Shifting the landscape: Dominant C-terminal rare missense FOXL2 variants in non-syndromic primary ovarian failure etiology.

Pathogenic germline variants in the FOXL2 gene are associated with Blepharophimosis, Ptosis, and Epicanthus Inversus syndrome (BPES) in humans, an autosomal dominant condition. Two forms of BPES have emerged: (i) type I (BPES-I), characterized by ocular signs and primary ovarian failure (POI), and (ii) type II (BPES-II) with no systemic associations. This study aimed to compare the distribution of FOXL2 variants in idiopathic POI/DOR (diminished ovarian reserve) and both types of BPES, and to determine the involvement of FOXL2 in non-syndromic forms of POI/DOR. We studied the whole coding region of the FOXL2 gene using next-generation sequencing in 1282 patients with non-syndromic POI/DOR. Each identified FOXL2 variant was compared to its frequency in the general population, considering ethnicity. Screening of the entire coding region of the FOXL2 gene allowed us to identify 10 different variants, including nine missense variants. Of the patients with POI/DOR, 14 (1%) carried a FOXL2 variant. Significantly, six out of nine missense variants (67%) were overrepresented in our POI/DOR cohort compared to the general or specific ethnic subgroups. Our findings strongly suggest that five rare missense variants, mainly located in the C-terminal region of FOXL2 are high-risk factors for non-syndromic POI/DOR, though FOXL2 gene implication accounts for approximately 0.54% of non-syndromic POI/DOR cases. These results support the implementation of routine genetic screening for patients with POI/DOR in clinical settings.

Qualitative and quantitative analysis of MED12 c.887G>A causing both missense and splicing variants in X-linked Ohdo syndrome.

The phenotypes associated with MED12 pathogenic variants are diverse. Male patients usually have missense variants, but the effects of base substitutions on mRNA splicing have not been investigated. Here, we report a Japanese brother with intellectual disability, characteristic facial appearance with blepharophimosis, cleft palate, Fallot tetralogy, vesicoureteral reflux, and deafness. A known missense pathogenic variant was detected in MED12, NM_005120.3:c.887G>A p.(Arg296Gln), and X-linked Ohdo syndrome was diagnosed in combination with their phenotype. mRNA splicing of MED12 was evaluated qualitatively and quantitatively using long-range PCR-based targeted RNA sequencing (reverse transcribed long amplicon sequencing), and it was shown that this missense variant simultaneously causes aberrant splicing of the 42-bp in-frame deletion in exon 7, r.847_888del, which accounts for approximately 30% of the mRNAs in both siblings. The X chromosome inactivation study showed that the X chromosome carrying the mutant allele was 100% inactivated in the carrier mothers. mRNA level analysis is essential for the accurate interpretation of the effects of variants. In this case, the MED12 protein function may be reduced by more than just an amino acid substitution, resulting in the patients with the most severe phenotype of MED12-related syndrome in males.

The First Korean Case with Cardiac, Facial, and Digital Anomalies with Developmental Delay Caused by De Novo TRAF7 p.Arg655Gln Variant.

TRAF7-related disorders represent some of the rarest inherited disorders, exhibiting clinical features that overlap with cardiac, facial, and digital anomalies with developmental delay (CAFDADD) syndrome, as well as blepharophimosis-mental retardation syndrome (BMRS). A 36-year-old male, presenting with total blindness, blepharophimosis, and intellectual disability, was admitted for the assessment of resting dyspnea several months previously. He had a history of being diagnosed with obstructive sleep apnea (OSA). Transesophageal and transthoracic echocardiography unveiled right ventricular dilatation without significant pulmonary hypertension, bicuspid aortic valve with aortic root aneurysm, and aortic regurgitation in the proband. Sanger sequencing identified a de novo TRAF7 variant (c.1964G>A; p.Arg655Gln). Subsequently, aortic root replacement using the Bentall procedure was performed. However, despite the surgery, he continued to experience dyspnea. Upon re-evaluating OSA with polysomnography, it was discovered that continuous positive airway pressure support alleviated his symptoms. The underlying cause of his symptoms was attributed to OSA, likely exacerbated by the vertebral anomaly and short neck associated with CAFDADD syndrome. Clinicians should be attentive to the symptoms associated with OSA as it is a potentially serious medical condition in patients with TRAF7 variants.

Outcomes for expanded polytetrafluoroethylene strip in frontalis suspension surgery.

PURPOSE: This study evaluates surgical outcomes and complication rates of frontalis suspension with expanded polytetrafluoroethylene (ePTFE). METHODS: This retrospective cohort study reviewed all patients undergoing frontalis suspension surgery using ePTFE as the sling material from January 1 2012 to March 3 2020 by a single surgeon at a single academic center. Two different surgical techniques were evaluated in the placement of the sling material. Demographic, clinical, and operative data were extracted. Outcome data including postoperative lid height, reoperation, and complication rate were extracted for the cohort and compared between the two surgical techniques. Descriptive statistics were utilized. RESULTS: Sixty-four eyes from 49 unique patients were included in this study. Forty-three (67.2%) patients had isolated congenital blepharoptosis; 14 (21.9%) had blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES); and 2 (3.1%) had cranial nerve III palsy. Fifty-one (79.7%) patients had no prior blepharoptosis surgery. Lid crease incision and stab incision techniques were utilized for 24 (37.5%) and 40 (62.5%) eyes, respectively. Overall, 21 (32.8%) eyes required reoperation with ePTFE to achieve appropriate eyelid height or contour. Only one patient experienced implant infection, requiring removal of ePTFE sling after a second reoperation. There were no cases of implant exposure or granuloma formation noted during the study period. CONCLUSION: An ePTFE strip soaked in cefazolin prior to utilization in surgery is a viable material for frontalis suspension surgery, with a lower infectious or inflammatory complication rate than previously reported. However, reoperation rate was still relatively high.

De novo KAT6B mutation causes Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome in an Iranian boy: a case report.

BACKGROUND: Say-Barber-Biesecker-Young-Simpson (SBBYS) (OMIM #603736, Ohdo syndrome variant) is a rare type of severe blepharophimosis intellectual disability syndrome, which is generally characterized by a global developmental delay, distinctive facial features, and intellectual disability with multiple congenital anomalies, including skeletal involvement, missing, or underdeveloped kneecaps, and genital anomalies, in affected males. It has been shown that mutations in the KAT6B gene, which is a lysine acetyltransferase-encoding gene, have been associated with SBBYS syndrome. All the known variants are dominant de novo mutations that result in protein truncation. CASE PRESENTATION: A 14-year-old Iranian Azeri boy with an intellectual disability, distinct dysmorphic facial features such as open-mouth expression, sparse medial eyebrows, widely spaced upward-slanted eyes, epicanthal folds, broad nasal bridge, low-set ears, anteverted ears, short philtrum, hypertelorism, microphthalmia is presented in this case study. Cryptorchidism was reported. Neurologically, the patient presented with poor eye contact, hypotonia, and speech difficulties. In the skeletal X-ray, underdeveloped kneecaps with some new features were observed. CONCLUSION: We present the first case of SBBYS syndrome in association with some new anomaly features in the Iranian population. Based on this diagnosis, we could provide the patient with a suitable plan of management as well as appropriate genetic counseling for his family.

Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice.

Mutations in genes encoding chromatin modifiers are enriched among mutations causing intellectual disability. The continuing development of the brain postnatally, coupled with the inherent reversibility of chromatin modifications, may afford an opportunity for therapeutic intervention following a genetic diagnosis. Development of treatments requires an understanding of protein function and models of the disease. Here, we provide a mouse model of Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736) and demonstrate proof-of-principle efficacy of postnatal treatment. SBBYSS results from heterozygous mutations in the KAT6B (MYST4/MORF/QFK) gene and is characterized by intellectual disability and autism-like behaviors. Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice (Kat6b+/-), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation. Kat6b+/- mice displayed learning, memory, and social deficits, mirroring SBBYSS individuals. Treatment with a histone deacetylase inhibitor, valproic acid, or an acetyl donor, acetyl-carnitine (ALCAR), elevated histone acetylation levels in the human cells with SBBYSS mutations and in brain and blood cells of Kat6b+/- mice and partially reversed gene expression changes in Kat6b+/- cortical neurons. Both compounds improved sociability in Kat6b+/- mice, and ALCAR treatment restored learning and memory. These data suggest that a subset of SBBYSS individuals may benefit from postnatal therapeutic interventions.

Tratamento cirúrgico da ptose palpebral moderada e grave: análise de resultados / Surgical treatment of moderate and severe ptosis: analysis of results

Introdução: A ptose palpebral é uma afecção comum na prática clínica na qual uma perfeita avaliação torna-se mandatória. Definimos ptose quando a margem palpebral encontra-se abaixo de 2 mm da junção córneo escleral e pode ser classificada em leve, moderada e grave. Existem inúmeras técnicas de reparo e a escolha dependerá da classificação da função do músculo levantador. Métodos: Foram analisados de forma prospectiva, no período de março de 2013 a maio de 2015, quatorze (n = 14) pacientes submetidos ao tratamento cirúrgico de ptose palpebral moderada e grave (n = 21). Inúmeros fatores foram estudados, tais como grau de ptose e função do músculo elevador da pálpebra, tipo de técnica de reparo, complicações imediatas e tardias, etc. Resultados: Quatorze pacientes foram opera-dos, totalizando 21 pálpebras, sendo que, 85% foram de etiologia adquirida e 15% congênita. Com relação ao grau de ptose, 64,3% (n = 9) foram moderadas e 35,7% (n = 5) graves. No que tange à função do músculo levantador, encontramos função boa 28,5% (n = 4), moderada 28,5% (n = 4) e pobre 43% (n = 6). Em relação às com-plicações, 2 casos de hiperemia conjutival e um caso de edema. Obtivemos um alto índice de satisfação com 85,7% (n = 12), com baixas taxas de complicações. Conclusão: A ptose palpebral é uma enfermidade comum na prática clínica e exige por parte do cirurgião um perfeito conhecimento anatômico da delicada estrutura palpebral e também de sua fisiopatologia. Uma perfeita avaliação desse paciente torna-se mandatória para o emprego do tratamento mais adequado.

Introduction: Eyelid ptosis is a common condition in clinical practice for which a complete evaluation is mandatory. Ptosis is defined when the eyelid margin is 2 mm below the corneoscleral junction and can be classified as mild, moderate, and severe. There are numerous repair techniques, and the choice will depend on the classification of the function of the levator muscle. Methods: We evaluated prospectively, from March 2013 to May 2015, 14 patients who underwent surgical treatment of moderate and severe ptosis (n = 21). Several factors were studied, such as degree of ptosis and function of the eyelid levator muscle, type of repair technique, and immediate and late complications. Results: Fourteen patients (21 eyelids) underwent operation. The etiology was acquired in 85% of the cases and congenital in 15%. With respect to the degree of ptosis, 64.3% (n = 9) of the cases were moderate and 35.7% (n = 5) were severe. With respect to the muscle function of the levator, good, moderate, and poor functions were observed in 28.5% (n = 4), 28.5% (n = 4), and 43% (n = 6) of the cases, respectively. With regard to complications, 2 cases of conjunctival hyperemia and one case of edema were observed. We obtained a high satisfaction rate of 85.7% (n = 12), with low complication rates. Conclusion: Eyelid ptosis is a common presentation in clinical practice and requires on the part of the surgeon a detailed anatomical knowledge of the delicate structure of the eyelid and its pathophysiology. A complete evaluation of these patients is mandatory for the employment of the most appropriate treatment.

Accidental lacrimal gland removal during resection of the levator palpebrae superioris muscle / Remoção acidental da glândula lacrimal em cirurgia de ressecção do músculo levantador da pálpebra superior

ABSTRACT Accidental removal of the lacrimal gland is a rare complication of ptosis surgery. We report two children who underwent large unilateral levator palpebrae superioris resections (LPSr). After surgery, both patients developed dry eye. Post-operatively, the parents of both patients noticed no tears in the affected eye when their child cried. Computed tomography proved the absence of the lacrimal gland in the operated eye in both patients. Oculoplastic surgeons should pay close attention to the anatomy of the levator muscle and its proximity to surrounding tissues in order to avoid lesions on important orbital structures, including the lacrimal gland, and to avoid the development of long-term dry eye.

RESUMO A remoção acidental da glândula lacrimal é uma complicação rara da cirurgia de ptose. Relatamos duas crianças que foram submetidas à grandes ressecções unilaterais do músculo levantador da pálpebra superior que desenvolveram olho seco após a cirurgia. No pós-operatório, os pais notaram ausência de secreção lacrimal durante o choro no olho operado. Tomografia computadorizada de órbitas comprovou ausência da glândula lacrimal no olho submetido à cirurgia, em ambos os casos. Cirurgiões oculoplásticos devem estar atentos à anatomia do músculo levantador e estruturas relacionadas para evitar lesões em importantes estruturas orbitais como as da glândula lacrimal que podem induzir permanente olho seco.

Tratamento cirúrgico da blefaroptose congênita / Surgical treatment of congenital blepharoptosis

A blefaroptose é o posicionamento inadequado da pálpebra superior, estando abaixo de sua posição normal na posição primária do olhar, a qual seria 0,5 – 2mm abaixo do limbo superior. Pode causar bloqueio parcial ou completo do campo visual superior, além do comprometimento estético. As causas são categorizadas em congênitas ou adquiridas. É considerada congênita se presente ao nascimento ou diagnosticada no primeiro ano de vida. As principais técnicas utilizadas para o tratamento da ptose congênita são a ressecção da aponeurose do músculo levantador da pálpebra superior (MLPS) e a suspensão frontal. A medida da função do MLPS é o parâmetro mais importante na escolha da técnica cirúrgica. Quando a função é fraca, a suspensão frontal é mais indicada; a ressecção supramáxima do MLPS também pode ser empregada. Acima de 4 ou 5mm de função do MLPS, prefere-se a ressecção da aponeurose. Para a cirurgia de suspensão frontal, vários são os materiais utilizados, portanto apresentamos uma comparação entre os estudos mais relevantes. Discutiremos também particularidades em casos mais complicados, como as Síndromes da Blefarofimose e de Marcus-Gunn, além de técnicas cirúrgicas menos utilizadas e as complicações relatadas.

The blepharoptosis is the improper positioning of the upper eyelid, being below its normal position in primary gaze, which is 0.5 - 2mm below the superior corneal limbus. It may block partially or completely the upper visual field, and lead to aesthetic commitment. The causes are categorized as congenital or acquired. It is considered congenital if present at birth or diagnosed during the first year of life. The main techniques used for the treatment of congenital ptosis are the resection of the levator muscle aponeurosis and the frontalis suspension. The function of the levator muscle is the most important parameter to define the surgical technique. When the function is weak, the frontalis suspension is more appropriate; the supra-maximal resection of the levator muscle may also be employed. With function above 4 or 5mm, the resection of the aponeurosis is preferred. For the frontalis suspension surgery, various materials can be used, so we present a comparison of the most relevant studies. We also discuss some characteristics in more complicated cases, such as the Blepharophimosis syndrome and the Marcus-Gunn syndrome, and surgical techniques less performed and complications reported.

Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) and cleft lip and palate. Report of two Brazilian families

Os autores descrevem uma menina e um menino com a síndrome de blefarofimose, ptose e epicanto inverso (BPES). A menina apresentou fissura de palato e o menino mostrou fissura de lábio e palato como sinais clínicos adicionais. Ambos mostraram recorrência familial em quatro e três geraçöes, respectivamente. Outros membros de ambas as famílias apresentaram também blefarofimose, ptose e epicanto inverso, mas sem envolvimento de lábio e palato. Näo existem sinais clínicos adicionais nem infertilidade nestes pacientes. De acordo com o nosso conhecimento, este é o primeiro relato de fissura de lábio e palato registrada como sinal adicional na síndrome BPES.

Estudos moleculares em anomalias craniofaciais raras: sindrome blefaroqueilodontica e efeitos de linha media facial com hipertelorismo / Molecular biological studies in rare craniofacial anomalies

A Síndrome Blefaroqueilodôntica (BCD) e os Defeitos de Linha Média Facial com Hipertelorismo (DLMFH) são defeitos craniofaciais raros. Por esse motivo, os estudos de grandes casuísticas têm sido limitados. Contribuição científica significativa neste assunto tem sido dada por nosso grupo, que delineou características clínicas e diretrizes para seguimento de longo prazo e evidenciou achados neuroradiológicos em ambas as anomalias. Embasado nesses achados preliminares e evidências recentes da literatura pertinente, foi possível estabelecer uma estratégia inicial para investigação etiológica da BCD e dos DLMFH, sendo os objetivos desse projeto: investigar a etiologia da BCD nos indivíduos afetados pela síndrome, por meio de estudo dos genes candidatos IRF6, P63, OSR2, TBX10, FOXE1, SHH, FGF8 e PAX3; pesquisar, nos indivíduos com DLMFH, a presença de mutações nos genes candidatos SHH, FGF8 e PAX3; identificar, em ambas as malformações, possíveis alterações cromossômicas; e, por último, associar os achados clínicos detectados nas investigações anteriores aos possíveis achados moleculares. Foram utilizadas técnicas de sequenciamento direto, array-CGH, genotipagem automática e hibridação in situ por fluorescência. Não foi possível relacionar nenhuma mutação pontual nos genes estudados associadas às malformações em questão, pois não foram encontradas alterações gênicas patogênicas. Entretanto foram detectadas em pacientes com DLFMH três aberrações cromossômicas em regiões distintas do genoma, tratando-se de um caso de duplicação no cromossomo...

The Blepharocheilodontic Syndrome (BCD) and Midline Facial Defects with Ocular Hypertelorism (MFDH) are rare craniofacial anomalies. Considering the rarity of these two groups of congenital defects, studies with large casuistry have been limited. Our group has significantly contributed to the scientific knowledge about both anomalies, delineating clinical characteristics, evidencing neurological findings and designing protocols for long term follow-up. Based in these preliminary findings and recent evidences of pertinent literature, it was possible to determine an initial etiologic investigation strategy for the BCD and the MFDH. The objectives of this project are to investigate the etiology of the BCD in affected individuals through IRF6, P63, OSR2, TBX10, FOXE1, SHH, FGF8 and PAX3 candidate genes study; to search MFDH patients for mutations in the SHH, FGF8 and PAX3 candidate genes; to identify, in both syndromes...

Síndrome da Blefarofimose: relato de caso / Blepharofimosis syndrome: case report

Este trabalho apresenta um caso clínico da Síndrome da Blefarofimose, em uma criança de cinco anos de idade com retardo mental moderado. Trata-se de uma síndrome na qual ocorre diminuição da fenda palpebral, tanto no sentido horizontal quanto no sentido vertical, devido a uma parada do desenvolvimento embrionário em torno do terceiro mês de vida intra-uterina. É caracterizada por uma tríade semiológica composta pela associação de ptose palpebral, epicanto inverso e telecanto, formando uma verdadeira síndrome clínica. O trabalho clínico realizado consistiu em manejo do comportamento, educação preventiva para a mãe, tratamento restaurador e ortodôntico através da expansão rápida da maxila visando, principalmente, a melhora da função respiratória

Ptose palpebral: estudo de 390 casos / Blepharoptosis: study of 390 cases

Foram examinados 390 pacientes com queixa de queda da pálpebra superior no setor de Plástica Ocular da Universidade de Säo Paulo - Escola Paulista de Medicina, no período de janeiro 1985 a fevereiro 1995. Encontrou-se 68,9 por cento de ptose congênita, 22,8 por cento de ptose adquirida e 8,2 por cento de pseudoptose. Com relaçäo ao sexo, 54,8 por cento eram do sexo masculino e 45,1 por cento do sexo feminino. O estudo dos pacientes com ptose congênita mostrou: ambliopia em 5,9 por cento; fenômeno de Marcus Gunn em 5,3 por cento e síndrome de blefarofimose em 6,3 por cento. Alteraçäo na motilidade ocular extrínseca estava presente em 30 por cento dos casos de ptose congênita e 29 por ceneto de ptose adquirida. A alteraçäo palpebral mais comum foi o epicanto inverso. Os autores analisam as alteraçöes oculares e palpebrais associadas ao quadro de ptose palpebral

Caracterización clínica y citogenética del síndrome de blefarofimosis familiar entre familias del departamento de Antioquia / Clinical and cytogenetic characterization of the familiar blepharophimosis syndrome between families from Antioquia, Colombia

El syndrome denominado blefarofimosis familiar (SBF) comprende varias anomalías asociadas entre las cuales se destacan: blefarofimosis, blefaroptosis, epicanto inverso y telecanto. Se hereda en forma autonómica dominante con una penetrancia completa. Se han informado numerosos casos en la literatura y en varios de ellos se identifican alteraciones cromosómicas (deleciones y translocaciones) que comprometen el brazo largo del cromosoma 3, bandas 3q22-q23. El objetivo del presente estudio es la caracterización clínica y citogenética con alta resolución, de varios miembros afectados en tres familias antioqueñas. Veintisiete presentaban las manifestaciones del SBF; el análisis citogenético en 9 de ellos, mediante bandeo R de alta resolución no reveló alteraciones numéricas ni estructurales de los cromosomas. Se discuten aspectos clínicos, embriológicos, genéticos, citogenéticas relacionados con el síndrome

Blefarofimose: uma síndrome clínica de tratamento cirúrgico / Blepharophimosis: a clinical syndrome with a surgical management

A blefarofimose é uma deformidade congênita caracterizada pela diminuiçäo da fenda palpebral nos diâmetros horizontal e vertical, sem a participaçäo da borda palpebral. Caracteriza-se por uma tríade clássica constituída de epicanto, telecanto e ptose palpebral, além do caráter hereditário. Os autores apresentam sete pacientes, todos submetidos à correçäo cirúrgica pela técnica de Mustardé para epicanto e telecanto. A ptose foi corrigida pela ressecçäo ou plicatura do músculo levantador da pálpebra ou suspensäo frontal por fascia lata. Foram realizados tempos cirúrgicos únicos ou em 2 tempos, sendo em dois tempos o mais acertado, com resultados satisfatórios