Hypotrichosis-lymphedema-telangiectasia syndrome: Report of ileal atresia associated with a SOX18 de novo pathogenic variant and review of the phenotypic spectrum.

Hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) is a rare condition caused by pathogenic variants in the SOX18 gene. SOX18 plays a key role in angio- and lymphangiogenesis due to its expression in venous endothelial cells from which the lymphatic system develops. It is also expressed in embryonic hair follicles, heart, and vascular smooth muscle cells. The main clinical symptoms of HLTS include sparse hair, alopecia totalis, lymphedema, most often affecting lower limbs, and telangiectatic lesions. Only 10 patients with a SOX18 pathogenic variant have been described that presented with additional features such as hydrocele, renal failure, arterial or pulmonary hypertension, aortic dilatation, and facial dysmorphism. Here, we summarize these phenotypic variations and report an additional HLTS patient, with a 14-nucleotide de novo duplication in SOX18 and congenital ileal atresia, a feature not previously associated with HLTS.

Epilepsy in Nicolaides-Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects.

Nicolaides-Baraitser syndrome (NCBRS), caused by a mutation in the SMARCA2 gene, which goes along with intellectual disability, congenital malformations, especially of face and limbs, and often difficult-to-treat epilepsy, is surveyed focusing on epilepsy and its treatment. Patients were recruited via "Network Therapy of Rare Epilepsies (NETRE)" and an international NCBRS parent support group. Inclusion criterion is NCBRS-defining SMARCA2 mutation. Clinical findings including epilepsy classification, anticonvulsive treatment, electroencephalogram (EEG) findings, and neurodevelopmental outcome were collected with an electronic questionnaire. Inclusion of 25 NCBRS patients with epilepsy in 23 of 25. Overall, 85% of the participants (17/20) reported generalized seizures, the semiology varied widely. EEG showed generalized epileptogenic abnormalities in 53% (9/17), cranial magnetic resonance imaging (cMRI) was mainly inconspicuous. The five most frequently used anticonvulsive drugs were valproic acid (VPA [12/20]), levetiracetam (LEV [12/20]), phenobarbital (PB [8/20]), topiramate (TPM [5/20]), and carbamazepine (CBZ [5/20]). LEV (9/12), PB (6/8), TPM (4/5), and VPA (9/12) reduced the seizures' frequency in more than 50%. Temporary freedom of seizures (>6 months) was reached with LEV (4/12), PB (3/8), TPM (1/5, only combined with PB and nitrazepam [NZP]), and VPA (4/12). Seizures aggravation was observed under lamotrigine (LTG [2/4]), LEV (1/12), PB (1/8), and VPA (1/12). Ketogenic diet (KD) and vagal nerve stimulation (VNS) reduced seizures' frequency in one of two each. This first worldwide retrospective analysis of anticonvulsive therapy in NCBRS helps to treat epilepsy in NCBRS that mostly shows only initial response to anticonvulsive therapy, especially with LEV and VPA, but very rarely shows complete freedom of seizures in this, rather genetic than structural epilepsy.

Anaesthesia and orphan disease: management of a case of Nicolaides-Baraitser syndrome undergoing cleft palate surgery.

BACKGROUND: Nicolaides-Baraitser syndrome (NCBRS) is a rare disease caused by mutations in the SMRCA2 gene, which affects chromatin remodelling and leads to a wide range of symptoms including microcephaly, distinct facial features, recurrent seizures, and severe mental retardation. Until now, less than 100 cases have been reported. CASE PRESENTATION: A 22-month old male infant with NCBRS underwent elective cleft palate surgery. The anaesthetists were challenged by the physiological condition of the patient: narrow face, very small mouth, mild tachypnea, slight sternal retractions, physical signs of partial monosomy 9p, and plagiocephalus, midface hypoplasia, V-shaped cleft palate, enhanced muscular hypotension, dysplastic kidneys (bilateral, estimated GFR: approx. 40 ml/m2), nocturnal oxygen demand, and combined apnea. In addition, little information was available about interaction of the NCBRS displayed by the patient and anaesthesia medications. CONCLUSIONS: The cleft palate was successfully closed using the bridge flap technique. Overall, we recommend to perform a trial video assisted laryngoscopy in the setting of spontaneous breathing with deep inhalative anaesthesia before administration of muscle relaxation to detect any airway difficulties while remaining spontaneoues breathing and protective reflexes.

Hypotrichosis with cone-rod dystrophy in a patient with cadherin 3 (CDH3) mutation.

PURPOSE: To investigate a very rare case of hypotrichosis with cone-rod dystrophy caused by a P-cadherin CDH3 mutation. METHODS: A 16-year-old Syrian girl was examined at age 9 and 14 years with an ophthalmological examination, fundus imaging, OCT and electrophysiological recordings (ERG and PERG). A disease-targeted gene panel sequencing was performed. RESULTS: Fundus images showed pigmentations at the posterior eye pole to the mid periphery, as well as vessel tortuosity. OCT images revealed a loss of the outer retinal segments and IS/OS in the central macula. The scotopic and photopic ERGs showed moderately reduced amplitudes at age 9 years that became severely reduced at age of 14 years. The PERG was undetectable at age 9 years. In color vision testing, protan-deutan confusion errors occurred. Gene panel analysis revealed one homozygous mutation in CDH3 (c.1508G>A; p.Arg503His). CONCLUSION: This case shows that a CDH3 mutation besides macula dystrophy can cause widespread cone-rod dystrophy with hypotrichosis without any other pathology besides hypoplastic nails. This points to a common pathway of hair growth and photoreceptor development that can be disturbed by a CDH3 mutation (c.1508G>A; p.Arg503His) located in the EC4 repeat region of the gene.

The role of objective facial analysis using FDNA in making diagnoses following whole exome analysis. Report of two patients with mutations in the BAF complex genes.

The genetic basis of numerous intellectual disability (ID) syndromes has recently been identified by applying exome analysis on a research or clinical basis. There is significant clinical overlap of biologically related syndromes, as exemplified by Nicolaides-Baraitser (NCBRS) and Coffin-Siris (CSS) syndrome. Both result from mutations affecting the BAF (mSWI/SNF) complex and belong to the growing category of BAFopathies. In addition to the notable clinical overlap between these BAFopathies, heterogeneity exists for patients clinically diagnosed with one of these conditions. We report two teenagers with ID whose molecular diagnosis of a SMARC2A or ARID1B mutation, respectively, was established through clinical exome analysis. Interestingly, using only the information provided in a single clinically obtained facial photograph from each patient, the facial dysmorphology analysis detected similarities to facial patterns associated with NCBRS as the first suggestion for both individuals, followed by CSS as the second highest ranked in the individual with the ARID1B mutation. Had this information been available to the laboratory performing the exome analysis, it could have been utilized during the variant analysis and reporting process, in conjunction with the written summary provided with each test requisition. While the available massive parallel sequencing technology, variant calling and variant interpretation are constantly evolving, clinical information remains critical for this diagnostic process. When trio analysis is not feasible, additional diagnostic tools may become particularly valuable. Facial dysmorphology analysis data may supplement the clinical phenotype summary and provide data independent of the clinician's personal experience and bias. © 2016 Wiley Periodicals, Inc.

Development and Validation of the Eyelash Satisfaction Questionnaire.

BACKGROUND: Patient-reported outcome (PRO) measures have been used to assess treatment benefit in a variety of therapeutic areas and are now becoming increasingly important in aesthetic research. OBJECTIVES: The objective of the current study was to develop and validate a new PRO measure (Eyelash Satisfaction Questionnaire [ESQ]) to assess satisfaction with eyelash prominence. METHODS: The content of the questionnaire (including conceptual framework and questionnaire items) was generated by review of literature, participant interviews, and expert opinion. Cognitive interviews were conducted to pilot test the questionnaire. Psychometric properties of the questionnaire were examined in a combined sample of participants (n = 970) completing Internet- (n = 909) and paper-based (n = 61) versions. Item- and domain-level properties were examined using modern and classical psychometrics. RESULTS: Content-based analysis of qualitative data demonstrated the presence of 3 distinct domains (Length, Fullness, Overall Satisfaction; Confidence, Attractiveness, and Professionalism; and Daily Routine). Initial confirmatory factor analysis (CFA) results of 23 items revealed insufficient model-data fit (comparative fit index [CFI] of 0.86 and a non-normed fit index [NNFI] of 0.82). A revised model using 9 items (3 per domain) achieved appropriate fit (CFI of 0.99 and NNFI of 0.97). Analyses revealed measurement equivalence across the Internet- and paper-based versions. The 3 ESQ domains had strong internal consistency reliability (Cronbach's α [range] = 0.919-0.976) and adequate convergent and discriminant validity. CONCLUSIONS: The ESQ was found to be a reliable and valid PRO measure for assessing satisfaction with eyelash prominence. LEVEL OF EVIDENCE 3: Therapeutic.

[Not Available]. / Síndrome de Graham-Little-Piccardi-Lassueur: variante disseminada de líquen plano folicular.

Graham-Little-Piccardi-Lassueur syndrome is a rare lichenoid dermatosis. It is characterized by the triad of scarring alopecia of the scalp, alopecia of the axilla and or groin, and keratotic follicular papules of the body. The present paper reports on two cases affecting young women. Histopathological findings suggest the disorder represents a generalized form of lichen planus follicularis.

Patient-reported outcomes of bimatoprost for eyelash growth: results from a randomized, double-masked, vehicle-controlled, parallel-group study.

BACKGROUND: Hypotrichosis of the eyelashes may negatively influence an individual's self-perception and appearance. Assessing the impact of treatment from a patient's perspective may be particularly relevant in trials of aesthetic agents. Once-daily dermal (topically applied) administration of bimatoprost ophthalmic solution 0.03% has been associated with increased eyelash prominence (ie, length, thickness, darkness). OBJECTIVES: The authors assess patient-reported outcomes (PRO) after treatment with bimatoprost for hypotrichosis of the eyelashes. METHODS: In this multicenter, double-masked, randomized, vehicle-controlled, parallel clinical trial, 4 PRO questionnaires were distributed to 278 patients (bimatoprost [n = 137] and vehicle [n = 141]). The primary PRO questionnaire was the 23-item Eyelash Satisfaction Questionnaire (ESQ), which measured satisfaction in 3 domains: length, fullness, and overall satisfaction (LFOS); confidence, attractiveness, and professionalism (CAP); and impact on daily routine (DR). RESULTS: By week 16, the bimatoprost group reported significantly greater improvements from baseline on all ESQ items (P ≤ .0433). These improvements were sustained through the 4-week posttreatment study visit. Patient satisfaction was significantly greater in the bimatoprost group than in the vehicle group for all 3 domains: LFOS (weeks 8-20; P ≤ .0052), CAP (weeks 12-20; P < .0001), and DR (weeks 16 and 20; P ≤ .01). CONCLUSIONS: The bimatoprost group reported significantly greater levels of positive patient outcomes and satisfaction than the vehicle group across all 23 questions and all 3 domains of the primary PRO questionnaire. These results support the effectiveness, as measured by objective measures and PRO, of once-daily bimatoprost ophthalmic solution 0.03% at producing more prominent eyelashes in adults.

Vascular defects in a mouse model of hypotrichosis-lymphedema-telangiectasia syndrome indicate a role for SOX18 in blood vessel maturation.

Mutations in the transcription factor gene SOX18 cause vascular, lymphatic and hair follicle defects in humans with dominant and recessive forms of hypotrichosis-lymphedema-telangiectasia (HLT) syndrome. Here, we clarify the role of SOX18 in the vascular dysfunction in HLT by ultrastructural, immunofluorescence, molecular and functional analysis of vascular anomalies in embryos of the naturally occurring Sox18-mutant mouse strain ragged-opossum (Ra(Op)). Early genesis and patterning of vasculature was unimpaired in Ra(Op) embryos, but surface capillaries became enlarged from 12.5 dpc and embryos developed massive surface hemorrhage by 14.5 dpc. Large focal breaches in the endothelial barrier were observed, in addition to endothelial hyperplasia associated with impaired pericyte recruitment to the microvasculature. Expression of the genes encoding the endothelial factors MMP7, IL7R and N-cadherin was reduced in Ra(Op) embryos, suggesting that these are downstream targets of SOX18. Together, our results indicate that vascular anomalies in HLT arise from defects in regulation of genes required for the acquisition of structural integrity during microvascular maturation.

Striking phenotypic overlap between Nicolaides-Baraitser and Coffin-Siris syndromes in monozygotic twins with ARID1B intragenic deletion.

The chromatin remodeling AT-Rich interaction domain containing 1B protein (ARID1B) also known as BAF-associated factor, 250-KD, B (BAF250B) codified by the ARID1B gene (MIM#614556), is a small subunit of the mammalian SWI/SNF or BAF complex, an ATP-dependent protein machinery which is able to activate or repress gene transcription, allowing protein access to histones through DNA relaxed conformation. ARID1B gene mutations have been associated with two hereditary syndromic conditions, namely Coffin-Siris (CSS, MIM#135900) and Nicolaides-Baraitser syndromes (NCBRS, MIM#601358), characterized by neurodevelopment delay, craniofacial dysmorphisms and skeletal anomalies. Furthermore, intellectual impairment and central nervous system (CNS) alterations, comprising abnormal corpus callosum, have been associated with mutations in this gene. Moreover, ARID1B anomalies resulted to be involved in neoplastic events and Hirschprung disease. Here we report on two monozygotic male twins, displaying clinical appearance strikingly resembling NCBRS and CSS phenotype, who resulted carriers of a novel 6q25.3 microdeletion, encompassing only part of the ARID1B gene. The deleted segment was not inherited from the only parent tested and afflicted the first exons of the gene, coding for protein disordered region. We also provide, for the first time, a review of previously published ARID1B mutated patients with NCBRS and CSS phenotype and a computer-assisted dysmorphology analysis of NCBRS and ARID1B related CSS individuals, through the Face2Gene suite, confirming the existence of highly overlapping facial gestalt of both conditions. The present findings indicate that ARID1B could be considered a contributing gene not only in CSS but also in NCBRS phenotype, although the main gene related to this latter condition is the SMARCA2 gene (MIM#600014), another component of the BAF complex. So, ARID1B study should be considered in such individuals.

Effects of LATISSE (bimatoprost 0.03 per cent topical solution) on the ocular surface.

PURPOSE: LATISSE is marketed for the treatment of hypotrichosis (loss of eyelashes), using a prostamide analogue and preserved with benzalkonium chloride, which is an effective preservative; however, it also causes irritation to the ocular surface. LATISSE is applied to the lid margin; however, with the blink, some solution may fall onto the ocular surface. The objective of this study was to assess the effects of LATISSE on the ocular surface over two months. METHODS: Non-dry eye participants interested in eyelash lengthening were invited to a prospective uncontrolled, open-label clinical study using LATISSE for two months. Eyelash length, subjective symptoms, tear film stability, osmolarity, ocular redness and intraocular pressure were evaluated at baseline (T0) and at one (T1) and two months (T2). RESULTS: Twenty-eight women (ages 18 to 29) entered the study. Fifteen completed the study with five who discontinued due to burning upon instillation and eight were lost to follow-up. Average eyelash length increased at each time (p < 0.001). Dryness, burning and grittiness remained low (less than 25/100) throughout the trial with dryness showing a significant change between T0 and T1 (p = 0.04), but not between T1 and T2 (p > 0.05). No difference (p > 0.05) was noted for the non-invasive break-up time, photochromametry or tear osmolarity. Intraocular pressure showed a decrease with time but translated to only a one to two mmHg change, which was not clinically relevant. CONCLUSIONS: LATISSE increases eyelash length within a short time (less than two months). Patients seeking eyelash enhancement options should be educated as to the use, precautions and any secondary effects, including the potential for discomfort upon instillation.

Hypotrichosis with juvenile macular dystrophy: clinical and electrophysiological assessment of visual function.

PURPOSE: To evaluate retinal function in subjects suffering from hypotrichosis with juvenile macular dystrophy (HJMD). DESIGN: Retrospective case-control study. PARTICIPANTS: Sixteen HJMD patients belonging to 2 genetic groups and 20 control subjects. METHODS: The HJMD patients underwent clinical ophthalmological examination and electrophysiological testing for a period of as many as 14 years. The electroretinogram (ERG), electro-oculogram (EOG), and visual evoked potential (VEP) were recorded serially to assess visual function and to follow possible progression of the disease. MAIN OUTCOME MEASURES: Amplitudes and implicit times of ERG and VEP, and Arden ratio of EOG. RESULTS: Fundus examination revealed pigmentary abnormalities with atrophic changes at the posterior pole extending to regions beyond the macular area. A slow and time-dependent decline in visual acuity was noted. The ERG responses were subnormal in amplitude. The ERG deficit was similar for light- and dark-adapted responses. There was a gradual but consistent decrease in the ERGs with time. The EOG measurements were within the normal range. Pattern reversal VEPs were very subnormal, even in patients with mild deterioration of visual acuity. The flash VEPs were of slightly subnormal amplitudes and implicit times in the upper limit of the normal range. CONCLUSIONS: The fundus pictures and electrophysiological tests were consistent with retinal involvement extending beyond the macular region. Follow-up of visual acuity and ERG testing indicated a slowly progressing retinal disorder affecting cone-mediated vision as well as rod-mediated vision. Therefore, we suggest that a more appropriate name for this syndrome is hypotrichosis with cone-rod dystrophy.

Increased hair shedding may be associated with the presence of Pityrosporum ovale.

BACKGROUND AND OBJECTIVE: Although the available data show that hair loss is an important cosmetic problem worldwide, the pathogenesis of common hair shedding is not fully understood. The aim of this study was to evaluate the association between hair shedding and cutaneous Malassezia infection. Malassezia fungi have been the suspected cause of dandruff for more than a century. Previously referred to as Pityrosporum ovale or P. orbiculare, these fungi are now known to consist of at least seven species. METHODS: Over a 4-year period, we obtained 300 hair samples from medical students. Based on the clinical history and a hair-pull test, the participants were divided into two groups: normal subjects and subjects with hair shedding. The students' scalp skin was gently scraped, smeared on a slide, colored by methylene blue, and observed under 10x magnification. RESULTS: All participants who had positive smears with >or=3 P. ovale organisms per low-power microscopic field (10x) were defined as 'carriers.' Seventy-six percent of students were Malassezia carriers. The prevalence of positive smears was significantly higher among subjects with hair shedding than among normal subjects (89.92% vs 9.52%, p<0.001). Furthermore, participants with positive smears had a significantly higher frequency of hair loss complaints and positive hair-pull tests. CONCLUSION: The proportion of subjects who were carriers of Malassezia yeasts was significantly higher in the group with hair shedding, and our results therefore raise the possibility of a relationship between this unicellular organism and hair loss. Our study findings should be explored in a larger series of patients.

Chronic telogen effluvium: a study of 5 patients over 7 years.

Chronic telogen effluvium is said to be self-limiting in the long run; the natural history of this condition, however, has not been investigated prospectively. Four women, aged between 18 and 64 years and diagnosed with chronic telogen effluvium between 1996 and 1997, were followed up prospectively for a minimum of 7 years. One (previously reported) woman diagnosed in 1998 developed female pattern hair loss confirmed on biopsy specimen within 18 months that was partially reversed by spironolactone. The remaining 4 women continued to experience chronic diffuse telogen hair shedding that fluctuated in severity. However, serial photography demonstrated no visible reduction in hair density, and serial scalp biopsy specimen showed no follicular miniaturization. Although 4 out of 5 of our patients showed no tendency toward development of female pattern hair loss or to spontaneous improvement, further work is required to define the natural history of chronic telogen effluvium and the relative risk of developing female pattern hair loss.

The genetics of cognitive epigenetics.

Cognitive disorders (CDs) are a heterogeneous group of disorders for which the genetic foundations are rapidly being uncovered. The large number of CD-associated gene mutations presents an opportunity to identify common mechanisms of disease as well as molecular processes that are of key importance to human cognition. Given the disproportionately high number of epigenetic genes associated with CD, epigenetic regulation of gene transcription is emerging as a process of major importance in cognition. The cognate protein products of these genes often co-operate in shared protein complexes or pathways, which is reflected in similarities between the neurodevelopmental phenotypes corresponding to these mutant genes. Here we provide an overview of the genes associated with CDs, and highlight some of the epigenetic regulatory complexes involving multiple CD genes. Such common gene networks may provide a handle for designing therapeutic interventions applicable to a number of cognitive disorders with variable genetic etiology.

P-cadherin regulates human hair growth and cycling via canonical Wnt signaling and transforming growth factor-ß2.

P-cadherin is a key component of epithelial adherens junctions, and it is prominently expressed in the hair follicle (HF) matrix. Loss-of-function mutations in CDH3, which encodes P-cadherin, result in hypotrichosis with juvenile macular dystrophy (HJMD), an autosomal recessive disorder featuring sparse and short hair. Here, we attempted to recapitulate some aspects of HJMD in vitro by transfecting normal, organ-cultured human scalp HFs with lipofectamine and CDH3-specific or scrambled control siRNAs. As in HJMD patients, P-cadherin silencing inhibited hair shaft growth, prematurely induced HF regression (catagen), and inhibited hair matrix keratinocyte proliferation. In situ, membrane ß-catenin expression and transcription of the ß-catenin target gene, axin2, were significantly reduced, whereas glycogen synthase kinase 3 ß (GSK3ß) and phospho-ß-catenin immunoreactivity were increased. These effects were partially reversed by inhibiting GSK3ß. P-cadherin silencing reduced the expression of the anagen-promoting growth factor, IGF-1, whereas that of transforming growth factor ß 2 (TGFß2; catagen promoter) was enhanced. Neutralizing TGFß antagonized the catagen-promoting effects of P-cadherin silencing. In summary, we introduce human HFs as an attractive preclinical model for studying the functions of P-cadherin in human epithelial biology and pathology. This model demonstrates that cadherins can be successfully knocked down in an intact human organ in vitro, and shows that P-cadherin is needed for anagen maintenance by regulating canonical Wnt signaling and suppressing TGFß2.

Nicolaides-Baraitser syndrome: two new cases with autism spectrum disorder.

Nicolaides-Baraitser syndrome is a rare clinical condition characterized by mental retardation with impairment of expressive language, short stature, microcephaly, sparse hair, typical facial dysmorphisms, and interphalangeal joint swellings. To date 24 cases have been reported, most of them being sporadic. The genetic background of Nicolaides-Baraitser syndrome is unclear in terms of cause and mode of inheritance, one of the more probable explanations is de novo mutation of a dominant gene. Some reported patients presented autistic features, although in none of these patients was the diagnosis of autism spectrum disorder formally made. We describe two unrelated patients with clinical features suggesting Nicolaides-Baraitser syndrome and, in addition, autism spectrum disorder is defined by the presence of the three cardinal core features: qualitative impairments in social, communicative, and behavioral development.