Liebenberg syndrome is caused by a deletion upstream to the PITX1 gene resulting in transformation of the upper limbs to reflect lower limb characteristics

Background Structural variants (SVs) affecting non-coding cis -regulatory elements are a common cause of congenital limb malformation. Yet, the functional interpretation of these non-coding variants remains challenging. The human Liebenberg syndrome is characterised by a partial transformation of the arms into legs and has been shown to be caused by SVs at the PITX1 locus leading to its misregulation in the forelimb by its native enhancer element Pen. This study aims to elucidate the genetic cause of an unsolved family with a mild form of Liebenberg syndrome and investigate the role of promoters in long-range gene regulation. Methods Here, we identify SVs by whole genome sequencing (WGS) and use CRISPR-Cas9 genome editing in transgenic mice to assign pathogenicity to the SVs. Results In this study, we used WGS in a family with three mildly affected individuals with Liebenberg syndrome and identified the smallest deletion described so far including the first non-coding exon of H2AFY . To functionally characterise the variant, we re-engineered the 8.5 kb deletion using CRISPR-Cas9 technology in the mouse and showed that the promoter of the housekeeping gene H2afy insulates the Pen enhancer from Pitx1 in forelimbs; its loss leads to misexpression of Pitx1 by the pan-limb activity of the Pen enhancer causing Liebenberg syndrome. Conclusion Our data indicate that housekeeping promoters may titrate promiscuous enhancer activity to ensure normal morphogenesis. The deletion of the H2AFY promoter as a cause of Liebenberg syndrome highlights this new mutational mechanism and its role in congenital disease.

https://jmg.bmj.com/content/jmedgenet/early/2019/02/02/jmedgenet-2018-105793.full.pdf

H2AFY promoter deletion causes PITX1 endoactivation and Liebenberg syndrome

The Liebenberg syndrome was first described in 1973 in a five- generation family. A sixth generation was added in 2001, and in 2009 a hitherto unknown branch of the same family with similar anomalies extended the family tree significantly. This article describes the clinical findings and illustrates the abnormalities with radiographs and three-dimensional computed tomography scans. We discuss the genetic abnormality that causes Liebenberg syndrome, the genomic rearrangement at the PITX1 locus on chromosome 5.The structural variations seem to result in an ectopic expression of paired-like homeodomain transcription factor 1 (PITX1) in the forelimb causing a partial arm-to-leg transformation in these patients.

The Liebenberg syndrome: in depth analysis of the original family

A Chromosomal 5q31.1 Gain Involving PITX1 Causes Liebenberg Syndrome Deirdre Máire Seoighe, Veselina Gadancheva, Regina Regan, Jennifer McDaid, Clare Brenner, Sean Ennis, David Richard Betts, Patricia Anne Eadie, and Sally Ann Lynch* Department of Plastic Surgery, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland National Centre for Medical Genetics, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland School of Medicine & Health Science, UCD, Dublin 4, Ireland Department of Radiology, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland

A chromosomal 5q31.1 gain involving PITX1 causes Liebenberg syndrome

Carpal tunnel syndrome (CTS) leads to distortion of axonal architecture, demyelination and fibrosis within the median nerve. Diffusion tensor imaging (DTI) characterises tissue microstructure and generates reproducible proxy measures of nerve ‘health’ which are sensitive to myelination, axon diameter, fiber density and organisation. This meta-analysis summarises the normal DTI values of the median nerve, and how they change in CTS. This systematic review included studies reporting DTI of the median nerve at the level of the wrist in adults. The primary outcome was to determine the normal fractional anisotropy (FA) and mean diffusivity (MD) of the median nerve. Secondarily, we show how the FA and MD differ between asymptomatic adults and patients with CTS, and how these differences are independent of the acquisition methods. We included 32 studies of 2643 wrists, belonging to 1575 asymptomatic adults and 1068 patients with CTS. The normal FA was 0.58 (95% CI 0.56, 0.59) and the normal MD was 1.138 × 10–3 mm2/s (95% CI 1.101, 1.174). Patients with CTS had a significantly lower FA than controls (mean difference 0.12 [95% CI 0.09, 0.16]). Similarly, the median nerve of patients with CTS had a significantly higher mean diffusivity (mean difference 0.16 × 10–3 mm2/s [95% CI 0.05, 0.27]). The differences were independent of experimental factors. We provide summary estimates of the normal FA and MD of the median nerve in asymptomatic adults. Furthermore, we show that diffusion throughout the length of the median nerve becomes more isotropic in patients with CTS.

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Meta-analysis of the normal diffusion tensor imaging values of the median nerve and how they change in carpal tunnel syndrome

Purpose To study the efficacy of diffusion tensor imaging (DTI) in the diagnosis of carpal tunnel syndrome (CTS). Materials and Methods Twenty-three wrists of healthy subjects (age between 29 and 71 with mean of 44 years) and 47 wrists of CTS patients (age between 19 and 84 with mean of 46 years) were evaluated with DTI and electrophysiological studies (EPS). The DTI was performed on a 1.5T scanner. Fraction anisotropy (FA) and apparent diffusion coefficient (ADC) of the median nerve were calculated. Electrophysiological tests were also performed. Paired student’s t-test, ANOVA, Mann-Whitney, Wilcoxon, Post Hoc, Kruskal-Wallis, Chi-Square, Spearman’s Rho and Pearson statistical tests were used. Results There was a significant difference between healthy individuals and patients with CTS (P  Conclusion DTI can contribute to CTS diagnosis on the basis of FA and ADC measurements.

Role of diffusion tensor imaging in carpal tunnel syndrome: A case control comparative study to electrophysiological tests and clinical assessment

We report a case of Liebenberg syndrome in a 6-year-old girl, including the clinical, radiological, angiographic, and operative findings. We note that the forearm and hand malformations have similarities to leg and foot anatomy. Our observations may help provide insight into the etiology of this unusual condition.

Liebenberg syndrome: case report and insight into molecular basis

Background: Carpal Tunnel Syndrome (CTS) is the most common peripheral neuropathy of an upper extremity. The diagnosis of CTS is commonly based on findings from the medical history, physical examination, and provocative tests. To confirm the diagnosis, some clinician accepts Electrophys-iological Studies (EPS) as the reference standard. Diffusion-Tensor Imaging (DTI) is a subtype of diffusion-weighted imaging based on measurement of molecular diffusion along multiple directions in space. Directional anisotropy of water diffusibility can be quantified by imaging indices such as Apparent Diffusion Coefficient (ADC) and Fractional Anisot-ropy (FA) used to characterize the degree of diffusion anisot-ropy.Aim of Work: The aim of this study is to study the efficacy of diffusion tensor imaging in the diagnosis of carpal tunnel syndrome.Material and Methods: Twenty-three wrists of 15 healthy subjects and 47 wrists of 31 CTS patients were evaluated with DTI and EPS. FA and ADC of the median nerve were calculated at four locations: Distal radioulnar joint, pisiform bone, hamate bone and hamate hook, and also determined from the whole median nerve. Electrophysiological test, including nerve conduction velocity was also performed for comparison with clinical assessment as a standard of reference.Results: There was a significant difference between healthy individuals and patients with carpal tunnel syndrome (p<0.01 for both FA and ADC). FA value less than 0.54 and ADC value more than 1.19 X 1 0–3mm2/sec might be used in the diagnosis of carpal tunnel syndrome. As regards the DTI results, the sensitivity, specificity, negative predictive value, positive predictive value and accuracy were 97.8%, 95.6%, 95.6%, 97.8% and 97.1% respectively.Conclusion: DTI scan contribute to carpal tunnel syndrome diagnosis on the basis of FA and ADC measurements.

https://mjcu.journals.ekb.eg/article_55383_774f38a811e566fd4b9f95af21994987.pdf

Role of Diffusion Tensor Imaging of the Median Nerve in Carpal Tunnel Syndrome: A Case Control Comparative Study with Electrophysiological Tests and Clinical Assessment

Background: Carpal Tunnel Syndrome (CTS) is the most common peripheral neuropathy of an upper extremity. The diagnosis of CTS is commonly based on findings from the medical history, physical examination, provocative tests and Electrophysiological Studies (EPS) as the reference standard, but in some cases the results may be equivocal due to discrepancies in the different measured clinical parameters. Imaging has the potential to resolve these discrepancies. Fat-saturated, T2-weighted Magnetic Resonance Imaging (MRI) can reveal morphological changes in CTS patients, such as nerve enlargement, nerve flattening, increased nerve signal intensity, and bowing of the flexor retinaculum. Aim of Work: The aim of this study is to study the role of conventional MRI in the diagnosis of Carpal Tunnel Syndrome (CTS). Patients and Methods: Twenty-three wrists in 15 healthy subjects and 47 wrists in 31 CTS patients were evaluated with MRI and Electrophysiological Studies (EPS). The qualitative and quantitative analysis of MRI include: (1) The high signal intensity of the Median Nerve (MN) on the T2W and PD fat suppressed weighted images, (2) Flexor Retinaculum (FR) bowing and measurements of its height and area, (3) Flattening ratio of the MN, (4) MN CSA. EPS; including nerve conduction velocity was also performed for comparison with clinical assessment as a standard of reference. Results: There was a significant difference between healthy individuals and patients with CTS for all qualitative and quantitative MRI interpretation. This includes, the higher SI of the MN on both T2 and PD WIs, the greater FR bowing area and height, the higher flattening ratio of the MN at CT and the greater value of MN CSA. As regards the MRI results, the sensitivity, specificity, negative predictive value, positive predictive value and accuracy were 97.8%, 95.6%, 95.6%, 97.8% and 97.1% respectively. Correspondence to: Dr. Ahmad M. Wafaie, The Department of Radiology, Faculty of Medicine, Cairo University, Egypt Conclusion: MRI can contribute to carpal tunnel syndrome diagnosis on the basis of its qualitative and quantitative measurements.

https://mjcu.journals.ekb.eg/article_55776_651d4b09260858a480963e04dcac7ee5.pdf

Role of Conventional MR Imaging of the Median Nerve in Carpal Tunnel Syndrome: A Case Control Comparative Study with Electrophysiological Tests and Clinical Assessment

Background: Scaphoid nonunion result in a predictable pattern of wrist arthrosis. To minimize the incidence of arthrosis, the goal of treatment should be consolidation of the fracture of the scaphoid in anatomic alignment. Aim of Study: To evaluate different means of treatment of scaphoid nonunion and evaluate its clinical results. Patients and Methods: This study was conducted at EL-Helmya Military Hospital and Kasr El-Ainy Hospital during the period from 2011 to 2016 on fifty patients diagnosed as non-united fracture scaphoid and operated upon by fixation and graft if needed, then followed-up for a period of at least 18 months. Patients were 49 male and one female with an average age of 23 years. All operative management and follow-up. Results: This study proved that operative treatment of scaphoid nonunion can be summarized as follows: Grade I,II,III according to Slade and Geissler`s classification can be treated by percutaneous or open fixation by Herbert screw even if the nonunion in prox. Pole. Grade IV/V/VI we have to open volarly for waist or dorsally for prox. Pole and fixation with bone graft from iliac crest or distal radius. Conclusion: This study proves that the goal of treatment of scaphoid nonunion should be consolidation of the fracture in anatomic alignment. scaphoidnonunions with severe collapse and humpback deformity must be approached volarly with interposition of an intercalary bone graft and internal fixation. A dorsal approach to proximal scaphoid nonunions allows immediate access for removing the necrotic bone from small proximal pole nonunions and internal fixation.

https://mjcu.journals.ekb.eg/article_203337_6c14e7034b9b5e52c2b7d5e6f1ed0d93.pdf

Ayman M. Mansour

Papers

Role of diffusion tensor imaging in carpal tunnel syndrome: A case control comparative study to electrophysiological tests and clinical assessment

Liebenberg syndrome: case report and insight into molecular basis

Role of Diffusion Tensor Imaging of the Median Nerve in Carpal Tunnel Syndrome: A Case Control Comparative Study with Electrophysiological Tests and Clinical Assessment

Role of Conventional MR Imaging of the Median Nerve in Carpal Tunnel Syndrome: A Case Control Comparative Study with Electrophysiological Tests and Clinical Assessment

Operative Treatment of Scaphoid Nonunion