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.

Lethal multiple pterygium syndrome, large cystic hygroma, and cleft palate: Rare and severe fetal presentations of RYR1- and NEB-related congenital myopathies.

Congenital myopathies are a genetically heterogeneous group of neuromuscular disorders that commonly present with congenital hypotonia and weakness but can also present broadly. The most severe presentation is neonatal with arthrogryposis and, rarely, fetal akinesia and pterygia, features also seen in lethal multiple pterygium syndrome (LMPS). We describe two fetuses with similar phenotype, including hydrops fetalis, large cystic hygromas, bilateral talipes, and fetal akinesia in the second trimester. Genetic diagnoses were made using exome sequencing. Both fetuses had a severe form of congenital myopathy. In the first fetus, we identified two novel compound heterozygous likely pathogenic variants consistent with autosomal recessive RYR1-related congenital myopathy (congenital myopathy 1B). In the second fetus, we identified two likely pathogenic variants, one of which is novel, likely in trans consistent with a diagnosis of autosomal recessive NEB-related congenital myopathy. Reaching a genetic diagnosis for these fetuses allowed the families to receive accurate genetic counseling for future pregnancies. These fetuses highlight the genetic and phenotypic heterogeneity of LMPS, and support a broad approach to genetic testing.

Topical trametinib for epidermal and sebaceous nevi in a child with Schimmelpenning-Feuerstein-Mims syndrome.

We present the case of a 20-month-old girl with Schimmelpenning-Feuerstein-Mims (SFM) syndrome with extensive head, neck, and torso skin involvement successfully managed with topical trametinib. Trametinib interferes downstream of KRAS and HRAS in the MAPK signaling pathway, of which KRAS was implicated in our child's pathogenic variant. Although other dermatologic conditions have shown benefit from oral trametinib, its topical use has not been well reported. Our patient showed benefit from the use of twice-daily topical trametinib, applied to the epidermal and sebaceous nevi over a 16-month period, leading to decreased pruritus and thinning of the plaques.

The Plethora of Microbes with Anti-Inflammatory Activities.

Inflammation, which has important functions in human defense systems and in maintaining the dynamic homeostasis of the body, has become a major risk factor for the progression of many chronic diseases. Although the applied medical products alleviate the general status, they still exert adverse effects in the long term. For this reason, the solution should be sought in more harmless and affordable agents. Microorganisms offer a wide range of active substances with anti-inflammatory properties. They confer important advantages such as their renewable and inexhaustible nature. This review aims to provide the most recent updates on microorganisms of different types and genera, being carriers of anti-inflammatory activity.

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.

An Eye into the Aorta: The Role of Extracellular Matrix Regulatory Genes ZNF469 and PRDM5, from Their Previous Association with Brittle Cornea Syndrome to Their Novel Association with Aortic and Arterial Aneurysmal Diseases.

The extracellular matrix is a complex network of proteins and other molecules that are essential for the support, integrity, and structure of cells and tissues within the human body. The genes ZNF469 and PRDM5 each produce extracellular-matrix-related proteins that, when mutated, have been shown to result in the development of brittle cornea syndrome. This dysfunction results from aberrant protein function resulting in extracellular matrix disruption. Our group recently identified and published the first known associations between variants in these genes and aortic/arterial aneurysms and dissection diseases. This paper delineates the proposed effects of mutated ZNF469 and PRDM5 on various essential extracellular matrix components, including various collagens, TGF-B, clusterin, thrombospondin, and HAPLN-1, and reviews our recent reports associating single-nucleotide variants to these genes' development of aneurysmal and dissection diseases.

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.

A review of the gastrointestinal, olfactory, and skin abnormalities in patients with Parkinson's disease.

Parkinson's disease (PD) is a complex neurodegenerative motor disorder caused by the loss of dopaminergic neurons in the substantia nigra pars compacta. The substantia nigra is neither the first nor the only brain region affected by PD. Recent and old studies have shown that PD does not only affect the CNS; in fact, autonomic innervation in the GIT, skin, and olfactory system was found to be affected by α-synuclein pathology outside the CNS, affecting patients' quality of life. In the gastrointestinal system, dysphagia, constipation, and bacterial overgrowth in the small intestine are common in patients with PD. In addition, several skin conditions were reported in PD, including seborrheic dermatitis, rosacea, melanoma, and others. Finally, olfactory system dysfunction, such as reduced touch sensation and smell, was associated with motor abnormalities. Further high-quality studies are needed to develop reliable tests that could help in the early diagnosis of PD.