Molecular Diagnosis of Rare Autosomal Recessive Escobar Syndrome in a Consanguineous Pakistani Family.

Background: Escobar syndrome, a nonlethal variant of multiple pterygium syndromes (MPS), is a rare autosomal recessive disorder characterized by pterygia and multiple joint contractures along with other anomalies. Variants in cholinergic receptor nicotinic gamma subunit (CHRNG) have been previously reported in patients with Escobar syndrome. Objective: We studied a consanguineous Pakistani family affected with Escobar syndrome to identify the underlying genetic defect through short tandem repeat (STR) genotyping and direct DNA sequencing. Results: Genotyping with microsatellite markers (D2S427, D2S2344, and D2S206) revealed linkage of the disease phenotype in the family to the CHRNG locus. Using Sanger sequencing, we identified a homozygous nonsense CHRNG variant c.136C>T (p.R46*), predicted to produce a truncated protein that leads to acetylcholine receptor deficiency, causing MPS. The unaffected parents and siblings in the family were heterozygous carriers of this disease-causing variant. Conclusion: We report the identification of a nonsense CHRNG variant in a consanguineous Pakistani family affected with Escobar syndrome.

Ultrasound biomicroscopy image patterns in normal upper eyelid and congenital ptosis in the Indian population.

PURPOSE: To study the features of upper eyelid in healthy individual and different types of congenital ptosis in the Indian population using ultrasound biomicroscopy (UBM). METHODS: This was a prospective observational study at a tertiary care center. Eyelid structure of healthy individuals with no eyelid abnormalities (n = 19); simple congenital ptosis (n = 33) cases; Marcus Gunn jaw-winking ptosis (MGJWP, n = 7) cases, and blepharophimosis-ptosis-epicanthus inversus syndrome (BPES, n = 20) cases were studied on a vertical UBM scan using 50-MHz probe. Lid-thickness, tarsal-thickness, orbicularis oculi and levator-Muller-orbital septum-conjunctival (LMSC) complex were measured in primary gaze. Comparison was made between four groups and results were statistically analyzed using ANOVA test. In normal individuals, LMSC measurements were repeated in down-gaze imaging. RESULTS: Skin with subcutaneous tissue, LMSC complex and pre-aponeurotic fat-pad appeared echodense while orbicularis oculi and tarsus appeared echolucent. In primary gaze, mean thickness (± standard deviation) of the eyelid, tarsus, orbicularis oculi and LMSC, respectively, were: 1.612 ± 0.205, 0.907 ± 0.098, 0.336 ± 0.083, and 0.785 ± 0.135 mm in normal individual. LMSC showed 46.64% increase in thickness on down-gaze. The mean eyelid thickness and LMSC were thicker in MGJWP and BPES as compared to normal. In different types of congenital ptosis cases, various patterns of UBM imaging were observed. CONCLUSION: UBM allows noninvasive imaging of eyelid structures with good anatomical correspondence in normal eyelids and study the structural alterations of eyelids in different types of congenital ptosis. UBM can be used to highlight the anatomical difference in normal eyelids that may help modify the surgery for better cosmetic outcomes. Furthermore, it has the potential to be used in preoperative evaluation and operative planning in certain types of acquired ptosis, which needs to be evaluated.

Cosmetic Comparison Between the Modified Uchida Method and the Mustarde Method for Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome.

PURPOSE: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare, congenital, surgically challenging disease. We undertook an objective, functional, and cosmetic comparison between the modified Uchida procedure and the Mustarde procedure on Asian patients with BPES. DESIGN: This is a retrospective, comparative, interventional case series with the description of 2 surgical techniques. PARTICIPANTS: Twenty consecutive Japanese patients with BPES were studied. METHODS: The patients were assigned to either the modified Uchida or the Mustarde procedure on the basis of preoperative intercanthal distance (ICD) ratio (ICD/palpebral fissure width). Intercanthal distance and margin reflex distance were measured from photographs before and after surgery. Classifications were made according to epicanthal fold score and cosmetic score using a visual analog scale (VAS). MAIN OUTCOME MEASURES: The main outcome measures were postoperative improvement in ICD ratio and the VAS. RESULTS: Of the 20 patients, 5 underwent the modified Uchida procedure and the other 15 underwent the Mustarde procedure. The preoperative median ICD ratio was 2.0 (range, 1.9-2.5) and 2.5 (range, 2.0-3.4) for the modified Uchida and Mustarde procedures, respectively, and decreased to 1.5 (range, 1.5-1.7) and 1.6 (range, 1.5-1.8) postoperatively. The mean ICD reduction rate was 35.7% (SD, 1.0%) in the Mustarde group and 22.1% (SD, 1.3%) in the modified Uchida group (P < 0.001).The mean VAS for the modified Uchida and Mustarde procedures was 5.9 (SD, 1.3) and 2.8 (SD, 1.1), respectively, which was statistically significant (P = 0.0166). CONCLUSIONS: Both the modified Uchida and Mustarde procedures could effectively shorten the ICD; however, cosmetic results were significantly superior using the modified Uchida method.

Blepharophimosis, ptosis, epicanthus inversus syndrome with translocation and deletion at chromosome 3q23 in a black African female.

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disorder whose main features are the abnormal shape, position and alignment of the eyelids. Type I refers to BPES with female infertility from premature ovarian failure while type II is limited to the ocular features. A causative gene, FOXL2, has been localized to 3q23. We report a black female who carried a de novo chromosomal translocation and 3.13 Mb deletion at 3q23, 1.2 Mb 5' to FOXL2. This suggests the presence of distant cis regulatory elements at the extended FOXL2 locus. In spite of 21 protein coding genes in the 3.13 Mb deleted segment, the patient had no other malformation and a strictly normal psychomotor development at age 2.5 years. Our observation confirms panethnicity of BPES and adds to the knowledge of the complex cis regulation of human FOXL2 gene expression.

A new method of medial epicanthoplasty for patients with blepharophimosis-ptosis-epicanthus inversus syndrome.

PURPOSE: To describe a medial epicanthoplasty technique using the skin redraping method and review the surgical outcome in patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). DESIGN: Retrospective, noncomparative, interventional case series with the description of a new surgical technique. PARTICIPANTS: Sixteen consecutive Asian patients with BPES. METHODS: The charts of patients with BPES who underwent medial epicanthoplasty using the skin redraping method were reviewed retrospectively. Preoperative and postoperative inner intercanthal distance (IICD), interpupillary distance (IPD), horizontal palpebral fissure length (HPFL), and visibility of the scar were measured. The ratio of the IICD to IPD (IICD ratio) was calculated. MAIN OUTCOME MEASURES: Postoperative improvement in IICD ratio and the visibility of the surgical scar. RESULTS: The preoperative median IICD ratio was 1.65 (range, 1.49-1.83) and decreased to 1.27 (range, 1.02-1.48) postoperatively. The median reduction in IICD ratio was 21.7% (range, 16.7%-38.2%) (P<0.001, Wilcoxon signed-rank test). Fourteen patients (87.5%) had no visible scarring or scarring only visible under close inspection. Two patients (12.5%) had a more apparent scar, but no patient had severe scarring that required revision. CONCLUSIONS: Medial epicanthoplasty using the skin redraping method is an effective technique in the treatment of epicanthus inversus and telecanthus in patients with BPES, with excellent cosmetic outcomes.

Acquired lower eyelid epiblepharon in thyroid-associated ophthalmopathy of Koreans.

PURPOSE: To investigate the prevalence and clinical features of acquired lower eyelid epiblepharon in Korean patients with thyroid-associated ophthalmopathy (TAO) and compare the pathogenic features of acquired and congenital epiblepharon. DESIGN: Retrospective, nonrandomized, comparative case series, cross-sectional study. PARTICIPANTS: A total of 494 Korean patients with TAO and 845 Korean patients with congenital lower eyelid epiblepharon. METHODS: The medical records were reviewed, and the presence, location, and extent of epiblepharon were identified. Clinical features of TAO (lower eyelid retraction, exophthalmos, and elevation limitation) were compared between patients with TAO with and without epiblepharon. Acquired epiblepharon was classified into 3 types according to the location and extent. The prevalence of epiblepharon types was determined and evaluated for associations with TAO clinical features. Comparisons were made between the prevalence of epiblepharon types in acquired and congenital epiblepharon. MAIN OUTCOME MEASURES: Prevalence, location, and extent of epiblepharon; association with clinical features of TAO; and difference from congenital epiblepharon. RESULTS: An acquired lower eyelid epiblepharon was found in 42 (8.5%) of 494 patients with TAO. The mean age of patients with TAO with epiblepharon (34.2±13.5 years) was significantly lower than that of patients with TAO without epiblepharon (46.5±14.1 years) (P = 0.000). Lower eyelid retraction (0.78±1.11 mm) was more severe in patients with TAO with epiblepharon than in patients without epiblepharon (0.30±0.73 mm) (P = 0.000). Lower eyelid retraction was more severe in diffuse-type acquired epiblepharon than in central-type epiblepharon (P = 0.012). Elevation limitation was more severe in central-type acquired epiblepharon than in medial-type epiblepharon (P = 0.001). The occurrence of central-type epiblepharon was higher in TAO-associated acquired epiblepharon (20 eyelids, 30.8%) than in congenital epiblepharon (27 eyelids, 1.9%, P = 0.000). CONCLUSIONS: Acquired lower eyelid epiblepharon is one of the clinical features of patients with TAO. The association between lower eyelid retraction and acquired epiblepharon may lead to a better understanding of the cause of acquired epiblepharon in patients with TAO.

Genetic analysis of the FOXL2 gene using quantitative real-time PCR in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome.

PURPOSE: The purpose of this study was to identify the mutation(s) or deletion(s) of the forkhead box protein L2 (FOXL2) gene in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). METHODS: Genomic DNA extracted from peripheral blood was collected from two Chinese families and from one sporadic case. PCR direct sequencing and quantitative real-time PCR-based copy number screening for the whole exon of FOXL2 were performed. RESULTS: Direct sequencing revealed an indel mutation c.50C→TA in the sporadic case which resulted in a frameshift generating 78 novel amino acids and terminating prematurely at codon 95. Deletions in the FOXL2 gene were confirmed by quantitative real-time PCR (q-real-time PCR) in two families in which intragenic mutations were excluded by direct sequencing. These changes containing deletions and a de novo mutation were not detected either in the non-carrier relatives or in 100 normal controls. CONCLUSIONS: This study identified two deletions and a de novo mutation in the FOXL2 gene in Chinese BPES patients. This is the first study to report FOXL2 gene deletions detected by q-real-time PCR in this ethnic group. This technique enriches the diagnostic methods of molecular genetics in BPES patients. The de novo mutation expands the mutation spectrum of FOXL2.

Complex case study: nursing care of an infant with restrictive dermopathy.

This article is a complex case study of an infant, born at 33 2/7 weeks' gestation, with restrictive dermopathy, who died at 5 weeks of age. The review of perinatal and postnatal courses, as well as the rare disorder of restrictive dermopathy, a lethal genodermatosis laminopathy, is presented. Neonatal problems are identified. These include problems of prematurity, including need for a neutral thermal environment, nutritional support, and sepsis evaluation. Problems related to the diagnosis of restrictive dermopathy include skin abnormalities of mild hydropic appearance and ichthyosis-like exanthem, thrombocytophilia, pain, and respiratory insufficiency that led to death. The specific social issues of a non-English-speaking family from Russia faced with a lethal diagnosis for their infant are discussed. This infant was born in a community hospital with a perinatal center and tertiary-level neonatal intensive care unit and was transferred at 3 weeks of age to a regional pediatric medical center for subspecialist pulmonary, dermatologic, and genetic evaluation, where she died shortly afterward. Finally, recommendations are made for a nursing care plan related to the problems presented in this case.

Ethnic differences in congenital malformations in the Netherlands: analyses of a 5-year birth cohort.

Congenital malformations are among the major causes of perinatal mortality and morbidity at present. Research into the ethnic diversity of congenital malformations can form a basis both for aetiological studies and for health care advice and planning. This study compared the overall prevalence of congenital malformations, the prevalence in different organ systems and of several specific malformations between different maternal ethnic groups in the Netherlands using a 5-year national birth cohort (1996-2000) containing 881 800 births. Maternal ethnic groups considered were Dutch; Mediterranean (Moroccan/Turkish); other European; Black; Hindu and Asian. Mediterranean women had a 20% higher risk of having a child with a congenital malformation than Dutch women (age-adjusted OR = 1.21 [95% CI 1.16, 1.27]). They showed an increased risk of malformations in several organ systems such as the central nervous system and sensory organs, the urogenital system and skin and abdominal wall. Further, they had an increased risk of the group of chromosomal malformations/multiple malformations/syndromes. For the specific group of multiple malformations the maternal age adjusted OR was 1.80 [95% CI 1.47, 2.20]. The Black group showed a significantly increased risk of skeletal and muscular malformations (age adjusted OR = 1.76 [95% CI 1.53, 2.02]) with a sixfold increased risk of polydactyly compared with the Dutch group. For Mediterranean women, the largest and fastest growing group of immigrants in the Netherlands, this study demonstrated an increased risk of congenital malformations.