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Purpose: Congenital distichiasis is managed either by ablation, using laser, cryotherapy, or electroepilation, or by surgical excision with mucous membrane grafting. Ablative procedures are usually blind as the exact depth of distichiatic eyelashes is unknown. The described surgical technique utilizes meibography for imaging the root and depth of distichiatic eyelashes that aided in performing electroepilation., Methods: Six patients (n = 24 eyelids; mean age 15.5 ± 12.2 years) underwent infrared meibography (Oculus Keratograph 5 M) and noninvasive tear breakup time prospectively. Eyelashes were electroepilated using a premarked needle inserted at a depth based on meibography findings in 4 patients. Surgical success was defined as no distichiatic eyelash regrowth and functional success was defined as the resolution of symptoms at a minimum of 3 months of follow-up., Results: All 6 patients had all 4 eyelids involved to varying degrees, with a total of 230 distichiatic eyelashes. The median number of distichiatic eyelashes was 9 in the upper eyelids and 4.5 in the lower eyelids. Meibography revealed visible distichiatic eyelash roots in 70% of eyelashes in the upper eyelid and 87.8% in the lower eyelid, respectively. The median eyelash root depth was 2.7 mm (mean 2.9 mm, range 1.8-5.4 mm). The mean noninvasive tear breakup time was 12.2 seconds despite absent or rudimentary meibomian gland segments seen on meibography. The anatomical success was 75% (12/16 eyelids), and functional success was 87.5% (7/8 eyes) at a median follow-up of 5.5 months., Conclusion: Preoperative infrared meibography in eyelids with congenital distichiasis helps estimate the eyelash depth and can be used to guide eyelash ablation procedures., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2024 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Lymphedema-dissociated syndrome (LDS), of which the pathogenesis is not fully understood, afflicts many patients. In this study, we investigated the effect of FOXC2 gene loss-of-function on the development of LDS disease. Two Han Chinese families with LDS were recruited in this study, pathogenic mutations were identified by Sanger sequencing. Reverse-transcription PCR, subcellular localization, dual fluorescein enzymes, and other in vitro experiments were used to study the functional effects of eight FOXC2 mutations. Two pathogenic FOXC2 duplication mutations (c.930_936dup and c.931-937dup) were identified in the two families. Both mutations caused uneven distribution in the nucleus and a chromatin contraction phenotype, weakening the DNA binding activity and transcription activity. We then performed functional analysis on six additional mutations in different domains of FOXC2 that were reported to cause LDS. We found mutations located in the forkhead domain and central region dramatically reduced the transactivation ability, while mutations in activation domain-2 enhanced this ability. All 8 mutations down-regulated the transcription of ANGPT2 and affected the activity of the ERK-RAS pathway, which may cause abnormal formation of lymphatic vessels. Our findings also showed that all 8 mutations decreased the ability of interaction between FOXC2 and the Wnt4 promoter, suggesting mutations in FOXC2 may also affect the Wnt4-Frizzled-RYK signaling pathway, leading the abnormal differentiation of the meibomian glands into hair follicle cells during the embryonic period and causing distichiasis. This study expanded and revealed the potential pathogenesis mechanism., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022. Published by Elsevier Ltd.)

Interstitial deletions of 16q24.1-q24.2 are associated with alveolar capillary dysplasia, congenital renal malformations, neurodevelopmental disorders, and congenital abnormalities. Lymphedema-Distichiasis syndrome (LDS; OMIM # 153400) is a dominant condition caused by heterozygous pathogenic variants in FOXC2. Usually, lymphedema and distichiasis occur in puberty or later on, and affected individuals typically achieve normal developmental milestones. Here, we describe a boy with congenital lymphedema, distichiasis, bilateral hydronephrosis, and global developmental delay, with a de novo microdeletion of 894 kb at 16q24.1-q24.2. This report extends the phenotype of both 16q24.1-q24.2 microdeletion syndrome and of LDS. Interestingly, the deletion involves only the 3'-UTR part of FOXC2., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Distichiasis, an extra row of eyelashes emerging from meibomian gland orifices, occurs due to the metaplastic transition of sebaceous glands into the pilosebaceous unit. It can present congenitally, such as in lymphedema distichiasis syndrome, or secondary to acquired conditions, such as cicatrizing conjunctivitis, trachoma. This review summarizes the etiology of distichiasis, its presentation, the evolution of various surgical techniques, and their outcomes in human and animal eyes. The published literature has focused on the different treatment modalities and their outcomes; the etiopathogenesis of this condition remains elusive. Truncating mutations (missense, frameshift, and nonsense) in the Forkhead family gene FOXC2 are involved in the distichiasis-lymphedema syndrome. The treatment options are no different for congenital versus acquired distichiasis, with no specific available algorithms. Acquired distichiasis in cicatrizing ocular surface diseases is difficult to manage, and existing treatment options offer success rates of 50%-60%. The outcomes of electroepilation or direct cryotherapy are not as good as surgical excision of distichiatic lashes after splitting the anterior and posterior lamella under direct visualization. The marginal tarsectomy with or without free tarsoconjunctival graft has shown good results in eyes with congenital and acquired distichiasis. The details of differences between normal and distichiatic lash, depth, or course of distichiatic eyelashes remain largely unknown. Studies exploring the distichiatic eyelash depth might improve the outcomes of blind procedures such as cryotherapy or radiofrequency-assisted epilation., Competing Interests: None

Background: We studied a young woman with atypical diabetes associated with mild intellectual disability, lymphedema distichiasis syndrome (LDS) and polymalformative syndrome including distichiasis. We used different genetic tools to identify causative pathogenic mutations and/or copy number variations., Results: Although proband's, diabetes mellitus occurred during childhood, type 1 diabetes was unlikely due to the absence of detectable autoimmunity. DNA microarray analysis first identified a de novo, heterozygous deletion at the chr16q24.2 locus. Previously, thirty-three pathogenic or likely pathogenic deletions encompassing this locus have been reported in patients presenting with intellectual deficiency, obesity and/or lymphedema but not with diabetes. Of note, the deletion encompassed two topological association domains, whose one included FOXC2 that is known to be linked with LDS. Via whole-exome sequencing, we found a heterozygous, likely pathogenic variant in WFS1 (encoding wolframin endoplasmic reticulum [ER] transmembrane glycoprotein) which was inherited from her father who also had diabetes. WFS1 is known to be involved in monogenic diabetes. We also found a likely pathogenic variant in USP9X (encoding ubiquitin specific peptidase 9 X-linked) that is involved in X-linked intellectual disability, which was inherited from her mother who had dyscalculia and dyspraxia., Conclusions: Our comprehensive genetic analysis suggested that the peculiar phenotypes of our patient were possibly due to the combination of multiple genetic causes including chr16q24.2 deletion, and two likely pathogenic variants in WFS1 and USP9X., (© 2022. The Author(s).)

FREM2 is a member of the FREM2-FRAS1-FREM1 protein complex which contributes to epithelial-mesenchymal coupling. We report a Thai woman with cryptophthalmos, dental anomalies, and oral vestibule defect. A compound heterozygous mutation (c.6499C>T; p.Arg2167Trp and c.641_642del; p.Glu214GlyfsTer135) in the FREM2 gene was identified. The frameshift variant p.Glu214GlyfsTer135 is de novo and novel. It is predicted to result in the loss of most of the functional domains. The p.Arg2167Trp mutation was predicted to disrupt both Ca 2+ binding and conformational change. The Arg2167Trp mutant protein has been shown to cause partial loss of function, decrease its interaction with FREM1 and result in impaired function of the FRAS1-FREM2-FREM1 complex. Frem2 was shown to be expressed in the developing tooth and vestibular lamina. It is hypothesized that these mutations resulted in aberration of the FRAS1-FREM2-FREM1 protein complex, resulting in loss of nephronectin, basement membrane disruption, and abnormal epithelial-mesenchymal interactions leading to dental and oral vestibule malformations., (© 2021. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Forkhead-box C2 (FOXC2) is a transcription factor involved in lymphatic system development. FOXC2 mutations cause Lymphedema-distichiasis syndrome (LD). Recently, a natural antisense was identified, called lncRNA FOXC2-AS1, which increases FOXC2 mRNA stability. No studies have evaluated FOXC2 and FOXC2-AS1 blood expression in LD and healthy subjects. Here, we show that FOXC2 and FOXC-AS1 expression levels were similar in both controls and patients, and a significantly higher amount of both RNAs was observed in females. A positive correlation between FOXC2 and FOXC2-AS1 expression was found in both controls and patients, excluding those with frameshift mutations. In these patients, the FOXC2-AS1/ FOXC2 ratio was about 1:1, while it was higher in controls and patients carrying other types of mutations. The overexpression or silencing of FOXC2-AS1 determined a significant increase or reduction in FOXC2 wild-type and frameshift mutant proteins, respectively. Moreover, confocal and bioinformatic analysis revealed that these variations caused the formation of nuclear proteins aggregates also involving DNA. In conclusion, patients with frameshift mutations presented lower values of the FOXC2-AS1/ FOXC2 ratio, due to a decrease in FOXC2-AS1 expression. The imbalance between FOXC2 mRNA and its lncRNA could represent a molecular mechanism to reduce the amount of FOXC2 misfolded proteins, protecting cells from damage.

Lymphedema distichiasis syndrome (LDS) is a rare autosomal dominant condition characterized by lower limb lymphedema, distichiasis, and variable additional features. LDS is usually caused by heterozygous sequence variants in the FOXC2 gene located at 16q24, but in one previous instance LDS has resulted from a balanced reciprocal translocation with a breakpoint at 16q24, 120 kb distal to the FOXC2 gene suggesting a position effect. Here, we describe a second family with LDS caused by a translocation involving 16q24. The family were ascertained after detection of a paternally inherited balanced reciprocal translocation t(16;22)(q24;q13.1) in a pregnancy complicated by severe fetal hydrops. There was a past history of multiple miscarriages in the father's family, and a personal and family history of lymphedema and distichiasis, consistent with the diagnosis of LDS. Using whole genome amplified DNA from single sperm of the male proband, bead array analysis demonstrated that the FOXC2 gene was intact and the chromosome 16 breakpoint mapped to the same region 120Kb distal to the FOXC2 gene. This case highlights the clinical consequences that can arise from a translocation of genomic material without dosage imbalance, and that it is increasingly feasible to predict and characterize possible effects with improved access to molecular techniques., (© 2020 Wiley Periodicals LLC.)

Objective: To identify the genetic causes of a family with lymphedema-distichiasis syndrome (LDS)., Methods: The whole exome sequencing was performed in a aborted fetus as the proband, and a candidate gene was identified. Peripheral blood of 8 family members were collected. Genotypic-phenotypic analysis were carried out through PCR amplification and Sanger sequencing., Results: The proband, and the mother, grandmother, uncle, granduncle of the proband all had distichiasis or varix of lower limb carried a FOXC2 :c.595dupC frame shift mutation, and other subjects without any significant phenotypes did not present the mutation., Conclusions: The FOXC2 :c.595dupC frame shift mutation is the genetic cause of this family, which can lead to autosomal dominantly LDS, presenting nuchal translucency thickening and hydrops fetal during pregnancy, and the prognosis is usually good.

FOXC2 is a member of the human forkhead-box gene family and encodes a regulatory transcription factor. Mutations in FOXC2 have been associated with lymphedema distichiasis (LD), an autosomal dominant disorder that primarily affects the limbs. Most patients also show extra eyelashes, a condition known as distichiasis. We previously reported genetic and clinical findings in six unrelated families with LD. Half the patients showed missense mutations, two carried frameshift mutations and a stop mutation was identified in a last patient. Here we analyzed the subcellular localization and transactivation activity of the mutant proteins, showing that all but one (p.Y109*) localized to the nucleus. A significant reduction of transactivation activity was observed in four mutants (p.L80F, p.H199Pfs*264, p.I213Tfs*18, p.Y109*) compared with wild type FOXC2 protein, while only a partial loss of function was associated with p.V228M. The mutant p.I213V showed a very slight increase of transactivation activity. Finally, immunofluorescence analysis revealed that some mutants were sequestered into nuclear aggregates and caused a reduction of cell viability. This study offers new insights into the effect of FOXC2 mutations on protein function and shows the involvement of aberrant aggregation of FOXC2 proteins in cell death.

Purpose: To evaluate the clinical outcome, possible complications, and recurrence rate of distichiasis in dogs treated with partial tarsal plate excision (PTPE) technique using a transconjunctival approach., Methods: Retrospective study including 17 client-owned canine patients affected with distichiasis and presenting with associated clinical signs (ie, blepharospasm, epiphora, chronic keratoconjunctivitis, or corneal ulceration) that underwent surgical removal of the aberrant lashes using a PTPE technique between January 2018 and February 2019. Data collected included breed, age, sex, affected eyelid(s), number of distichia, and tear film breakup time (TBUT). Resected cilia-bearing tarsoconjunctival strips were submitted for histopathological analysis., Results: Thirty eyes (52 eyelids) from 17 dogs were included in the study. The median age was 688 days (range 118-4243 days). A successful outcome, defined as complete resolution of clinical signs attributable to the distichia, occurred in all eyes after a single procedure, with a mean follow-up time of 239 days (range 69-480 days). Appearance of new distichia occurred in 14/30 eyes (46.3%), and of these, three eyes needed a new PTPE procedure. Recurrence of the distichia only occurred in one eye (3.3%) which was asymptomatic. Following surgery, TBUT decreased below the normal value in 7/24 eyes (29.1%) although none developed clinical signs of qualitative tear film deficiency. Post-operative complications included trichiasis and cicatricial entropion, which developed in two eyes (6.6%), and these were successfully managed with corrective eyelid surgery., Conclusions: Partial tarsal plate excision, using a transconjunctival approach, had an excellent clinical outcome with a low incidence of complications., (© 2020 American College of Veterinary Ophthalmologists.)

Objective: To analyze FOXC2 gene variant in a family affected with lymphodema-distichiasis syndrome (LDS)., Methods: Peripheral blood samples were collected for the extraction of DNA and protein. Whole-exome sequencing was carried out to detect variants in the proband. Suspected variant was validated by Sanger sequencing. Western blotting was used to detect changes in protein expression., Results: The proband and his mother were both found to carry a heterozygous nonsense variant c.177C>G (p.Tyr59X) of the FOXC2 gene, which was previously unreported. Down-regulated expression of FOXC2 was detected by Western blotting. Prenatal ultrasonography of the fetus indicated increased nuchal thickness. Amniocentesis was performed at 21+1 weeks of pregnancy, genetic testing suggested that the fetus also carried the c.177C>G variant., Conclusion: The patients' condition may be attributed to the heterozygous nonsense variant c.177C>G of the FOXC2 gene, which resulted in a significant decrease in FOXC2 expression. Increased nuchal thickness may also be related with decreased FOXC2 expression. Above finding has expanded the variant spectrum of the FOXC2 gene.

Objective: We sought to evaluate the performance of exome sequencing (ES) in determining an underlying genetic etiology for cases of fetal pleural effusions., Study Design: We examined a prospective cohort series of fetal pleural effusions visualized sonographically between 1 April 2016 and 31 August 2017. Fetal pleural effusions attributed to twin sharing, anemia, or structural anomalies were excluded, as were all cases with a genetic diagnosis established by karyotype or chromosomal microarray analysis. The remaining cases with pleural effusions of unclear etiology were offered ES. ES was performed by clinical sequencing and/or sequencing under the Baylor-Hopkins Center for Mendelian Genomics' (BHCMG) research platform. All cases were evaluated for novel genes or phenotypic expansion of disease-causing genes., Results: ES was performed on six probands affected by pleural effusions. A pathogenic variant was identified in one case (16.7%). Four additional cases had variants of uncertain significance (VUS) in candidate genes of pathological interest. Neither clinical nor candidate genes were evident in the final case., Conclusion: ES should be considered in the evaluation of prenatally detected idiopathic pleural effusions when other diagnostic workup for a genetic etiology has failed., (© 2020 John Wiley & Sons, Ltd.)

Competing Interests: None

Background: Primary lymphedema is genetically heterogeneous. Two of the most common forms of primary lymphedema are Milroy disease (MD) and lymphedema-distichiasis syndrome (LDS). This study aims to look further into the pathogenesis of the two conditions by analyzing the lymphoscintigram images from affected individuals to ascertain if it is a useful diagnostic tool. Methods and Results: The lymphoscintigrams of patients with MD and LDS were analyzed, comparing the images and transport parameters of the two genotypes against a control population. Lymphoscintigrams were available for 12 MD and 16 LDS patients (all genetically proven diagnoses). Eight of the 12 (67%) lymph scans performed on patients with MD demonstrated little or no uptake from the initial lymphatics and poor visualization of the inguinal lymph nodes. These changes were consistent with a "functional aplasia," that is, the lymphatic vessels were present but appeared to be ineffective in absorbing the interstitial fluid into the lymphatic system. In patients with LDS the lymphoscintigraphic appearances were different. In 12 of the 16 scans (75%), the lymph scans were highly suggestive of lymphatic collector reflux. Quantification revealed a significantly reduced uptake of tracer within the inguinal lymph nodes and a higher residual activity in the feet at 2 hours in MD compared with LDS and compared with controls. Conclusion: Lymphoscintigraphic imaging and quantification can be characteristic in specific genetic forms of primary lymphedema and may be useful as an additional tool for in-depth phenotyping, leading to a more accurate diagnosis and providing insight into the underlying mechanism of disease.

Lymphedema-distichiasis syndrome (LDS) is an autosomal dominant condition associated with FOXC2 mutations. Patients with distichiasis are mostly symptomatic, and efforts to deal with their ocular complaints comprise of electrolysis, cryotherapy and a variety of surgical techniques. We describe an enhanced surgical technique for a case of symptomatic distichiasis of the right eye with scarred, irregular eyelid margins secondary to initial cryotherapy, whereby the distorted tarsus was excised to remove the aberrant hair follicles, the levator palpebrae superioris was released to extend the upper lid and prevent lagophthalmos and a mucous membrane graft was used to cover the exposed portion of the tarsal plate. At 14 months follow up, the lid cosmesis and position remained satisfactory, with no infection or rejection of the mucous membrane graft. Therefore, this surgical technique provides a sound option for symptomatic distichiasis, where cryotherapy can cause lid irregularity and keratinization.

Trichomegaly is a known adverse effect of systemic administration of cyclosporine but is less commonly associated with systemic tacrolimus or with topical calcineruin inhibitors. In this report, we describe the first case, to our knowledge, of trichomegaly due to long-term use of topical tacrolimus for periocular vitiligo., (© 2019 Wiley Periodicals, Inc.)

Background: Congenital epiblepharon with epicanthus (CEE) is a common eyelid malposition in Asian children, which generally involves the lower eyelid. The induced cilial entropion may cause constant ocular irritation that requires surgical repair. The purpose of this study is to report the outcomes and surgical details of a novel procedure, lower eyelid tension balance reconstruction (LETBR), for the correction of CEE., Methods: Patients diagnosed with CEE underwent LETBR, which consists of modified half Z epicanthoplasty, and fixation between marginal orbicularis oculi muscle and lower eyelid retractor was reviewed retrospectively. The outcomes were classified as 'good' with no cilia-ocular surface contact, 'fair' with 5 or fewer asymptomatic cilia-ocular surface points of contact and 'poor' with most of the eyelashes remaining in contact with the eyeball. The surgical outcomes (good, fair or poor), recurrence and complications were evaluated., Results: One hundred and forty-nine eyelids of 78 patients (43 females and 35 males; mean age 6.6 ± 2.4 years, range 4-17 years) were evaluated in this study. The mean follow-up time was 14 months (range 9-24 months). At the last follow-up time, 144 of 149 eyelids were judged as 'good' (96.6%), the other 5 eyelids were judged as 'fair' (3.4%) and no eyelid was assessed with a 'poor' outcome. There were no significant complications or complaints about scarring on eyelids from patients or their parents., Conclusion: LETBR is effective, safe and stable for patients with CEE., (Copyright © 2018 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Purpose: To describe a new modified technique of direct tarsal excision for treatment of distichiasis., Methods: Retrospective review of consecutive patients who underwent direct tarsal excision without grafting to treat distichiasis between December 2007 and November 2015. Gender, number of eyelids treated, follow-up time, and surgical outcome were recorded. The technique involved dividing the anterior and posterior lamella and excising a two mm tarsoconjunctival strip including the abnormal lash follicles, without suturing or mucosal graft., Results: Seventeen eyelids of 12 patients (Fourteen upper eyelids and 3 lower eyelids) were studied. Sixteen eyelids had acquired distichiasis and one eyelid had congenital distichiasis. Mean age was 64.8 (SD 22.0; range, 25-86 years) Mean postoperative follow-up time was 53 months (SD = 31, range 8 - 104 months). During this period, no recurrence was documented. There were no complications., Conclusions: Direct tarsal excision without a graft is a safe, quick, and effective method for the treatment of distichiasis.

Lymphoedema-distichiasis is an inherited autosomal dominant disorder of the lymphatic system. Rarely, it is associated with fetal hydrops; the risk and severity of which increases with successive generations. The causative gene is a member of the forkhead transcription factor family ( FOXC2 ). We describe a fetus presenting with early-onset, rapidly progressing body wall oedema, bilateral pleural effusions and a pericardial effusion in a mother with known FOXC2 mutation. First trimester chorionic villus sampling confirmed FOXC2 mutation in the fetus when there was only a large nuchal translucency. As the phenotype progressed, the couple consented to in utero ultrasound-guided insertion of sequential bilateral pleuro-amniotic chest drains (at 23 weeks) which successfully drained the pleural effusions. The fetus was delivered at 39 weeks gestation by elective caesarean section in good condition. The shunts were removed postnatally, and the baby was discharged after 7 days. This is the first case described of a fetus with severe early-onset fetal hydrops secondary to FOXC2 mutation successfully treated by the prenatal insertion of bilateral pleuro-amniotic shunts., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Eyelash trichomegaly (ET) is increased length (≥ 12 mm), curling, pigmentation, or thickness of eyelashes. Among acquired causes, allergic diseases and atopic dermatitis (AD) have been found to be associated with eyelash trichomegaly especially in children; however, to date, this claim has not been studied in detail. To compare the eyelash lengths of AD and ichthyosis vulgaris (IV) patients with those of age- and sex-matched patients with unrelated skin disorders, we measured (with a digital Vernier caliper) and compared the eyelash lengths of AD (n = 58) and IV (n = 31) patients to those of age- and sex-matched patients with unrelated skin disorders (n = 178). The eyelashes of the AD and male IV patients were found to be significantly longer than those of the controls (p < 0.05). The severity of atopic dermatitis, i.e., SCORAD of > 50, hyperlinearity of palms and soles, and high IgE levels significantly correlated with the long eyelashes. The limitations of study are single-center study and filaggrin gene mutation in patients of IV could not be studied., Conclusion: Thus, long eyelashes may act as surrogate marker of severe AD and serve as a cutaneous marker of IV patients. What is Known: • Among acquired causes, allergic diseases and atopic dermatitis have been found to be associated with eyelash trichomegaly especially in children. What is New: • The severity of atopic dermatitis, i.e., SCORAD of > 50, hyperlinearity of palms and soles, and high IgE levels significantly correlate with the long eyelashes; thus, long eyelashes may act as surrogate marker of severe atopic dermatitis. • It may also serve as a cutaneous marker of ichthyosis vulgaris especially in male patients and patients with palmoplantar hyperlinearity.

Background: Spinal extradural arachnoid cyst (SEDAC) is a cystic lesion that protrudes into the epidural space from a small dural defect. Early diagnosis of SEDAC is important because its expansion causes neurological damage. Two types of SEDAC, syndromic and sporadic, are present. Syndromic SEDAC is inherited as a part of lymphedema-distichiasis syndrome caused by mutations in the FOXC2 gene; however, it is often mistaken as sporadic because of low penetrance. It is not reasonable to conduct a genetic testing for all SEDAC patients and their family members. The aim of this study is to establish an effective screening method to distinguish syndromic SEDAC from sporadic SEDAC., Methods: We performed a retrospective review of medical records and imaging studies of 29 subjects who were diagnosed with SEDAC. Clinical features, family history and magnetic resonance imaging (MRI) were analyzed. Mutations in FOXC2 were examined by Sanger-sequencing of the entire coding region of the genes. SEDAC having a mutation in FOXC2 gene was defined with syndromic SEDAC., Results: Eleven subjects had a heterozygous mutation in FOXC2. They were all familial and hence syndromic SEDAC. Only one proband had known family history of SEDAC at diagnosis. MRI findings and physical examinations, especially eye and leg examinations, were quite useful to screen syndromic SEDAC. Physical examination often showed accompanying lymphedema and distichiasis in syndromic SEDAC. Syndromic SEDAC tended to have multiple cysts out of the thoracolumbar area., Conclusions: We established an effective screening method based on physical examinations and MRI findings., (Copyright © 2018 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

A 4 year-old-boy was referred for distichiasis of the upper and lower lids of both eyes that had been present since at least 1 year of age. The patient's family history was notable for distichiasis and lymphedema affecting numerous family members. The patient was found to have a novel heterozygous variant (c.741&#95;742insGG) in the FOXC2 gene. Mutations in the FOXC2 gene are associated with lymphedema-distichiasis syndrome. An important feature of lymphedema-distichiasis syndrome is that distichiasis is typically present prior to the onset of lymphedema.

Purpose: To describe a new technique to treat congenital distichiasis., Methods: Case series of three distichiatic patients undergoing a novel surgical technique combining splitting of the lid margin with the distichiatic lashes, marginal tarsectomy in the affected area, and tarsoconjunctival graft obtained from the upper region of the tarsus. The graft was sutured at the exposed region of the marginal tarsectomy., Results: Good cosmesis was obtained in all cases and the lids margins healed completely with good surgical outcome and no lashes contacted the cornea postoperatively., Conclusions: The split lamellae with a composite tarsoconjunctival graft results in satisfactory functional and cosmetic outcomes. The upper tarsal region represents an ideal donor site.

Distichiasis is a challenging condition that may require multiple surgical interventions. Besides ophthalmologic concerns in children, distichiasis may be part of the lymphedema-distichiasis syndrome, which presents with lymphedema of variable time of onset. Other significant systemic disorders such as coarctation of the aorta and varicose veins have been reported in association with this syndrome and must be reviewed for proper patient care. The authors report the case of a 22-year-old male patient who had been treated for distichiasis and followed for 16 years. At his initial evaluation, at 6 years of age, he presented solely with ocular complaints due to distichiasis. Only after 13 years of repeated ophthalmic treatments and continuous follow up, lymphedema was observed. Lymphedema-distichiasis syndrome diagnosis must be considered in children with distichiasis, even in the absence of lymphedema.

Lymphedema distichiasis syndrome (LDS) is a rare, autosomal dominant genetic condition, characterized by lower limb lymphedema and distichiasis. Other associated features that have been reported include varicose veins, cleft palate, congenital heart defects, and ptosis. We update a previously reported family with a pathogenic variant in FOXC2 (c.412-413insT) where five affected individuals from the youngest generation had congenital renal anomalies detected on prenatal ultrasound scan. These included four fetuses with hydronephrosis and one with bilateral renal agenesis. A further child with LDS had prominence of the left renal pelvis on postnatal renal ultrasound. We also describe a second family in whom the proband and his affected son had congenital renal anomalies; left ectopic kidney, right duplex kidney, and bilateral duplex collecting systems with partial duplex kidney with mild degree of malrotation, respectively. Foxc2 is expressed in the developing kidney and therefore congenital renal anomalies may well be associated, potentially as a low penetrance feature. We propose that all individuals diagnosed with LDS should have a baseline renal ultrasound scan at diagnosis. It would also be important to consider the possibility of renal anomalies during prenatal ultrasound of at risk pregnancies, and that the presence of hydronephrosis may be an indication that the baby is affected with LDS., (© 2017 Wiley Periodicals, Inc.)

A 25-year-old woman presented with a history of a cosmetically bothersome bulge over her left eyelid. She was diagnosed with cilium incarnatum externum. The subcutaneous cilium was surgically removed and examined.

Background: The WHO definition of trachomatous trichiasis (TT) is "at least one eyelash touching the globe, or evidence of recent epilation of in-turned eyelashes", reflecting the fact that epilation is used as a self-management tool for TT. In Fiji's Western Division, a high TT prevalence (8.7% in those aged ≥15 years) was reported in a 2012 survey, yet a 2013 survey found no TT and Fijian ophthalmologists rarely see TT cases. Local anecdote suggests that eyelash epilation is a common behaviour, even in the absence of trichiasis. Epilators may have been identified as TT cases in previous surveys., Methods: We used a preliminary focus group to design an interview questionnaire, and subsequently conducted a population-based prevalence survey to estimate the prevalence of epilation in the absence of trichiasis, and factors associated with this behaviour, in the Western Division of Fiji., Results: We sampled 695 individuals aged ≥15 years from a total of 457 households in 23 villages. 125 participants (18%) reported epilating their eyelashes at least once within the past year. Photographs were obtained of the eyes of 121/125 (97%) individuals who epilated, and subsequent analysis by an experienced trachoma grader found no cases of trachomatous conjunctival scarring or trichiasis. The age- and sex- adjusted prevalence of epilation in those aged ≥15 years was 8.6% (95% CI 5.7-11.3%). iTaukei ethnicity, female gender, and a higher frequency of drinking kava root were independently associated with epilation., Conclusion: Epilation occurs in this population in the absence of trichiasis, with sufficient frequency to have markedly inflated previous estimates of local TT prevalence. Individuals with epilated eyelashes should be confirmed as having epilated in-turned eyelashes in an eye with scarring of the conjunctiva before being counted as cases of TT., Competing Interests: The authors have declared that no competing interests exist.

Mutations in the Fms-related tyrosine kinase 4 (FLT4) and forkhead box protein C2 (FOXC2) genes cause Milroy disease (MD) and lymphedema-distichiasis syndrome (LDS), respectively, but the mechanism underlying disease pathology remains unclear. Applying whole-exome sequencing to two families with MD, one LDS family, and one sporadic LDS case, we identified four rare variants in the laminin subunit alpha-5 gene (LAMA5) in subjects carrying novel and known missense FLT4 mutations and a 7-bp duplication and 1-bp insertion in FOXC2. Phenotyping was expanded in some individuals using magnetic resonance lymphangiography, indiocyanine green fluorescence lymphography, and immunofluorescent lymphatic staining of skin tissue. Skin lymphatic staining showed the existence of dermal lymphatic vasculature in the MD case. Significant lymphatic dysfunction was observed in both MD and LDS patients. In the MD patient, tortuous lymphatics in the dorsum of the foot were slowly enhanced on indocyanine green fluorescent lymphography (ICG) imaging. Dilated lymph collectors with disruption and lymph leakage were observed in the familial LDS case on magnetic resonance lymphangiography (MRL). Numerous tortuous lymph collectors were visualized along the entire length of affected lower limbs on MRL imaging, and retrograde lymph flow was observed in the lymph collectors during ICG lymphography in the isolated LDS case. The finding of rare LAMA5 variants together with FLT4 and FOXC2 mutations suggests that these mutations may be co-responsible for these disorders and most likely interfere with the function of lymphatics. Further, larger studies are needed to confirm these results.

Nablus masklike facial syndrome (NMLFS), characterized by tight, expressionless facial features resembling a mask, was first described in 2000. Since then, 10 cases have been identified with the same phenotype and genotype. Although detailed descriptions of the facial and external ear characteristics unique to the syndrome exist, no clear description of the ocular anatomic findings and management of ocular complications has been detailed. We present a confirmed case of NMLFS with detailed descriptions of the ocular anatomy encountered in this patient and a discussion regarding the clinical significance of these findings., (Copyright © 2016 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Dominant mutations in the FOXC2 gene cause a form of lymphedema primarily of the limbs that usually develops at or after puberty. In 90-95% of patients, lymphedema is accompanied by distichiasis. FOXC2 is a member of the forkhead/winged-helix family of transcription factors and plays essential roles in different developmental pathways and physiological processes. We previously described six unrelated families with primary lymphedema-distichiasis in which patients showed different FOXC2 mutations located outside of the forkhead domain. Of those, four were missense mutations, one a frameshift mutation, and the last a stop mutation. To assess their pathogenic potential, we have now examined the subcellular localization and the transactivation activity of the mutated FOXC2 proteins. All six FOXC2 mutant proteins were able to localize into the nucleus; however, the frameshift truncated protein appeared to be sequestered into nuclear aggregates. A reduction in the ability to activate FOXC1/FOXC2 response elements was detected in 50% of mutations, while the remaining ones caused an increase of protein transactivation activity. Our data reveal that either a complete loss or a significant gain of FOXC2 function can cause a perturbation of lymphatic vessel formation leading to lymphedema.

Expanded human T cells from a Japanese male with lymphedema-distichiasis syndrome (LDS) were used to generate integration-free induced pluripotent stem cells (iPSCs) by exogenous expression of four reprogramming factors, OCT3/4, SOX2, cMYC, KLF4, using Sendai virus vector (SeVdp). The authenticity of established iPSC line, LDS-iPSC8, was confirmed by the expression of stem cell markers and the differentiation capability into three germ layers. LDS-iPSC8 may be a useful cell resource for the establishment of in vitro LDS modeling and the study for vascular and lymph vessel development., (Copyright © 2016 Roslin Cells Ltd. Published by Elsevier B.V. All rights reserved.)

Heterochromia of the hair involves the presence of two distinctive colors of scalp hair in one individual. We report the case of a 4-year-old girl with reddish streaks of scalp hair, heterochromia of the eyelashes, and cutaneous hypopigmentation following the lines of Blaschko., (© 2016 Wiley Periodicals, Inc.)

The generation of human induced pluripotent stem cells (hiPSCs) derived from an autologous extraembryonic fetal source is an innovative personalized regenerative technology that can transform own-self cells into embryonic stem-like ones. These cells are regarded as a promising candidate for cell-based therapy, as well as an ideal target for disease modeling and drug discovery. Thus, hiPSCs enable researchers to undertake studies for treating diseases or for future applications of in utero therapy. We used a polycistronic lentiviral vector (hSTEMCCA-loxP) encoding OCT4, SOX2, KLF4, and cMYC genes and containing loxP sites, excisible by Cre recombinase, to reprogram patient-specific fetal cells derived from prenatal diagnosis for several genetic disorders, such as myotonic dystrophy type 1 (DM1), β-thalassemia (β-Thal), lymphedema-distichiasis syndrome (LDS), spinal muscular atrophy (SMA), cystic fibrosis (CF), as well as from wild-type (WT) fetal cells. Because cell types tested to create hiPSCs influence both the reprogramming process efficiency and the kinetics, we used chorionic villus (CV) and amniotic fluid (AF) cells, demonstrating how they represent an ideal cell resource for a more efficient generation of hiPSCs. The successful reprogramming of both CV and AF cells into hiPSCs was confirmed by specific morphological, molecular, and immunocytochemical markers and also by their teratogenic potential when inoculated in vivo. We further demonstrated the stability of reprogrammed cells over 10 and more passages and their capability to differentiate into the three embryonic germ layers, as well as into neural cells. These data suggest that hiPSCs-CV/AF can be considered a valid cellular model to accomplish pathogenesis studies and therapeutic applications.

We report a male patient with retinitis pigmentosa, growth failure, long eyelashes, and sparse hair, which are typical signs of Oliver-McFarlane syndrome. The patient was born to healthy parents and developed night blindness at 2 years of age. Retinitis pigmentosa was diagnosed when he was 5 years old. To date, only 11 cases of Oliver-McFarlane syndrome have been documented, with the present case being the 12th overall and the first in China. Thus, the existence of typical Oliver-McFarlane syndrome in Asians was verified.

From February to March 2014, six natural villages in Zhoucheng Town, Binchuan County of Yunan Province, were randomly selected by cluster sampling. Serum anti-fascioliasis IgG was detected by ELISA. The sero-positive individuals were further tested for Fasciola infection using sediment detection with nylon bag (260 meshes) and Kato-Katz method. Among 1207 sampled persons, the sero-positive rate was 3.0% (36/1207). The rate in males and females was 2.3% (12/530) and 3.6% (24/677) (u=1.46, P>0.05). The sero-positive rate in Zhoucheng Village and Baizhuang Village was 4.0% (24/616) and 2.0% (12/591), respectively (u=2.07, P<0.05). The positive rate of stool examination in serum-positive persons was 6.5% (2/31). One stool-egg-positive patients was the case in 2012 outbreak, and the eggs were stale. The other patient was newly infected, and further clinical diagnosis indicated that it was a case of chronic fascioliasis.

Lymphoedema-distichiasis syndrome (LDS) is a syndromic form of primary lymphoedema associated with double rows of eyelashes (distichiasis). Mutations in the FOXC2 gene were reported to be associated with this syndrome. In this study, we identified in a Chinese LDS pedigree a novel FOXC2 gene mutation, C.370C>T, leading to p.Leu124Phe. The novel mutation is not a common polymorphism, but is co-inherited with the disease., (© 2014 British Association of Dermatologists.)

A 4-year-old intact male ferret was presented to the Ophthalmology Service of the Department of Clinical Sciences of Companion Animals of Utrecht University with chronic blepharospasm, epiphora, and conjunctivitis of the right eye. Examination of the eye revealed mild conjunctivitis and three hairs protruding from the openings of meibomian glands in the upper eyelid, providing the clinical diagnosis of distichiasis. The distichia were removed by transconjunctival unipolar electrocautery. Recovery was uneventful, but the original signs recurred 10 weeks after surgery. Ophthalmic examination revealed another distichia at a different location in the same eyelid and it was removed by full-thickness wedge excision. Histopathological examination failed to reveal the exact origin of the distichia. To our knowledge, this is the first reported case of distichiasis in a ferret., (© 2013 American College of Veterinary Ophthalmologists.)

Reasons for Performing Study: Distichiasis is very uncommon in horses and treatment options and outcome remain unknown., Objectives: To describe treatment and long-term follow-up of distichiasis in the horse., Study Design: Retrospective clinical study., Methods: Case records of horses admitted for diagnosis and treatment of uni- or bilateral distichiasis between 2003 and 2012 were reviewed. Long-term (>6 months after last treatment) follow-up was by telephone conversation with the owner or referring veterinarian. Data were analysed using a Chi-squared test., Results: Eighteen cases were identified, of which 17 were Friesians. All horses had signs of corneal irritation or ulceration concurrent with distichiasis. In total, 29 eyes were affected with distichiasis of which 23 had clinical signs. All corneas were stained with fluorescein and 13 had fluorescein positive defects (45%). The lower eyelid was affected more often. Two different electrocautery devices were used for treatment. The complications were slight scarring of the eyelids (100%) and clinical recurrence (54%). Successful resolution of the clinical signs after one treatment occurred in 46% of the horses and in 77% of the horses satisfactory long-term results were found after a mean of 2 treatments (range: 1- 6 treatments). There was significant correlation between number of hairs and recurrence (P<0.002)., Conclusions: There is a breed predisposition of distichiasis in the Friesian horse. In Friesian horses that present with uni- or bilateral corneal irritation or corneal ulceration, careful examination of the eyelid margins should be performed to diagnose distichiasis. Electrocautery is a valid and successful therapeutic modality which is minimally invasive, inexpensive, has a low complication rate and is easy to perform in the standing sedated horse. The recurrence rate is low in horses with less than 5 distichiae., (© 2013 EVJ Ltd.)

Two questions arise when considering the treatment of varicose veins and the development of lymphedema: can the treatment cause lymphedema? Can it worsen it? Primary lymphedema is rarely associated with varicose veins except in the lymphedema-distichiasis syndrome. Data available in the literature is essentially based on surgical treatment. Stripping on a normal limb may induce chronic lymphedema in almost 0.1% of cases. The risk of lymphedema after stripping in patients with previous pelvic surgery including lymph node excision and/or radiotherapy remains unknown. In patients with lower limb lymphedema wearing strong elastic compression stockings, stripping provides little clinical improvement and can worsen volume. The main objective is also to avoid venous complications. Lymphatic lesions related to stripping can be evaluated by lymphography or lymphoscintigraphy. New techniques for treating varicose veins (sclerotherapy, endovenous laser treatment, radiofrequency ablation) seem to induce fewer lymphatic complications. Further studies are required to confirm these results. Indications for treatment should be unquestionable and patients must be alerted to the potential risk of lymphedema or its worsening., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Lymphedema associated with other developmental malformations (Milroy syndrome, Hennekam syndrome, Noonan syndrome, Gorham-Stout syndrome, yellow nail syndrome) are unfrequent disease, but explorations led to the identification of genetic mutations that have then been validated in mouse models. However, lymphatic vessels complexity and its proximity with the venous system suggest the need for further researches, especially in the comprehension of pulmonary symptoms., (Copyright © 2013. Published by Elsevier Masson SAS.)