Biallelic TYR and TKFC variants in Egyptian patients with OCA1 and new expanded TKFC features.

BACKGROUND: Oculocutaneous albinism type1 (OCA1) is caused by the TYR gene's homozygous and compound heterozygous variants. TKFC gene variants cause triokinase & FMN cyclase deficiency syndrome with variable multisystemic disorders. OBJECTIVES: To determine the potential disease-causing variants in two deceased patients presenting atypical OCA1 features by demonstrating three generations for a single family. The two deceased neonates had severe skeletal abnormalities and fatal hypertrophic cardiomyopathy. We also explored the potential mechanisms for the causative relationship between TKFC and multisystem disorders. PATIENTS AND METHODS: Due to the new emerging symptoms that weren't reported before with the TYR gene, the following methods were performed: Sanger sequencing for the TYR gene, followed by whole exome sequencing, co-segregation, and computational analyses. RESULTS: Extensive parental consanguinity was found, and consequently an autosomal recessive mode of inheritance was prioritized. Upon performing sequencing and segregation data, the following has been confirmed: positive co-segregation of nonsense homozygous NM_000372.5:c.346C > T p.(Arg116*) variant in TYR gene and multisystem disease-missense homozygous NM_015533.4:c.598G > A p.(Val200Ile) variant in TKFC gene in the two affected index patients who deceased due to hypertrophic cardiomyopathy. Using computational analysis, we found that c.598G > A p.(Val200Ile) pathogenicity has led to the failure of L2-K1 active site closure due to the potential differential fluctuation between valine and isoleucine residues. Subsequently, disruption of endogenous DHA phosphorylation was found. Two potential mechanisms exploring the causative relationship between TKFC gene and multisystem disorders have been suggested. CONCLUSIONS: This study presented a first family with the co-existence of biallelic variants in TYR and TKFC genes associating severe skeletal abnormalities and lethal hypertrophic cardiomyopathy. Neither of these genes would have been pursued in the standard genetic counseling. Such discovery is paving the way for more efficient genetic counseling. Comparing TKFC results with literature data showed that our relevant expanded TKFC variant is the 3rd worldwide.

Management of pediatric distal humerus metaphyseal-diaphyseal junction fracture: A systematic review and meta-analysis.

Purpose: Fractures occurring at the metaphyseal-diaphyseal junction of the distal humerus in children are not commonly documented in the literature. Until this moment, there is no gold standard technique regarding its management and most surgeons treat it as a regular supracondylar humerus fracture by conventional pinning. This systematic review explores the relevant literature to assess the efficacy of different techniques. Methods: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Our literature search encompassed several online databases, including PUBMED/MEDLINE, Scopus, Web of Science Core Collection, and Google Scholar. Data from articles that met our general inclusion criteria were extracted and categorized into treatment method groupings. Functional and cosmetic outcomes, demographic characteristics, and complications were the main parameters used to analyze the data. Results: Ten retrospective studies met our inclusion criteria with a total of 178 participants of unilateral pediatric distal humerus metaphyseal-diaphyseal junction fractures. Most literature chose closed reduction and percutaneous pinning in seven articles, followed by elastic stable intramedullary nail technique used in three articles, then conservative treatment was chosen in two articles, while only one article used lateral miniplate and assisted K-wire and another article used combined closed reduction and percutaneous pinning and intramedullary K-wire. As regards the operation time; elastic stable intramedullary nails had the shortest time with a mean of 39.7 min (range: 37.5-41.9 min), while closed reduction and percutaneous pinning had the longest time with a mean of 75.47 min (range: 55.9-92.1 min). The shortest healing time was observed in miniplate with a mean of 7.2 weeks, while the most prolonged was in conservative management with a mean of 12 weeks and closed reduction and percutaneous pinning was a mean of 10 weeks. Regarding Flynn's criteria, all participants received excellent and good except in closed reduction and percutaneous pinning; 13 cases were fair and 2 cases were poor. Regarding complications, the most commonly observed complication after metaphyseal-diaphyseal junction fracture was cubitus varus, the highest incidence was in conservative management (33% of cases), followed by closed reduction and percutaneous pinning (10.9% of cases), the least incidence was observed in elastic stable intramedullary nails (3.77% of cases), and none of the cases treated with mini plate developed this complication. Other complications were observed only with closed reduction and percutaneous pinning; 8.5% of cases developed fixation loss, 6.2% of cases had a significantly reduced range of motion, and one case refractured. Conclusion: Pediatric distal humerus metaphyseal-diaphyseal junction fractures should be distinguished from the more prevalent supracondylar humerus fractures, as conventional pinning techniques are associated with a higher incidence of complications and increased both operative and healing times.Level of evidence: III.

The Diagnostic Value of Whole-Exome Sequencing in a Spectrum of Rare Neurological Disorders Associated with Cerebellar Atrophy.

Several neurological disorders, neurodevelopmental disorders, and neurodegenerative disorders have a genetic element with various clinical presentations ranging from mild to severe presentation. Neurological disorders are rare multifactorial disorders characterized by dysfunction and degeneration of synapses, neurons, and glial cells which are essential for movement, coordination, muscle strength, sensation, and cognition. The cerebellum might be involved at any time, either during development and maturation or later in life. Herein, we describe a spectrum of NDDs and NDs in seven patients from six Egyptian families. The core clinical and radiological features of our patients included dysmorphic features, neurodevelopmental delay or regression, gait abnormalities, skeletal deformities, visual impairment, seizures, and cerebellar atrophy. Previously unreported clinical phenotypic findings were recorded. Whole-exome sequencing (WES) was performed followed by an in silico analysis of the detected genetic variants' effect on the protein structure. Three novel variants were identified in three genes MFSD8, AGTPBP1, and APTX, and other previously reported three variants have been detected in "TPP1, AGTPBP1, and PCDHGC4" genes. In this cohort, we described the detailed unique phenotypic characteristics given the identified genetic profile in patients with neurological "neurodevelopmental disorders and neurodegenerative disorders" disorders associated with cerebellar atrophy, hence expanding the mutational spectrum of such disorders.

Comparison between lengthening over nail and conventional Ilizarov lengthening: a prospective randomized clinical study.

The aim of this study is to compare lengthening over an intramedullary nail to the conventional Ilizarov method with regard to percentage length increase, external fixation index, consolidation index and incidence of complications. This is a prospective randomized controlled study. Thirty-one limbs in 28 patients were included in the study; 15 were lengthened over an intramedullary nail, and 16 limbs were lengthened conventionally. The mean duration of external fixation in the lengthening over nail group was 52.2 days compared to 180.4 days in the conventional group. There was higher incidence of complications in the conventional method group. In comparison with conventional Ilizarov lengthening, lengthening over an intramedullary nail offers a shorter period of external fixation and fewer complications overall, but there is a high incidence of deep intramedullary infection which is serious.

Methods to shorten the duration of an external fixator in the management of tibial infections.

Massive segmental bone loss due to chronic osteomyelitis represents a considerable challenge to orthopedic surgeons and is a limb threatening condition. The only option available in such a clinical situation is segment transport using the Ilizarov technique of distraction osteogenesis; yet the most common problem in cases of bone transport with the Ilizarov technique in massive bone loss, is the long duration of the fixator. In addition to autologous bone grafting, several mechanical, biologic, and external physical treatment modalities may be employed to promote bone formation and maturation during segment transport in osteomyelitis patients. Mechanical approaches include compressive loading of the distraction regenerate, increased frequency of small increments of distraction, and compression-distraction. Intramedullary nailing and hemicorticotomy can reduce the time in external fixation; however, these techniques are associated with technical difficulties and complications. Exogenous application of low-intensity pulsed ultrasound or pulsed electromagnetic fields may shorten the duration of external fixation. Other promising modalities include diphosphonates, physician-directed use (off-label use) of bone morphogenetic proteins, and local injection of bone marrow aspirate and platelet gel at the osteotomy site. Well-designed clinical studies are needed to establish safe and effective guidelines for various modalities to enhance new bone formation during distraction osteogenesis after segment transfer.