, the efficacy of the clinically-used chelator, diethylenetriamine pentaacetate (Ca-DTPA), to enhance transportability was determined. This report shows that it is possible to evaluate physicochemical properties and to predict bioavailability of filter swipe-associated actinides.

Homozygous SMN1 exons 1-6 deletion: pitfalls in genetic counseling and general recommendations for spinal muscular atrophy molecular diagnosis.

We report on a rare homozygous intragenic deletion encompassing exons 1-6 of the SMN1 gene in a patient with spinal muscular atrophy (SMA) born into a consanguineous family. This exceptional configuration induced misinterpretation of the molecular defect involved in this patient, who was first reported as having a classic SMN1 exon 7 deletion. This case points out the possible pitfalls in molecular diagnosis of SMA in affected patients and their relatives: exploration of the SMN1 exon 7 (c.840C/T alleles) may be disturbed by several non-pathological or pathological variants around the SMN1 exon 7. In order to accurately describe the molecular defect in an SMA-affected patient, we propose to apply the Human Genome Variation Society nomenclature. This widely accepted nomenclature would improve the reporting of the molecular defect observed in SMA patients and thus would avoid the commonly used but imprecise terminology "absence of SMN1 exon 7."

What do French patients and geneticists think about prenatal and preimplantation diagnoses in Marfan syndrome?

OBJECTIVES: Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with manifestations mainly involving the skeletal, ocular, and cardiovascular systems. The phenotypic variability observed in MFS makes genetic counselling difficult. Prenatal diagnosis (PND) and preimplantation genetic diagnosis are technically feasible when a causal mutation is identified, but both raise many ethical questions in this condition. Little is known about opinions and practices in such reproductive issues in MFS. The goal of this study was to report on patients' points of view and geneticists' standard practices. METHODS: Two different questionnaires were produced. RESULTS: Fifty geneticists filled in the questionnaire. Twenty-two per cent thought that PND was acceptable, 72% debatable and 6% not acceptable. Preimplantation genetic diagnosis was more often reported acceptable (34% of answers). Results varied according to the physician's experience with the disease. Fifty-four answers were collected for patients' questionnaires. Most of them (74%) were favourable to the development of prenatal testing, and believed that the choice should be given to parents. However, only a minority would opt for prenatal diagnosis for themselves. CONCLUSION: This study showed that the majority of patients were in favour of PND and that opinions among practitioners varied widely, but that overall, practitioners favoured a systematic multidisciplinary evaluation of the couple's request.

Neonatal screening for congenital hypothyroidism: Time to lower the TSH threshold in France.

Neonatal screening for congenital hypothyroidism (CH) is based on the measurement of thyroid-stimulating hormone (TSH) in whole dried blood samples on filter paper in all newborns. The objective of screening for CH is to prevent mental retardation, which is irreversible in the event of a late diagnosis, by setting up prompt treatment (before day 15) with levothyroxine. The threshold value of TSH on filter paper on day 3 is 17 mIU/L in France in the GSP method (GSP, Genetic Screening Processor, Perkin Elmer): It is one of the highest thresholds used in the world. In many countries, the TSH threshold is between 6 and 12 mIU/L. Studies have found that a threshold of > 17 mIU/L may miss as much as 30% of cases of CH, with 30-80% of these being permanent CH. Recent studies suggest that mild CH (currently missed by the French TSH threshold) is associated with cognitive consequences if left untreated. An inverse relationship between TSH at screening (below the current threshold) and cognitive development at preschool or school age has been shown. These studies advocate for the evaluation of a lowering of the threshold of TSH on filter paper in France: (a) to determine the number of CH diagnoses with the new threshold and whether these "new cases" would be transitory or permanent; and (b) to analyze the cost-effectiveness of the strategy.

Renal insufficiency, a frequent complication with age in oral-facial-digital syndrome type I.

The oral-facial-digital syndrome type I (OFD I) is characterized by multiple congenital malformations of the face, oral cavity and digits. A polycystic kidney disease (PKD) is found in about one-third of patients but long-term outcome and complications are not well described in the international literature. Renal findings have been retrospectively collected in a cohort of 34 females all carrying a pathogenic mutation in the OFD1 gene with ages ranging from 1 to 65 years. Twelve patients presented with PKD - 11/16 (69%) if only adults were considered -with a median age at diagnosis of 29 years [IQR (interquartile range) = (23.5-38)]. Among them, 10 also presented with renal impairment and 6 were grafted (median age = 38 years [IQR = (25-48)]. One grafted patient under immunosuppressive treatment died from a tumor originated from a native kidney. The probability to develop renal failure was estimated to be more than 50% after the age of 36 years. Besides, neither genotype-phenotype correlation nor clinical predictive association with renal failure could be evidenced. These data reveal an unsuspected high incidence rate of the renal impairment outcome in OFD I syndrome. A systematic ultrasound (US) and renal function follow-up is therefore highly recommended for all OFD I patients.